DISCLAIMERParticipants have an implied responsibility to use the newly acquired information     to enhance patient outcome...
Disclosure of Conflicts of Interest          Sandra E. Kurtin, MS, RN, ANP, AOCN®Reported a financial interest/relationshi...
Activity OverviewSandra E. Kurtin, MS, RN, ANP, AOCN®       Arizona Cancer Center
Learning Objectives        Upon completion of this activity, participants                should be better able to:   Eval...
Activity Agenda   8:00 – 8:30 AM     Registration and Breakfast   8:30 – 8:35 AM     Welcome and Activity Overview   8:...
Introduction to Lymphoma  Sandra E. Kurtin, MS, RN, NP, AOCN®  The University of Arizona Cancer Center
Incidence             NHL              – A heterogeneous group of neoplasms with differing patterns of                gro...
Risk Factors Associated With NHL            Age            Immunodeficiency               – AIDS, organ transplants, aut...
Common Sites of Disease in Lymphoma       Lymphatic vessels, nodes,                                                Waldey...
Lymphoma: A Blood-Related CancerYarbro et al, 2000; Canellos et al, 2006.
B-Cell Development             Malignancies occur at all stages             Specific disease depends upon when malignanc...
Where Do B-Cell Lymphomas Originate?CLL = chronic lymphocytic leukemia; SLL = small lymphocytic lymphoma; MALT = mucosa-as...
Normal LN OrganizationAdapted from Willard-Mack, 2006.
Ann Arbor Staging System           Stage I              – Single LN group           Stage II              – Multiple LNs...
NHL Subtypes   N = 1,403REAL = Revised European American Lymphoma; DLBCL = diffuse large B-cell lymphoma; FL = follicular ...
Clinical Behavior of NHL Subtypes                  Indolent                       Aggressive           Very Aggressive    ...
General Diagnostic Workup                      for Lymphoma        History and Physical           – Physical exam        ...
Diagnostic Evaluation: Tissue Biopsy       Diagnostic Study                                 Clinical Significance       Mo...
Diagnostic Evaluation: Peripheral Blood         Diagnostic Study                                    Clinical Significance ...
Diagnostic Evaluation: Bone Marrow     Diagnostic Study                           Clinical Significance     Aspirate      ...
Flow Cytometry: The Zip Code for            Primary Cell Type of B-Cell NeoplasmsCML-LBC = chronic myeloid leukemia-lympho...
Immunohistochemistry:   Unraveling the Patchwork of B-Cell Malignancies                                           Normal L...
Diagnostic Evaluation: Imaging       Diagnostic Study                       Clinical Significance       MUGA scan or      ...
The Role of PET                                                      PET is most useful for                              ...
Recommendations for PET Scans         in Lymphoma Therapy and Trials       Histology                                      ...
Risk Stratification in NHL:                  IPI, FLIPI, MIPI, and Beyond          Risk stratification systems           ...
IPI Stratifies Risk by Clinical                      Factors in Aggressive NHL             Prognostic factors (APLES)    ...
Revised IPI Criteria       Proposes 3 risk groups based on the        number of IPI risk factors with        recommendati...
Follicular Lymphoma IPI                                                                                   Survival as defi...
Gene Profiling and Survival Rates in          Different DLBCL Genetic Groups                                        Activa...
Mantle Cell Lymphoma IPI         Established in 2008 to identify                                                         ...
Molecular Indices in                      Lymphocytic Malignancies     Lymphoma          Morphology                  Immun...
Molecular Indices in           Lymphocytic Malignancies (cont.)          Lymphoma      Morphology          Immunophenotypi...
Response Criteria for NHL                          (not including PET)      Response                    Physical          ...
Revised Response Criteria for NHL                 (including PET) Response Definition                       Nodal Masses  ...
General Treatment Strategies       Dependent          on               – Type of disease               – Indolent or aggr...
Key Takeaways Non-Hodgkin lymphomas are a heterogeneous group of  neoplasms with differing patterns of growth and respons...
Diffuse Large B-Cell          Lymphoma           Kevin E. Brigle, PhD, NP            Massey Cancer Center atVirginia Commo...
Diffuse Large B-Cell Lymphoma            Most common form of adult NHL: 30%               – Peak incidence in 6th decade ...
Gene Profiling and Survival Rates in          Different DLBCL Genetic Groups                                        Activa...
Molecular Markers and Survival                                                   Molecular Marker                         ...
Evaluating the New Patient With DLBCL                                          All Patients                               ...
The Fusion PET/CT Scan for Staging          Provides information on both structure and activity          Recommended bot...
Interim PET Analysis in DLBCL          Study of 112 patients with DLBCL treated with rituximab-           anthracycline-b...
Initial Treatment Regimens               First-Line Therapy                                                               ...
First-Line Consolidation With                         HDT and ASCT        No      clear consensus but recommended if     ...
Treatment by Stage for DLBCL          Disease Stage                                                         Regimens      ...
Second-Line Therapy for DLBCL                       Patient Considerations                                                ...
HDT With ASCT in                     Relapsed/Refractory DLBCL            HDT with ASCT is the treatment of choice for re...
Prevention of CNS Relapse          CNS involvement uncommon at diagnosis               – Most events occur during therapy...
DLBCL Key Takeaways   DLBCL is a heterogeneous disease with unique molecular subtypes    that respond differently to trea...
Tumor Lysis Syndrome (TLS)            Oncologic emergency that occurs as a result of rapid tumor cell             breakdo...
Features of TLS                                Salient Features of TLS                     • High potassium (> 6.0 nmol/L)...
TLS PathophysiologyHoward et al, 2011.
TLS: Prevention and Treatment         Identify patients at risk            – Obtain baseline labs and identify disease- a...
TLS: Prevention and Treatment                          (cont.)          Aggressive intravenous fluid and monitoring of ur...
Anthracycline-Induced                          Cardiomyopathy            Clinical heart failure: 1%–5%            Asympt...
Anthracycline-Induced                              Cardiomyopathy Risk Factors                               Risk Factor  ...
Types of Anthracycline-Induced                         Cardiomyopathy            Type                           Onset     ...
Anthracycline-Induced                                     Cardiomyopathy           Cumulative Doxorubicin Dose (mg/m2)    ...
Common Cumulative Doses              of Doxorubicin    Regimen                                             Cumulative     ...
Monitoring High-Risk Patients              There are no specific guidelines for monitoring for chemotherapy-             ...
Preventing Cardiomyopathy in                       High Risk Patients             Maintain adequate blood pressure contro...
Anthracycline-Induced                         Cardiomyopathy Treatment              ACE inhibitors                 – Enal...
Anthracycline-Induced        Cardiomyopathy Patient Education             Discuss short- and long-term risks based on ind...
TLS Case Study         62-yr-old Caucasian man with a PMH of hypertension and          hypercholesterolemia both well con...
TLS Case Study (cont.)        Baseline laboratory analysis           – WBC: 6.0 × 109/L (normal); Hgb: 11.2 g/dL (low); P...
Cardiotoxicity Case Study          67-yr-old Caucasian woman with PMH of HTN and           osteoporosis. Meds include HCT...
Cardiotoxicity Case Study (cont.)        Baseline laboratory analysis           – WBC: 5.2 × 109/L (normal); Hgb: 11.5 g/...
T-Cell Non-Hodgkin           LymphomaBarbara Barnes Rogers, MN, CRNP, ANP-BC, AOCN®            Fox Chase Cancer Center
NHL Subtypes   N = 1,403REAL = Revised European American Lymphoma; DLBCL = diffuse large B-cell lymphoma; FL = follicular ...
2008 WHO Classification of                          T-Cell Neoplasms       Cutaneous                    Extranodal        ...
Peripheral T-Cell Lymphoma SubtypesALCL = anaplastic large-cell lymphoma; ALK = anaplastic lymphoma kinase; PTCL = periphe...
Presenting Symptoms of PTCL            Generalized lymphadenopathy            Mild anemia or thrombocytopenia          ...
Clinical Presentations of PTCL and                 B-Cell Lymphoma        Clinical Characteristics   PTCL (%)   BCL (%)   ...
Workup of Patients With                               Suspected TCL      Physical exam                                   ...
IPI/PIT: Prognostic Indices for PTCL-NOS              Prognostic Factors                           OS: PIT                ...
Overall Survival in PTCL            The International PTCL and NK/T-Cell Lymphoma Study                                   ...
Front-Line Treatment Regimens              for Management of PTCL          Front-line chemotherapy typically consists of ...
ASCT in the Management of PTCL           Front-line consolidation with high-dose chemotherapy and stem            cell re...
ASCT as First-Line Therapy in                        PTCL: Survival       OS in Transplanted and Non-Transplanted Patients...
Treatment Options for PTCL     Romidepsin                                              Pralatrexate        – ORR 30%–38%...
Treatment Options for PTCL (cont.)     Denileukin diftitox                                     Alemtuzumab        – ORR ...
Therapies Under Investigation for              the Management of PTCL         Class of Agent                    Agent     ...
Management of PTCL:    How to Improve Beyond CHOP?   CHOP will not cure most patients with PTCL   Transplant might conso...
Cutaneous T-Cell Lymphoma
Patient With Stage IB Disease With             Folliculotropic Plaques on the Trunk© 2009 by American Society of Hematolog...
Patient With Stage IB Disease                   With Patches and Thin Plaques© 2009 by American Society of Hematology; Pri...
Mycosis Fungoides: Tumor StageHabif, 2010.
Mycosis Fungoides:                        TNM Staging System    Primary Tumor (T)       – T1: Limited patch/plaque (< 10%...
Mycosis Fungoides:               TNM Staging System (cont.)        Visceral (M)          – M0: No visceral organ involvem...
Mycosis Fungoides:               TNM Staging System (cont.)          Stage IA:     T1, N0, M0, B0-1          Stage IB:  ...
Sézary Syndrome             Leukemic form of mycosis fungoides             Aggressive lymphoma             Accounts for...
Sézary CellAnderson & Poulsen, 2003.
General Approach to Management            of Cutaneous T-Cell NHL        Lack     of evidence based approach        Appr...
Skin Directed Therapies          Topical steroids: Triamcinolone, clobetasol             – ORR 75%–95%          Topical ...
Stage Based Therapy for CTCL        IA: Limited Patch/Plaque                        IB/IIA: Generalized Patch/Plaque    ...
Stage Based Therapy for CTCL (cont.)          IIB Tumors             – Topical steroids-triamcinolone, clobetasol        ...
Stage Based Therapy for CTCL (cont.)          III Erythroderma               – Topical steroids-triamcinolone, clobetasol...
Stage Based Therapy for CTCL (cont.)          IV Extracutaneous Disease               – ECP               – Single-agent ...
Systemic Therapies for MF or SS                      CTCL        Category A in NCCN Guidelines               Category C ...
Systemic Therapies             Pralatrexate                – Dose 15 mg/m2 wkly for 3 wks (4-wk cycle)                – B...
TCL Key Takeaways   T-cell lymphomas are rare disorders   Behavior is different from B-cell lymphomas-often less    resp...
Chemotherapy-Induced Peripheral                 Neuropathy (CIPN)           Common dose-limiting side effect of:        ...
CIPN         Exact mechanism not clear         Can be disabling and negatively impact functional ability          and qu...
CIPN           No well-accepted proven therapy for CIPN           Agents with strongest preliminary data for preventing ...
Neuropathy Case Study   68-yr-old man with anaplastic large cell NHL (ALK neg) that    presented in his right calf   Tre...
Neuropathy Case Study (cont.)   He had PD while receiving MINE   Brentuximab vedotin was initiated on a clinical trial ...
BREAK
Follicular Lymphoma    Amy L. Goodrich, MSN, RN, CRNP-BCThe Sidney Kimmel Comprehensive Cancer Center               at Joh...
Follicular Lymphoma (FL)         Median        age: 60 yrs         Treatment        is not curative in most cases       ...
Follicular Lymphoma: Grades 1–3                   Grade 1         Grade 2                 Grade 3             Predominantl...
The 2012 Oncology Nurse Hematology Conference
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The 2012 Oncology Nurse Hematology Conference

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Review a downloadable slide deck by Sandra E. Kurtin, MS, RN, ANP, AOCN®, covering the most clinically relevant new data reported from The 2012 Oncology Nurse Hematology Conference.


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This activity has been designed to meet the educational needs of medical oncologists, radiation oncologists, surgical oncologists, APNs, RNs, pharmacists, managed care pharmacy directors, pathologists, medical directors, allied health professionals, and other physicians affiliated with medical facilities treating patients with head and neck cancers (HNC).

Format: Microsoft PowerPoint (.ppt) | File size: 10.1 MB | Date posted: 4/19/2012

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This slide deck in its original and unaltered format is for educational purposes and is current as of April 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CE provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.



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  • It is estimated that in 2012 over 70,000 men and women will be diagnosed with NHL and approximately 19,000 men and women will die of non-Hodgkin lymphoma. (http://caonline.amcancersoc.org/cgi/content/full/caac.20073v1). Non-Hodgkin ’s lymphomas (NHLs) are a heterogeneous group of B-cell malignancies. The histologies, growth patterns, and response to therapy are variable among the subtypes of these lymphoid neoplasms. The prognosis of various subtypes of NHL is also quite variable but is largely dependent on the histology and the stage of disease. Estimated 5-year survival for all NHLs is 50%-60%.
  • Several risk factors are associated with NHL, including increasing age, immunodeficiency, and a variety of infections and environmental factors. Immune disorders that have been associated with NHL include: Congenital disorders, such as ataxic telangiectasia Autoimmune disorders, such as systemic lupus erythematosus ( “ lupus ” or “ SLE ” if preferred), rheumatoid arthritis, and Hashimoto ’ s thyroiditis Acquired immune deficiencies, such as those seen with acquired immune deficiency syndrome ( “ AIDS ” if preferred) and long-term immunosuppression following organ transplantation Infectious agents associated with increased risk include: HIV Epstein-Barr virus (EBV) Helicobacter pylori , associated with mucosa-associated (MALT) lymphomas Borrelia burgdorferi , the causative agent of Lyme disease, which is associated with the development of cutaneous B-cell lymphoma Exposure to various environmental agents may also increase risk, including: Drugs – phenytoin, aspirin, antibiotics, steroids, and others have been implicated as risk factors Chemicals – including chlorophenols, phenoxyacetic acids, hair dyes, and others Occupations associated with exposure to these hazards also increase risk and include agriculture, construction, leather working, and chemistry.
  • Lymphoma is a cancer of the lymphocytes, the cells that specifically recognize and respond to antigens in the immune response. There are two types of lymphocytes, B and T lymphocytes, which are commonly called B and T cells. The lymphatic organs are divided into two groups. The primary lymphoid organs include the bone marrow and thymus. This is where lymphocyte development takes place.  The secondary lymphoid organs include the lymph nodes, spleen, and Waldeyer ’s ring—a series of lymphoid tissue encircling the nasopharynx and oropharynx. It consists of the palatine tonsils, lingual tonsils, and pharyngeal tonsils or adenoids, and is a common site of extranodal involvement of mantle cell lymphoma. Specialized aggregates of lymphoid tissue are also present in the gastrointestinal and respiratory systems, called mucosa-associated lymphoid tissue, or MALT. After lymphocytes develop in the primary lymphoid organs, they enter the bloodstream and migrate to the secondary lymphoid tissues, where they congregate and interact with other cells involved in the immune response. The lymphatic vessels can also be considered part of this system. They transport lymph—a clear fluid that is derived from interstitial fluid—lymphocytes, and antigens to the circulatory system via the thoracic duct. Lymph nodes are positioned along the lymphatic vessels. Lymphocytes are carried from node to node by the lymph, and the lymph nodes filter debris out of the lymph as it passes through them.
  • Both B cells and T cells originate from hematopoietic stem cells, located in the bone marrow. Hematopoietic stem cells differentiate into progenitor cells for each of the different cell lines and are the source for all red and white blood cells. Common lymphoid progenitor cells become committed to either the B-cell line or the T-cell line while they are in the bone marrow. B-cell progenitors remain in the bone marrow where they continue to develop. T-cell progenitors migrate to the thymus to continue their development. References: Yarbro CH, et al., Cancer Nursing: Principles and Practice , 2000, p. 1330 Canellos GP, et al., The Lymphomas , 1998, p. 337 American Cancer Society Web site, Non-Hodgkin ’s Lymphoma
  • Both B cells and T cells originate from hematopoietic stem cells, located in the bone marrow. Hematopoietic stem cells differentiate into progenitor cells for each of the different cell lines and are the source for all red and white blood cells. Common lymphoid progenitor cells become committed to either the B-cell line or the T-cell line while they are in the bone marrow. B-cell progenitors remain in the bone marrow where they continue to develop. T-cell progenitors migrate to the thymus to continue their development. B cells eventually mature to become plasma cells, which produce antibodies and are involved in humoral immunity. T cells mature into activated T cells and are involved in cell-mediated immunity. Since the majority of non-Hodgkin ’s lymphomas encountered in clinical practice are B-cell lymphomas, this presentation will focus on B cells in more detail. As B cells mature from stem cells through plasma cells, malignancies can occur. The disease that results depends upon when during the lymphocyte maturation cycle the malignancy occurs. For example: If there is a malignancy of premature and pro-B cells, leukemia results. If there is a malignancy of mature B cells, lymphoma, including CLL, results. If there is a malignancy of plasma cells, Waldenström ’ s macroglobulinemia and multiple myelomas result. References: Yarbro CH, et al., Cancer Nursing: Principles and Practice , 2000, pp. 1332-1333 Canellos GP, et al., The Lymphomas , 1998, p. 339
  • This slide shows the evolution of the immature B cell as it differentiates out into the peripheral tissue. For the purpose of this talk on DLBCL, one can trace the immature B cell either the follicle or the surrounding follicular tissue (perifollicular) for Diffuse Large B-cell lymphomas. DLBCL compared to other lymphomas are fairly maturated cells. B-cell malignancies are the most common lymhpoma, and of that group, 31% of Diffuse, Large B-cell lymphomas. Armitage JO, Weisenberger DD. New approach to classifying non-Hodgkins Lymphomas: clinical features of the major histiological subtypes. Non-Hodgkin ’s Lymphoma Classification Project. J Clin Oncol. 1998;16:2780-2795. Jaffe E, Harris NL, Stein H, Isaacson P. Classification of lymphoid neoplasms: the microscope as a tool for disease discovery Blood. 2008;112:4384-4399
  • This slide shows a normal lymph node and illustrates the importance of an adequate tissue sample for assessment of surrounding architecture for accurate diagnosis. Lymph nodes comprise a network of reticular tissue organized into sinuses and encapsulated by fibrous connective tissue. Phagocytic cells lining the sinuses act to filter lymph flowing through lymph nodes. The cortex of the lymph node contains distinct B- and T-cell lymphoid areas. Primary follicles containing aggregates of B lymphocytes are found in the cortex of the unstimulated lymph node. After antigenic challenge these become secondary follicles, comprising a mantle of resting small B lymphocytes and memory cells encircling a germinal center that contains large B cells and macrophages. There is an adjacent surrounding marginal zone containing mature B cells. In the medulla of the lymph node, antigenic stimulation promotes the differentiation of B lymphoblasts to plasma cells in the medullary cords between the medullary sinuses. Various subtypes of indolent B-cell lymphomas originate in distinct microanatomic compartments in the lymph node. Fine needle or core biopsies often do not retain enough of the surrounding lymph node architecture for exact classification. Follicular lymphomas may arise from the germinal centers: MCL from the mantle zone and monocytoid B-cell lymphomas and MALTomas from the surrounding marginal zone. SLL, CLL, and LPL can arise preferentially in the medullary cords at the physiologic site of abundant plasma cells. Legend : Cortex Green = T-cell cortex Blue = B-cell areas of germinal center Red = mantle zone Gold = lymphatic sinuses Medulla Beige = medullary cords Gold = medullary sinuses http://images.google.com/imgres?imgurl=http://www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi%3Fbook%3Dimm%26part%3DA35%26blobname%3DCH1F8.jpg&amp;imgrefurl=http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi%3Fbook%3Dimm%26part%3DA38&amp;usg=__dflIELBoqpFtXEDKJeGrKs51BkI=&amp;h=315&amp;w=701&amp;sz=110&amp;hl=en&amp;start=2&amp;um=1&amp;tbnid=o2DOvxEGNw5K1M:&amp;tbnh=63&amp;tbnw=140&amp;prev=/images%3Fq%3DNormal%2BLymph%2BNode%2BOrganization%2Bmedulla%26ndsp%3D18%26hl%3Den%26client%3Dsafari%26rls%3Den%26sa%3DN%26um%3D1 IV. HISTOLOGY SLIDE 14 Lymph Node
  • The Ann Arbor system is the current standard for staging lymphoma.* In Stage 1 disease, patients show involvement in a single lymph-node region or structure, such as Waldeyer ’s ring. Stage 2 disease involves 2 or more lymph node regions on the same side of the diaphragm, whereas with stage 3, the disease is present on both sides of the diaphragm. In Stages 1 through 3, involvement of a single extranodal site that is contiguous with a known nodal site does not upstage the patient, but is acknowledged with a designation of “E.” We’ve lit up the liver here. Stage 4 disease describes involvement of extranodal sites beyond those of E, and as with most solid tumors, suggests the presence of widespread disease. The presence or absence of B symptoms (weight loss &gt; 10%,, fever without infection, drenching night sweats) is noted by the designation of A or B, and the Cotswold modifications, which we have not addressed here, define the tumor burden from microscopic to bulky clinical disease, with a definition of the various sites of involvement. *The Ann Arbor Staging system was initially developed for Hodgkin ’s disease but carried over to NHL.
  • Follicular lymphomas are the second most commonly diagnosed Non-Hodgkins Lymphomas, second to diffuse large b-cell lymphoma. They account for between one fifth and one quarter of all NHL.
  • The tissue obtained from the biopsy is generally sent to a hematopathologist. The specimen is processed using several diagnostic tools including morphology, cytogenetics, immunophenotyping, flow cytometry and in some cases fluorecent in-situ hybridization (FISH) or polymerase chain reaction (PCR) testing for specific cytogenetic or molecular attributes. The first step in the diagnostic process is review of cytology using a low-power microscope to define basic architecture of the lymphatic tissue. This will provide evidence of a follicular vs diffuse pattern. High power microscopic evaluation is then applied to determine morphology – small or large cells, and shape – cleaved or non-cleaved. These basic tests will differentiate follicular vs diffuse large B-cell NHL in most cases. Additional testing using more recent techniques of immunophenotyping, cytogenetics, and molecular testing have provided more precise characterization of NHL subtypes including specific targets for therapy. References: Morice WG, Kurtin PJ, Hodnefield JM, et al. Predictive value of blood and bone marrow flow cytometry in B-cell lymphoma classification: Comparative analysis of flow cytometry and tissue biopsy in 252 patients. Mayo Clin Proc. 2008;83(7):776-785. Lebien T &amp; Tedder T. B lymphocytes: how they develop and function. Blood. 2008;112:157-580.
  • Federico et al. Haematologica. 2007;92 (11): 1482 National Comprehensive Cancer Network (NCCN) 2011. Non-Hodgkin ’s Lymphoma: Clinical Practice Guidelines: v.2.2011. available at nccn.org Kurtin, 2009
  • References: The bone marrow biopsy and aspirate are used to perform morphological evaluation, immunohistochemistry, immunophenotyping, cytogenetics, and in some cases molecular profiling necessary for WHO classification and prognostic estimate. These are also used to exclude other bone marrow abnormalities. Several mature B-cell neoplasms including DLBCL have characteristic genetic abnormalities that are important in determining their biological features and in differential diagnosis. References: Jaffe ES, Harris NL, Stein H, Campo E, Pileri SA, Swerdlow SH. Introduction and overview of the classification of the lymphoid neoplasms. In WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues, 4 th Ed. Swerdlow S, Campo E, Harris N, Jaffe E, Pileri S, Stein H, Thiele J, Vardiman J. Eds. WHO Press. 2008, 158-166. Kurtin, SE. Unraveling the Complexities of Non-Hodgkin ’s Lymphomas: Part 1. The Oncology Nurse. 2008;1(5): 1, 15. Kurtin SE. Unraveling the complexities of Non-Hodgkin ’s Lymphoma, Part 3: Diagnostic Strategies for Determining the Extent of Disease. The Oncology Nurse. 2009;1(6):12,30.
  • Human B-cell malignancies. Selected cell surface, cytoplasmic, and nuclear markers expressed during normal B-cell development that are generally expressed in B-cell malignancies Molecules within parentheses are variable in their expression at the indicated stage of development. ALL indicates acute lymphoblastic leukemia; BL, Burkitt lymphoma; CLL, chronic lymphocytic leukemia; CML-LBC, chronic myelocytic leukemia– lymphoid blast crisis; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; HCL, hairy cell leukemia; HL, Hodgkin lymphoma; MCL, mantle cell lymphoma; MM, multiple myeloma; MZL, marginal zone lymphoma; PL, plasmablastic lymphoma; SLL, small lymphocytic lymphoma; and WM, Waldenstro¨m macroglobulinemia. Illustration by A. Y. Chen. The clusters of differentiation (CD) provide a “Zip-code” for the primary cell type. Lebien T &amp; Tedder T. B lymphocytes: how they develop and function. Blood. 2008;112:157-580.
  • The tissue obtained from the biopsy is generally sent to a hematopathologist. The specimen is processed using several diagnostic tools including morphology, cytogenetics, immunophenotyping, flow cytometry and in some cases fluorecent in-situ hybridization (FISH) or polymer chain reaction (PCR) testing for specific cytogenetic or molecular attributes. The first step in the diagnostic process is review of cytology using a low-power microscope to define basic architecture of the lymphatic tissue. This will provide evidence of a follicular vs diffuse pattern. High power microscopic evaluation is then applied to determine morphology – small or large cells, and shape – cleaved or non-cleaved. These basic tests will differentiate follicular vs diffuse large B-cell NHL in most cases. Additional testing using more recent techniques of immunophenotyping, cytogenetics, proliferative rate, and molecular testing have provided more precise characterization of NHL subtypes including specific targets for therapy. Lebien T &amp; Tedder T. B lymphocytes: how they develop and function. Blood. 2008;112:157-580.
  • Recent analyses of PET and PET/CT in particular, which evaluate glycolytic activity as a surrogate for increased metabolic activity, have changed the recommendations for staging and restaging for NHL. These technologies provide functional imaging techniques and an advantage in certain cases of MCL. The introduction of computed tomography (CT) in the 1970s provided a means for evaluating abnormal lymph nodes (&gt; 1 cm) or extranodal sites. CT scans remain the standard imaging strategy for estimating the anatomic extent of disease. More recently, 18 F-fluoro-2-deoxyglucose (FDG) positron emission technology (PET), whole-body magnetic resonance imaging (WB-MRI), and FDG-PET/CT fusion imaging have provided complimentary strategies for characterization of NHL. Each of these technologies has advantages and disadvantages in terms of sensitivity, specificity, risk to the patient, and cost. National Comprehensive Cancer Network (NCCN) 2011. Non-Hodgkin ’s Lymphoma: Clinical Practice Guidelines: v.2.2009. available at nccn.org Podoloff D, Advani R, Allred C, Benson A, et al. NCCN task force report: positron emission tomography (PET)/computed tomography (CT) scanning in cancer. J Natl Compr Canc Netw . 2007;5(Suppl 1):S1-S22. Dupuis J, Gaulard P, Hemery F, Itti E. etal. Respective prognostic values of germinal center phenotype and early 18fluorodeoxyglucose emission tomography sacnning in previously untreated patients with diffuse large B-cell lymphoma. Haematologica. 2007;92:778-783. Kurtin S. Unraveling the Complexities of Non-Hodgkin ’s Lymphomas. Part 3 Diagnostic Strategies for Determining the Extent of Disease. The Oncology Nurse. 2009;
  • Rituximab and its strong immune response may increase risks of false-positive results. Waiting 8 weeks avoids false-positive results. The precise role of in diagnosis, interval assessment, and follow up remains undefined. Figure 1. Initial staging FDG-PET image. Maximum intensity projection image (anterior) in female with diffuse large B-cell lymphoma, showing several areas of abnormally high FDG uptake in the supraclavicular, axillary, mediastinal, abdominal, and inguinal regions, as well as extensive sites of involvement in the bone marrow (arrowheads pointing to the right). Several smaller areas are not marked. Note the normal areas of FDG uptake (arrows pointing to left) in the left ventricular myocardium, vascular organs, urinary tract, and shoulder arthropathy. Friedberg, JW, Changazi V. PET Scans in the Staging of Lymphoma: Current Status . The Oncologist , Vol. 8, No. 5, 438–447, October 2003 Cheson BD, Stroobants S. Ongoing challenges in imaging in lymphoma. Am Soc Hematol Ann Meeting 2010. Pfreundschuh M. How I treat elderly patients with diffuse large B-cell lymphoma. Blood 116 (24): 5103. (2010)
  • This slide depicts current recommendations on the utilization of PET scans in several subtypes of lymphoma.
  • The International Prognostic Index (IPI) predicts the outcome of treatment for aggressive NHL based on the number of pretreatment risk factors present. 1 This system of prognostication pre-dates the introduction of Rituxan in the standard front-line therapy of DLBCL. 2 The IPI was developed to predict treatment outcomes for patients with aggressive NHL. 1 The five pretreatment risk factors considered (abbreviated APLES) are 1 Age &gt; 60 years Performance status score &gt; 1 Lactate dehydrogenase (LDH) &gt; normal Extranodal sites of involvement &gt; 1 Stage (Ann Arbor system) III or IV Risk category was based on number of risk factors present Risk stratification accurately predicted overall survival across 2031 patients of all ages Low risk 73% Low-intermediate 51% High-intermediate 43% High risk 26% The top graph shows overall survival by IPI risk grouping in 2031 patients with complete data necessary for risk stratification 1 Because treatment outcomes in the 2 age groups (≤ 60 and &gt; 60 years of age) were significantly different, an age-adjusted IPI was developed. Risk stratification using the age-adjusted IPI was able to predict overall survival in patients ≤ 60 years of age. 1 Background The age adjusted IPI uses 3 of the previously identified indicators 1 Performance status ≥ 2 LDH &gt; 1 times normal Stage III or IV The risk stratification was able to predict 5-year overall survival in 1274 patients ≤ 60 years of age in a clinical study. 5-year overall survival by risk grouping was 1 Low risk 83% Low-intermediate 69% High-intermediate 46% High risk 32% The bottom graph shows overall survival based on the age adjusted IPI risk grouping for 1274 patients ≤ 60 years 1 The International Non-Hodgkin ’ s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin ’ s lymphoma. N Engl J Med. 1993;329:987–994. Sehn L, Berry B, Chhanabhai M, Fitzgerald C, et al. The Revised International Prognostic Index (R-IPI) is a better predictor of outcome than standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007;109:1857-1861.
  • The IPI (or R-IPI) no longer identifies a risk group with less than a 50% chance of survival. In the era of R-CHOP treatment, the R-IPI is a clinically useful prognostic index that may help guide treatment planning and interpretation of clinical trials. 365 Patients in the Lyhmphoid Data Base from British Columbia were included for analysis in this study if they were at least 16 years of age with a biopsy-proven, newly diagnosed, CD20 DLBCL prior to January 15, 2005, and were treated with standard R-CHOP with curative intent The OS curves are presented for the revised IPI. The very good, good, and poor prognosis groups in the R-IPI can all be distinguished from each other and have significantly different OS curves compared with each other ( P &lt;0.0001 for all comparisons). Because the 2 lowest risk groups and the 2 highest risk groups cannot be discerned from one another with the IPI, the R-IPI has been devised, where there are 3 unique risk groups. The very good prognosis risk group contains 10% of patients, and they have an estimated 4-year OS of 92%. The good prognosis risk group contains the middle 45% of patients, and these patients have an estimated 4-year OS of 82%. The poor prognosis risk group contains 45% of patients, and they have an estimated 4-year OS of 58%. The new poor prognosis group contains all patients with 3 to 5 risk factors. Reference: Sehn L, Berry B, Chhanabhai M, Fitzgerald C, et al. The Revised International Prognostic Index (R-IPI) is a better predictor of outcome than standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007;109:1857-1861.
  • The IPI for diffuse large B-cell lymphoma was not an accurate predictor of outcomes in MCL, nor was it accurate for low-grade follicular lymphomas. This led to the development of the FLIPI (pronounce as “flippy”), which was shown to be superior to the IPI for determining prognosis in patients with follicular lymphoma. You can see that it varies from the IPI in the inclusion of a low hemoglobin at the expense of performance status and more than 4 involved nodes instead of more than 1 site of extranodal disease. The scale remains the same, with 1 point awarded for each factor encountered. You can see by the graph, taken from an external validation group derived from more than 1100 patients who were not used to establish the FLIPI criteria, that FLIPI does a nice job in segmenting risk among these patients. So let ’s apply the index to our patient. He is over 60 years old (*check*) with a normal LDH and hemoglobin, and has stage IV disease (*check*) with more than 5 nodal areas involved (*check*). This would give him a FLIPI score of 3, and places him at intermediate risk.
  • Survival Rates in Different DLBCL Genetic Groups It became clear that examining characteristics of the tumor might provide targets for subsequent therapy. Through gene expression profiling by the Leukemia/Lymphoma Molecular Profiling Project, 3 different categories of aggressive lymphoma have been identified: activated B-cell, germinal center B-cell, and primary mediastinal B-cell. Survival rates differ between these different genetic groups: primary mediastinal B-cell malignancy has the longest survival, then germinal center B-cell, and finally activated B-cell Studies are underway to evaluate if certain chemotherapy regimens are more/less effective based on common phenotypic variants of DLBCL Lenz and colleagues evaluated the GCB and ABC subtypes of DLBCL to determine whether they retained prognostic significance. Results showed that the prognosis for patients with GCB DLBCL is still better than ABC, although both are improved over the CHOP-alone era Dunleavy and colleagues conducted a trial of dose-adjusted R-EPOCH plus bortezomib in patients with DLBCL. Results showed that patients with the activated B-cell phenotype did better compared with those with germinal center B-cell DLBCL. This had not been previously observed, and asks the question of whether bortezomib actually benefited patients with activated B-cell DLBCL However, these data are quite provocative and set the stage for the use of this regimen in a randomized phase II clinical trial that will look at the combination of bortezomib and R-CHOP vs R-CHOP in non-GCB diffuse large B-cell lymphoma. In this trial, the Hans algorithm will be used as the strategy to define patients based on immunohistochemistry who have GCB or non-GCB diffuse large B-cell lymphoma. Patients will then be randomized to receive bortezomib given on Days 1 and 4 with R-CHOP chemotherapy given every 21 days for 6 cycles vs the same R-CHOP chemotherapy regimen. The primary endpoint for this study is progression-free survival at 1 year. Given the expected poor prognosis for the non-GCB subgroup and the poor outcomes shown earlier for R-CHOP chemotherapy, this approach and others to augment R-CHOP chemotherapy are warranted in this up-front setting for poor-risk patients References 1. Dave SS, Fu K, Wright GW. Molecular diagnosis of Burkitt ’s lymphoma. N Engl J Med. 2006;354:2430-2442. 2. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal b cell lymphoma identifies a clinically favorable subgroup of diffuse large b cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198:851-862. 3. Lenz G, Wright G, Dave SS, et al. Stromal gene signatures in large-b-cell lymphomas. N Engl J Med. 2008;359:2313-2323. 4. Dunleavy K, Pittaluga S, Czuczman MS. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large b-cell lymphoma. Blood. 2009;113:6069-6076. 5. ClinicalTrials.gov. NCT00931918.  
  • The Mantle Cell Lymphoma Prognostic Index (MIPI) provides a combined clinical and biological score to estimate prognosis. It is based on data from &gt;450 MCL patients who received treatment in prospective randomized clinical trials (ECOG) It is important to note that these patients were treated with different regimens and only an estimated one-third of patients received Rituximab. Since the development of the MIPI – additional treatment strategies have developed and more definitive indicators of tumor behavior have been elucidated. It has been demonstrated that the tumor proliferation index (Ki67) has prognostic significance in patients with MCL. Smith MR. Mantle cell lymphoma: advances in biology and therapy. Curr Opin Hematol. 2008;15:415-421. Hoster et al.: A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008 Jan 15;111(2):558-65. Epub 2007 Oct 25
  • Unraveling the Complexities of Non Hodgkin ’s Lymphomas: Second in a Series What a Difference a Decade Makes: Recent advances and clinical implications of pathobiology
  • This response criteria grid reflects a restaging work-up utilizing CT, MRI or other non-PET forms of radiologic assessment. Physical exam, lymph node assessment and bone marrow examination are three critical pieces to determining response.
  • The revised response criteria takes into account PET scan results, as well as physical exam and bone marrow findings. This tool is more detailed but utilizes similar verbiage to describe response as the previous tool. The major differences are that this PET-included tool has a stable disease determination, not included in the previous criteria and the PET-included tool does not include CRu.
  • Sehn et al. Ann Oncol . 2005;16:v69. Abstract 107.
  • Diffuse Large B-Cell Lymphoma DLBCL is the most common NHL accounting for 30% of all cases of NHL, with the peak incidence occurring in the 6th decade of life It is curable in 40% to 50% of cases; however, if not treated, median survival is weeks to months DLBCL is a clinically and biologically heterogeneous group of lymphomas and the WHO lists 15 subtypes. As discussed in the opening talk, multiple clinical features such as age &gt; 60, Stage III/IV disease, and elevated LDH (all features included in the IPI) have been associated with poorer outcome. However, even within the IPI categories, a wide range of outcomes is observed. More recently, gene expression profiling has revealed major divisions of DLBCL based on the cell of origin and 3 molecular subtypes have been identified, each with differing survival rates. Under the microscope, these appear to be large cells with loss of follicular architecture of lymph node Clinically, about 40% of patients will present with a rapidly enlarging, symptomatic mass and the presence of B symptoms. DLBCL often presents as extranodal disease (stomach, CNS, testis, skin) and bone marrow involvement is common. Reference: Michallet A-S, Coiffier B. Recent developments in the treatment of aggressive non-Hodgkin lymphoma. Blood Rev . 2009;23:11-23. 2. National Comprehensive Cancer Network Inc. NCCN Practice Guidelines in Oncology: Non-Hodgkin ’s Lymphomas Version.4.2011 .
  •   Survival Rates in Different DLBCL Genetic Groups Shown on this slide are 3 lymphochips which are glass matrix chip about the size of 2 postage stamps that contain about 13,000 genes commonly expressed in NHL cells lines. We can look for the presence or absence of these genes in a particular path sample by isolating the RNA from that sample, tagging it with a fluorescent marker, and then incubating these tagged RNAs with the lymphochip. Based on the color and intensity of the chip display, it is possible to identify which genes are expressed in the path sample and at what level. Here, red implies a high level of expression and green a low level of expression. Using this technology, 3 distinct DLBC genetic subtypes have been identified: activated B-cell (ABC), germinal center B-cell (GCB), and primary mediastinal B-cell (PMBL). As shown in the bottom graph, ollowing treatment with anthracycline based therapy, survival rates differ greatly between these different genetic groups: primary mediastinal B-cell malignancy has the longest survival, followed by germinal center B-cell, and finally activated B-cell References 1. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal b cell lymphoma identifies a clinically favorable subgroup of diffuse large b cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198:851-862. 2. Lenz G, Wright G, Dave SS, et al. Stromal gene signatures in large-b-cell lymphomas. N Engl J Med. 2008;359:2313-2323.
  • In practice, few pathology labs have access to GEP and it is currently only in use in clinical trials. Most academic and community labs use immunohistochemical stains and polymerase chain reaction to subgroup DLBCL samples. The most commonly used algorithm to subclassify DLBCL uses the Hans criteria and includes some of the markers shown in this table. While the accuracy of this technique is not perfect, using these algorithms to identify the GCB and ABC subtypes, produces survival data similar to that obtained by GEP. Testing for these markers varies widely in practice and there are new markers and new testing procedures being explored to better sub classify the molecular subtypes. A couple of points should be noted in this slide: BCL-2 Overexpression – most common in the ABC subtype results from a translocation of t(14;18) that is commonly seen in follicular lymphoma; these cells are more resistant to chemotherapy and is implicated in higher relapse rates. BCL-6 gene is more common in GCB subtype and is associated with a better prognosis. In the ABC subtype, the NF-kappa B pathway is constitutively activated suggesting a role for the proteosome inhibitor Bortezomib in the treatment of this molecular subtype. Such studies are underway to evaluate if certain chemotherapy regimens are more/less effective in these DLBCL molecular subtypes. Note that FoxP is an oncogene. GCET1  (germinal center B cell–expressed transcript-1) gene codes for a serpin expressed in germinal center (GC) B cells Figure 4. Prediction of Survival According to Gene Expression in Diffuse Large-B-Cell Lymphoma. Survival rates for patients with a molecular diagnosis of the GCB or ABC subtype after R-CHOP therapy. Reference: Hans CP ,  Weisenburger DD ,  Greiner TC et al, Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood.  2004 Jan 1;103(1):275-82 Fu K, Weisenburger D, Choi W, Perry K et al. Addition of rituximab to Standard Chemotherapy Improves the Survival of Both the Germinal Center B-Cell and Non-Germinal Center B-cell Like Subtypes of Diffuse Large B-Cell Lymphoma. JCO. 2008;26:4587-4594. Kuppers, R. Mechanisms of B-cell lymphoma pathogenesis. Nature Reviews Cancer. 2005;5:251-262 William W.L. Choi, Dennis D. Weisenburger, Timothy C. Greiner, et al. A New Immunostain Algorithm Classifies Diffuse Large B-Cell Lymphoma into Molecular Subtypes with High Accuracy. Clin Cancer Res. 2009;15:5494-5502 Georg Lenza, George W. Wrightb, N. C. Tolga Emrea, et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. PNAS. 2008; 105: 13520-13525
  • Evaluating the New Patient With NHL This slide will be repeated to remind us of a few points that we will be discussing in the remainder of this talk (and they are highlighted in bold in the center and far right columns on this slide) We will discuss the need for lumbar puncture and CNS prophylaxis in patients with high risk features. We will discuss the need to obtain some very specific labs (electrolytes, Uric acid &amp; phosphate) in patients with aggressive lymphomas Finally, we will discuss the importance of cardiac pretesting in these patients who will be more than likely getting an anthracycline as part of their initial treatment. We will talk about the use of PET scans in DLBCL – their use in staging an predicting outcome. And lets move onto that now. References: National Comprehensive Cancer Network Inc. NCCN Practice Guidelines in Oncology: Non-Hodgkin ’s Lymphomas Version.1.2012 .
  • PET scans (positron emission tomography) use 18fluorodeoxyglucose – a radiolabeled sugar molecule, to look at the metabolic activity of cells. Cells which are “PET avid” include not only cancer cells but also normal actively growing cells and active infections. Combining a PET with a CT lets the radiologist differentiate between these possiblities. Thus, the PET/CT provides both structural and functional information. It fuses the activity profile seen in a PET scan with a low resolution CT scan obtained at the same time to give not only a picture of cancer-related metabolic activity, but it also identifies the structure (lymph node, organ, etc) associated with that activity. It has dramatically changed how we stage various cancers and also how we determine response to treatment. For these reasons, it is a diagnostic test that is recommended before starting treatment and once again, after treatment is completed. What is not so clear is the role of “interim” PET/CT scans. Image from UPMC (University of Pittsburg) Website References: National Comprehensive Cancer Network Inc. NCCN Practice Guidelines in Oncology: Non-Hodgkin ’s Lymphomas Version.4.2011 .
  • Because DLBCLs have such variable outcomes better methods are needed to predict prognosis to help determine the best treatment for each patient. IPI Scores, Immunophenotypic classification of the tumor as a germinal center (GC) or nongerminal center GC) subtype correlate with survival and, early respons evaluation with 18fluorodeoxyglucose positron emission tomography (18FDG-PET) scanning have been correlated with survival in DLBCL In this study recently published in the Journal of Clinical Oncology, 112 patients with DLBCL were evaluated after two cycles of a Rituxan-anthracycline based chemotherapy. With a median follow-up of 38 months, the estimated 3-year progression-free survival for patients with a negative PET scan was 84% compared with 47% for patients who were PET positive after 2 cycles. Similarly, OS survival was better for the early PET negative group compared with the PET Positive Group. Similar findings has been demonstrated in previous studies but most were done in the pre-Rituximab era. If one hypothesizes that an early change in chemotherapy could lead to a greater number of cures, a strategy of changing chemotherapy based on PET scans performed at different time points during treatment could improve survival rates in patients with DLBCL. For poor responders, a more intense regimen early in treatment may increase long term survival. Conversely, it may be possible to decrease the intensity of chemotherapy in early responders in an effort to prevent later treatment-related complications. This treatment strategy is currently being studied in young patients with Hodgkins disease. This is an area of further and ongoing study. Reference: Violaine Safar, Jehan Dupuis, Emmanuel Itti, Fabrice Jardin, Christophe Fruchart, Ste´phane Bardet, Pierre Ve´ra, Christiane Copie-Bergman, Alain Rahmouni, Herve´ Tilly, Michel Meignan, and Corinne Haioun, Interim [18F]Fluorodeoxyglucose Positron Emission Tomography Scan in Diffuse Large B-Cell Lymphoma Treated With Anthracycline-Based Chemotherapy Plus Rituximab, Published online before print December 12, 2011, doi:10.1200/JCO.2011.38.2648JCO December 12, 2011JCO.2011.38.2648 Dupuis J, Gaulard P, Hemery F, Itti E et al. Respective prognostic values of germinal center phenoty[e and early 18fluorodeoxyglucose-positron emission tomograpy scanning in previously untreated patients with diffuse large B-cell lymphoma. Haematologica. 2007;92:778-783.
  • Shown is this slide are the initial treatment regimens for DLBCL as recommended by the NCCN. Currently, R-CHOP is the standard of care but both dose-dense R-CHOP and Dose Adjusted R-EPOCH as listed as options. These regimens all contain an anthracycline and are not appropriate for patients with poor cardiac function. Show in the middle section of this table are the recommended regimens for patients with poor cardiac function. Compared to standard R-CHOP therapy, there is limited published data regarding the first-line therapy for patients with poor left ventricular function. While DA R-EPOCH is listed here as well, the anthracycline dose is not adjusted upward for this group of patients as it is in the above group. I nclusion of any anthracycline patients with impaired cardiac functioning should have more frequent cardiac monitoring. Of course, for all patients, NCCN believes that the best management of any cancer patient is in a clinical trial and participation in clinical trials is strongly encouraged. For patients who do achieve remission, NCCN guidelines would suggest consolidation with HDT with an ASCT while in this first remission for all patients who are considered high risk. Reference: National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin ’s Lymphomas Version.1.2012.
  • What is high risk and who should be considered? Although there is no clear consensus for who should be candidates for HDT and ASCT, NCCN guidelines suggest that this approach may benefit high-risk patients who are more likely to relapse while they are in first remission with adjuvant therapy These patients are at higher risk of recurrence and are typically younger (&lt;60 years), have high LDL at diagnosis, show multiple extranodal sites of disease, have Ann Arbor III or IV stage disease, or have an high IPI of 4-5 Reference: National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin ’s Lymphomas Version.1.2012. References: National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin ’s Lymphomas V.4.2011. Schmit-Pokorny S. Expanding indications for stem cell transplantation. Sem Onc Nurs . 2009;25:105-114. Armitage J. How I treat patients with diffuse large B-cell lymphoma. Blood . 2007;110:29-36.
  • This slide summarizes the first-line treatment regimens as recommended by the NCCN dependent upon the stage of the disease. For localized, stage I/II disease, there is evidence that reduced cycles of R-CHOP followed by radiation therapy may be appropriate treatment, thereby minimizing the toxicity of each modality. The decision to include radiation therapy is based upon a number of patient specific risk factors. Generally, in the era of rituximab, 6 cycles of R-CHOP is the preferred first-line treatment for patients with DLBCL and again, participation in a clinical trial is encouraged. Reference: National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin ’s Lymphomas Version.4.2011. Reference: National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin ’s Lymphomas Version.4.2011.
  • Unfortunately, many patients with DLBCL will relapse and will require additional chemotherapy. Shown is this slide are second-line treatment regimens for DLBCL as recommended by the NCCN. Once a patient has relapsed, there is very little chance that they will be cured with conventional chemotherapy and therefore, h igh-dose therapy with ASCT is the treatment of choice for patients with relapsed or refractory disease. Unfortunately, many patients will not be candidates for HDT and, NCCN has different treatment recommendations depending on whether the patient is a candidate for HDT. For all patients, there is no one recommended regimen but rather, therapy should be tailored to the individual and the treatment goal. Patients who are not candidates for high-dose therapy may benefit from enrolling in a clinical trial Reference: National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin ’s Lymphomas Version.4.2011.
  • As mentioned in the previous slide, patients with relapsed or refractory disease are unlikely to obtain a cure from conventional chemotherapy but may achieve long term remission following HDT and an ASCT. All patients will require salvage therapy prior to proceeding to transplant and some patients may also benefit from radiation therapy to sites of active disease to obtain local control. There is no single preferred regimen prior to transplant and often, there is an institutional bias for a preferred regimen. Only patients with demonstrated chemo-sensitive disease should proceed to HDT and ASCT. A fair number of patients may require two or more salvage regimens to obtain a complete or near complete response prior to proceeding to transplant. The role of allogenic transplant for DLBCL is less clear and few studies have been done. In general however, allogenic transplant in this patient population has shown very high non-relapse related mortality rates. Reduced intensity regimens have been used to help reduce these high mortality rates but more studies are needed. Unfortunately, regardless of the type of transplant, none of the published studies to date have shown a robust Graft versus Lymphoma effect for patients with DLBCL undergoing an allogeneic transplant. Reference: National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin ’s Lymphomas Version.4.2011. Thierry Philip, Cesare Guglielmi, Anton Hagenbeek, et al. Autologous Bone Marrow Transplantation as Compared with Salvage Chemotherapy in Relapses of Chemotherapy-Sensitive Non-Hodgkin&apos;s Lymphoma. N Engl J Med 1995; 333:1540-1545 P. Dreger. III. Role of allo transplantation for non-Hodgkin lymphoma and chronic lymphocytic leukemia. Annals of Oncology 22 (Supplement 4): iv36–iv39, 2011 Roel J.W. van Kampen, Carmen Canals, Harry C. Schouten, Allogeneic Stem-Cell Transplantation As Salvage Therapyfor Patients With Diffuse Large B-Cell Non-Hodgkin ’s Lymphoma Relapsing After an Autologous Stem-Cell Transplantation: An Analysis of the European Group for Blood and Marrow Transplantation Registry. JCO. 2011 vol. 29 no. 10: 1342-1348
  • CNS involvement is an uncommon finding upon diagnosis of DLBCL but it is a serious complication in 2-7% of patients during the course of the disease. Most CNS events occur soon after diagnosis and a substantial proportion present during therapy or shortly after completion of treatment and median survival times range from 2-5 months. Risk factors for CNS involvement include paranasal sinus, testicular, epidural, or bone marrow involvement, HIV lymphoma, or &gt; 2 extranodal sites and these patients all require diagnostic lumbar punctures with initial staging. While these are general risk factors which may indicate risk for initial CNS involvement, attempts to predict CNS recurrence have not been successful. There are many studies have looked at CNS prophylaxis as a means to prevent CNS relapse and the results have been equivocal. While several studies have shown a small benefit, many others have shown no benefit at all. Compounding the problem is the rarity of the problem which requires very large studies to see a treatment effect. Likewise, the optimal means of CNS prophylaxis is unclear. While the NCCN recommends 4 -6 doses of intrathecal chemotherapy (methothrexate, cytarabine, or both), there is little data to support this therapy. Several studies have shown that when delivered by lumbar puncture, distribution of the chemotherapy is erratic and poor brain penetration is achieved. While high dose methotrexate achieves higher and more consistent CNS penetration, it can be much more toxic and may delay systemic therapy. While these remain controversial issues, if given, CNS prophylaxis should occur early in the course of treatment when CNS relapse is most likely to occur. As there is no standard, the type and timing of CNS prophylaxis is often guided by institutional bias and guidelines. Reference: National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin ’s Lymphomas Version.1.2012. N. Schmitz, S. Zeynalova, B. Glass, et al. CNS disease in younger patients with aggressive B-cell lymphoma: an analysis of patients treated on the Mabthera International Trial and trials of the German High-Grade Non-Hodgkin Lymphoma Study Group. Annals of Oncology. Advance Access published October 11, 2011. doi:10.1093/annonc/mdr440 Naoto Tomita, Masahiro Yokoyama,Wataru Yamamoto, et al. Central nervous system event in patients with diffuse large B-cell lymphoma in the rituximab era. Cancer Sci, doi: 10.1111/j.1349-7006.2011.02139.x, 2011 Robert Kridel, Pierre-Yves Dietrich. Prevention of CNS relapse in diff use large B-cell lymphoma. Lancet Oncol 2011; 12: 1258–66
  • In summary, DLBCL is a heterogeneous disease with unique molecular subtypes that have been shown to have different rates of survival. GEP, while not yet widely available, may lead to treatment regimens unique to each subtype. For now however, R-CHOP chemotherapy continues to be the standard of care for all patients diagnosed with DLBCL. For patients with cardiac dysfunction, NCCN recommends a number of non-anthracycline containing regimens CNS involvement in DLBCL at presentation is rare as is CNS relapse. However, if often occurs early in the disease process and carries a very poor prognosis. Models to predict which patients will relapse have not been successful. Studies have failed to show a clear benefit for CNS prophylaxis and its use remains controversial. For DLBCL, PET scans are currently recommended both pre- and post-therapy. Use early in treatment appears to be predictive of survival but these should not yet be used to guide treatment. For relapsed disease, HDT and ASCT is the standard of care. Patients are unlikely to be cured with conventional therapy alone. The benefit of allogenic transplants has not been established.
  • Tumor lysis syndrome is the most common disease related emergency encountered in the treatment of hematologic cancers. It is a life-threatening complication resulting from the rapid turnover of tumor cells and the consequent release of intracellular metabolites into the bloodstream. It occurs commonly in rapidly proliferating , bulky, chemosensitive disease and it may occur spontaneously or upon exposure of cells to cytotoxic agents. It mainly involves the levels of calcium, phosphate, potassium and uric acid. These ions are typically cleared by the renal system but, when released in large amounts from dying cells, they overwhelm the body ’s normal ability to maintain their normal levels. Thus, optimal treatment of TLS involves preserving good renal function. Untreated, accumulation of these products can lead to kidney failure, cardiac arrhythmias and sudden death, seizures and neuromuscular irritability Primary management involves identifying patients at risk at starting treatment prior to initiating chemotherapy REFERENCES: National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin ’s Lymphomas Version.1.2012. Scott C. Howard, M.D., Deborah P. Jones, M.D., and Ching-Hon Pui, M.D. The Tumor Lysis Syndrome. N Engl J Med 2011; 364:1844-1854. Mark A. Lewis; Andrea Wahner Hendrickson, Timothy J. Moynihan. Oncologic Emergencies: Pathophysiology, Presentation, Diagnosis, and Treatment. Ca Cancer J Clin 2011;61:287–314 Alaa Muslimani,, Mohammad Muhsin Chisti, Shannon Wills, et al. How We Treat Tumor Lysis Syndrome. 2011. Oncology 25:369-375.
  • Tumor Lysis Syndrome Based on the NCCN guidelines, patients treated for DLBCL should be evaluated for risk of developing tumor lysis syndrome Some of the lab indicators of TLS include high levels of potassium, phosphorus, and uric acid, which we saw in the case study under discussion Symptoms include nausea and vomiting, shortness of breath, irregular heartbeat, clouding of urine, lethargy and joint discomfort High-risk features seldom include patients with DLBCL; some other high-risk features include pre-existing hyperuricemia and ineffectiveness of allopurinol prophylaxis Reference: National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin ’s Lymphomas Version.1.2011. Shown in the top row of this slide are lab findings typically found during tumor lysis syndrome. Potassium, phosphorous and uric acid are elevated while calcium levels fall very low. Clinically, patients may present with nausea and vomiting, shortness of breath, irregular heartbeat, lethargy, joint discomfort. There are many risk factors that predispose a patient to TLS and those are shown in the bottom row of this table. Those at greatest risk are patients with large tumor burdens (bulky tumors, elevated WBC, bone marrow or organ involvement) that proliferate at a high rate such as the lymphomas listed here (DLBCL can be one of these) Patients who are dehydrated, have renal disease, have had recent exposure to nephrotoxins , or who have renal involvement with tumor are at a very high risk. Finally, patients who present in spontaneous tumor lysis as noted on pre-treatment laboratory data run a very high risk. REFERENCES: National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin ’s Lymphomas Version.1.2012. Scott C. Howard, M.D., Deborah P. Jones, M.D., and Ching-Hon Pui, M.D. The Tumor Lysis Syndrome. N Engl J Med 2011; 364:1844-1854. Mark A. Lewis; Andrea Wahner Hendrickson, Timothy J. Moynihan. Oncologic Emergencies: Pathophysiology, Presentation, Diagnosis, and Treatment. Ca Cancer J Clin 2011;61:287–314 Alaa Muslimani,, Mohammad Muhsin Chisti, Shannon Wills, et al. How We Treat Tumor Lysis Syndrome. 2011. Oncology 25:369-375.
  • This slide depicts the pathways which give rise to the metabolic abnormalities seen during TLS. When cancer cells lyse, they release potassium, phosphorus, and nucleic acids, which are metabolized into hypoxanthine, then xanthine, and finally to uric acid, an end product in humans. If these products are produced at a level than can be managed by the renal system, no tumor lysis results. However, if the renal system is overwhelmed, the metabolites accumulate and TLS results. Uric acid is a major player in this pathway as it can induce acute kidney injury intrarenal crystallization, renal vasoconstriction, decreased renal blood flow, oxidation, and inflammation. Two drugs used to combat elevated levels of uric acid are shown by the arrows. Allopurinol, which prevents the production of uric acid works at this enzyme in the pathway (point to arrow) and rasburicase, which breaks down uric acid to a soluble product, works at this point in the pathway (point to arrow). Tumor lysis also releases cytokines that cause a systemic inflammatory response syndrome which may lead to often multiorgan failure REFERENCES: Scott C. Howard, M.D., Deborah P. Jones, M.D., and Ching-Hon Pui, M.D. The Tumor Lysis Syndrome. N Engl J Med 2011; 364:1844-1854.
  • TLS is best managed when anticipated and treated appropriately. Baseline labs will identify those patients experiencing spontaneous TLS. Identification of patient risk factors is an important aspect of initial staging studies. To prevent the accumulation of US, treatment with allopurinol is initiated 2-3 days prior to chemotherapy, then given for another 10-14 days after chemotherapy. The dose of allopurinol may need dose adjustment based on kidney function (CrCl &lt; 20) For patients with any high risk features especially if adequate hydration is not possible a single dose of rasburicase (0.2 mg/kg IV) is indicated; It may be repeated once daily for up to 5 days. It is contraindicated in patients with a GPD6 deficiency as it may result in severe hemolyis. It also carries a Black Box warning for potential anaphylactic reactions. REFERENCES: National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin’s Lymphomas Version.1.2012. Scott C. Howard, M.D., Deborah P. Jones, M.D., and Ching-Hon Pui, M.D. The Tumor Lysis Syndrome. N Engl J Med 2011; 364:1844-1854. Mark A. Lewis; Andrea Wahner Hendrickson, Timothy J. Moynihan. Oncologic Emergencies: Pathophysiology, Presentation, Diagnosis, and Treatment. Ca Cancer J Clin 2011;61:287–314 Alaa Muslimani,, Mohammad Muhsin Chisti, Shannon Wills, et al. How We Treat Tumor Lysis Syndrome. 2011. Oncology 25:369-375. Allopurninol dose adjustment GPD6 deficiency for XO May prevent by using low intensity initial therapy prior to start of intensive therapy
  • It is very important to make sure that the patient is properly hydrated and urine output is closely monitored. Electrolytes, Uric Acid, and creatinine should be checked every 4 – 8 hours depending on risks If hyperkalemia develops, patients will require telemetry May use an initial treatment regimen that prevents TLS by using low intensity initial therapy prior to start of intensive therapy. This is common in regimens that are used to treat Burkitt ’s lymphoma REFERENCES: National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin ’s Lymphomas Version.4.2011. Scott C. Howard, M.D., Deborah P. Jones, M.D., and Ching-Hon Pui, M.D. The Tumor Lysis Syndrome. N Engl J Med 2011; 364:1844-1854. Mark A. Lewis; Andrea Wahner Hendrickson, Timothy J. Moynihan. Oncologic Emergencies: Pathophysiology, Presentation, Diagnosis, and Treatment. Ca Cancer J Clin 2011;61:287–314 Alaa Muslimani,, Mohammad Muhsin Chisti, Shannon Wills, et al. How We Treat Tumor Lysis Syndrome. 2011. Oncology 25:369-375.
  • Cadiovascular toxicity is a potential short term and long term complication of anticancer therapy. Exposure to chemotherapy, especially the anthracyclines, can lead to irreversible clinically significant cardiac dysfunction. Studies report a wide range in the incidence of cardiotoxicity often related to differences in definition. The occurence of clinical heart failure is reported to be in the range of 1-5% while asymptomatic decrease in LVF is in the range of 5-20%. The onset of cardiotoxicity, even if asymptomatic, not only negatively affects survival and quality of life, it reduces the range of suitable anticancer therapies The cause of anthracycline-induce cardiotoxicity is unclear but is thought to be multi-factorial. It is widely thought to be attributed to an increase in the oxidative stress on the heart muscle caused by anthracycline-produced free radicals. Other hypotheses include the release of pro-inflammatory cytokines during treatment with anythracylcines. References: Granger, CB. Prediction and prevention of chemotherapy-induced cardiomyopathy: can it be done? Circulation. 2006;114:2432-243 Shakir DK, Rasul KI. Chemotherapy induced cardiomyopathy: pathogenesis, monitoring and management. J Clin Med Res . 2009;1:8-12. Anecita Fadol and Tara Lech. Cardiovascular Adverse Events Associated With Cancer Therapy. J Adv Pract Oncol 2011;2:229–242
  • As shown on this slide, there are a number of risk factors associated with the development of antracylcine-induced cardiomyapthy. NOTE: This table can be discussed very quickly and, for the most part, it is self explanatory except as noted: NOTE: Methotrexate, cyclophosphamide and cytarabine have been shown to cause Pericarditis while Cylcophosphamide has also been implicated in cardiomyopathy NOTE: As our chemotherapy regimens have improved and we have effected more cures, patients are living longer which makes them vulnerable to the long term effects of antracycline cardiotoxicity. References: Dolci, A et al. Biochemical markers for prediction of chemotherapy-induced cardiotoxicity: systematic review of the literature and recommendations for use. American Journal of Clinical Pathology 2008; 130(5):688-695 Shakir DK, Rasul KI. Chemotherapy induced cardiomyopathy: pathogenesis, monitoring and management. J Clin Med Res . 2009;1:8-12.
  • The onset of anthraclycline induced cardiomyopathy can be acute, early onset chronic, or late onset chronic as outlined in this table. Acute cardiomyopathy is seen after a single dose and is uncommon, transient in nature, and may be seen as abnormal ECG findings Early onset chronic cardiomyopathy is typically seen within a year of therapy and is more common in patients receiving higher cumulative doses of anthracyclines. This typically begins as asymptomatic heart disease and progresses to CHF manifesting as tachycardia, ventricular dilation, and pulmonary and venous congestion. Patients may be resistant to treatment Years or decades after therapy, cardiomyopathy may manifest as ventricular dysfunction, arrhythmias and CHF as a result of earlier myocyte damage References: Shakir DK, Rasul KI. Chemotherapy induced cardiomyopathy: pathogenesis, monitoring and management. J Clin Med Res . 2009;1:8-12. Dolci, A et al. Biochemical markers for prediction of chemotherapy-induced cardiotoxicity: systematic review of the literature and recommendations for use. American Journal of Clinical Pathology 2008; 130(5):688-695
  • This table shows the incidence of Anthracycline induced cardiomyopathy in relation to total cumulative dose. Above 400 mg/m2 total dose, the risk of delelping CHG increases rapidly. REFERENCE: Adriamycin PI ( http://bedfordlabs.com/products/inserts/ADR-P01.pdf )
  • With cumulative doses in mind, this table shows the typical cumulative doses of several common regimens used to treat DLBCL. Note that with Dose Adjusted R-EPOCH, the dose of anthracycline is adjusted upward by 20% with each successive cycle
  • There are not specific guidelines for monitoring for chemo-induced cardiomyopathy. However, it is generally agreed that serial monitoring from baseline to the end of treatment is ideal. What this monitoring entails is not firmly established but at a minimum PE and cardiac specific studies are indicated. A CXR may be helpful is CHF is suspected. In terms of laboratory data, studies have been inconsistent but, one large study has shown that elevation of troponin just after high-dose chemotherapy and 1 month later are predictive of who will develop cardiac events (mainly heart failure and asymptomatic left ventricular dysfunction) during the next year. Nearly 10% of patients in this study had a persistent elevation of troponin one month after treatment, and more than 80% of these patients developed a greater than 15% decrease in left ventricular ejection fraction. REFERENCES: Dolci, A et al. Biochemical markers for prediction of chemotherapy-induced cardiotoxicity: systematic review of the literature and recommendations for use. American Journal of Clinical Pathology 2008; 130(5):688-695 Daniela Cardinale, MD; Alessandro Colombo, MD; Maria T. Sandri. Prevention of High-Dose Chemotherapy–Induced Cardiotoxicity in High-Risk Patients by Angiotensin-Converting Enzyme Inhibition. Circulation. 2006;114:2474-2481.
  • The best treatment for heart failure in cancer patients is to prevent its occurrence. Measures that have been suggest to help prevent heart failure are shown on this slide. The first two suggestions are applicable to all patients receiving anthracycline therapy. Following these two suggestions are measures that are applicable only to specific subsets of patients. The use of cardioprotectants is controversial and may impact the anticancer activity of the chemotherapy. Several studies have shown that analogs of anthyracylines (such as liposomal anthyracline and Pixantrone) have efficacy in treating DLBCL and may be useful in patients who are unable to receive IV anthrycline. At the recent 2011 ASH meeting, a non-anthracline containing regimen utiiizing Gemcitabine in place of Adriamycin was shown to be an effective, low toxicity alternative for elderly patients unable to receive an anthracycline containing regimen. REFERENCES: Gaetano Corazzelli, Ferdinando Frigeri,Manuela Arcamone, Anna Lucania et al. Biweekly rituximab, cyclophosphamide, vincristine, non-pegylated liposome-encapsulated doxorubicin and prednisone (R-COMP-14) in elderly patients with poor-risk diffuse large B-cell lymphoma and moderate to high ‘life threat’ impact cardiopathy. 2011. British Journal of Haematology, 154, 579–589 Raoul Herbrecht, David MacDonald, Florian Weissinger, Martin Wilhelm et al CPOP-R Versus CHOP-R As First-Line Therapy for Diffuse Large B-Cell Lymphoma (DLBCL): A Phase 2, Randomized, Open-Label, Multicenter Study. Blood (ASH Annual Meeting Abstracts), Nov 2011; 118: 4966. Paul Fields, Andrew Webb, Christopher FE Pocock et al. First Analysis of a Phase II Study of Rituximab-Gemcitabine, Cyclophosphamide, Vincristine and Prednisolone (R-GCVP) for Diffuse Large B Cell Lymphoma (DLBCL) Patients Considered Unsuitable for Anthracycline Containing Chemo-Immunotherapy. An NCRI Lymphoma Clinical Studies Group Trial. Blood (ASH Annual Meeting Abstracts), Nov 2011; 118: 1634.   Daniela Cardinale, MD; Alessandro Colombo, MD; Maria T. Sandri. Prevention of High-Dose Chemotherapy–Induced Cardiotoxicity in High-Risk Patients by Angiotensin-Converting Enzyme Inhibition. Circulation. 2006;114:2474-2481.
  • Several studies have shown that cardiomyopathy may be prevented by treating patients identified to be at risk with ACE inhibitors (enalapril) or beta blockers (carvedilol). In one study, patients with elevated troponin I levels after high-dose chemotherapy were randomized to receive either enalapril or control. 43% of patients who received placebo had a &gt;10% drop in left ventricular ejection fraction. No patient receiving enalapril showed a drop in LVEF. As with any patient with cardiomyopathy, supportive care should be used and assistive heart devices may be required Finally, in case of permanent severe damage, a heart transplant may be necessary. REFERENCES: Granger CB. Prediction and prevention of chemotherapy-induced cardiomyopathy: can it be done? Circulation. 2006;114:2432-2433. Daniela Cardinale, MD; Alessandro Colombo, MD; Maria T. Sandri. Prevention of High-Dose Chemotherapy–Induced Cardiotoxicity in High-Risk Patients by Angiotensin-Converting Enzyme Inhibition. Circulation. 2006;114:2474-2481. Shakir DK, Rasul KI. Chemotherapy induced cardiomyopathy: pathogenesis, monitoring and management. J Clin Med Res . 2009;1:8-12.
  • Prior to starting therapy, identify patients who may be at risk and discuss the potential short and long tem risks. Discuss the plan for monitoring for cardiotoxic effects prior to, during, and after treatment with anthracyclines Educate patients about the signs and symptoms of heart failure and stress the importance of prompt reporting Encourage strict compliance to current cardiac regimens REFERENCES: Shakir DK, Rasul KI. Chemotherapy induced cardiomyopathy: pathogenesis, monitoring and management. J Clin Med Res . 2009;1:8-12.
  • MJ is a 62 year old healthy white male with a good performance status. His past medical history is significant only for hypercholesterolemia and hypertension, both of which are well controlled with medications. His medication list includes HCTZ, amlodipine, simvastatin, and an 81 mg aspirin. MJ presented to his primary care provider with painless swelling in his neck and axillary regions. He had been experiencing drenching night sweats for the past 3 weeks and he had unintentionally lost 20 pounds over the past 3 months. He believed that he had caught “a bug” and that his weight loss was related to the persistent nausea he had been experiencing during that time. A biopsy of an enlarged cervical node returned the diagnosis of DLBCL. Initial staging studies with CT scans and a PET/CT scan show neck and bilateral axillary lymphadenopathy, bulky abdominal lymphadenopathy, and spleen involvement. A bone marrow biopsy is positive for DLBCL and therefore, he is Ann Arbor Stage IVB, IPI High Intermediate (age&gt;60, ↑LDH, Stage IV).
  • His echocardiogram and EKG were normal. His baseline labs are as follows (labs in bold are abnormal): WBC 6.0 × 10 9 /L (normal); Hgb 11.2 g/dL (low); Platelets 135 × 10 9 /L (low) Potassium 5.9 nmol/L (high), Phosphorous 3.8 mg/dL (normal), Uric acid: 10.8 mg/dL (high), Corrected Calcium 7.2 mg/dL (low) LDH: 920 U/L (250 U/L is the ULN – high) BUN/creatinine: 30/1.3 mg/dL , Creatinine Clearance 70 ml/min (low) LFTs: normal   What therapy would he get to treat his disease? How would you interpret his laboratory data? What are his risk factors for TLS? What specific steps should be taken to prevent or treat TLS in this patient?
  • AR is a 67 year old active white female with a good performance status and a past medical history of hypertension and osteoporosis. Her hypertension has been controlled with HCTZ and her osteoporosis treated with monthly ibandronate and daily Calcium-Vitamin D. AR presented to her primary care provider with a complaint of a sore throat and a swollen lymph node in her neck. The lymph node did not respond to a course of antibiotics and she was sent for a biopsy. The lymph node biopsy returned the diagnosis of DLBCL. Initial staging studies with CT scans and a PET/CT scan showed cervical, right axillary, and bilateral inguinal lymphadenopathy. A bone marrow biopsy was negative for DLBCL and, therefore, she is Ann Arbor Stage IIIA, IPI High Intermediate (age&gt;60, ↑LDH, Stage III)
  • Her EKG was normal and her echocardiogram showed a Left Ventricular Ejection Fraction of 54% with normal wall motion. Her baseline labs are as follows (labs in bold are abnormal): WBC 5.2 × 10 9 /L (normal); Hgb 11.5 g/dL (low); Platelets 205 × 10 9 /L (low) Potassium 3.5 nmol/L (low), Phosphorous 2.7 mg/dL (normal), Uric acid: 5.1 mg/dL (normal), Corrected Calcium 8.1 mg/dL (low) LDH: 305 g/dL (250 U/L is the ULN – high) BUN/creatinine: 17/1.0 mg/dL , Creatinine Clearance 85 ml/min (low) LFTs: normal except ALT 75 U/L (high)   What therapy would she get to treat her disease? How would you interpret her laboratory data? What are her risk factors for anthracycline-induced cardiomyopathy? What specific steps would you take to monitor for or prevent anthracycline-induced cardiotoxicity?
  • Follicular lymphomas are the second most commonly diagnosed Non-Hodgkins Lymphomas, second to diffuse large b-cell lymphoma. They account for between one fifth and one quarter of all NHL.
  • Fig 1. Distribution of 1,314 cases by consensus diagnosis. NOS, not otherwise specified; ALCL, anaplastic large-cell lymphoma; PTCL, peripheral T-cell lymphoma.
  • Majority of patient received anthracycline containing regimen (85%).
  • Figure 1: Kaplan-Meier curve for Overall Survival Figure 2: Overall survival in patients who did and did not receive transplantation
  • Patient with stage IB disease with folliculotropic plaques on the trunk.
  • Patient with stage IB disease with patches and thin plaques.
  • WS is a 68 year old male with anaplastic large cell NHL (ALK neg) that presented in his right calf. He was treated with 6 cycles of CHOP. He had slight increased FDG uptake on PET/CT at the completion of therapy and was treated with involved field XRT. He then achieved a metabolic CR. Six months later, he complained of right upper arm discomfort and was diagnosed with recurrent ALCL. He received radiation therapy to the site with a PR. He then received pralatrexate with gemcitabine on a clinical trial with stable disease. He was then treated with MINE with the anticipation he would go on to an autologous transplant.
  • WS is a 68 year old male with anaplastic large cell NHL (ALK neg) that presented in his right calf. He was treated with 6 cycles of CHOP. He had slight increased FDG uptake on PET/CT at the completion of therapy and was treated with involved field XRT. He then achieved a metabolic CR. Six months later, he complained of right upper arm discomfort and was diagnosed with recurrent ALCL. He received radiation therapy to the site with a PR. He then received pralatrexate with gemcitabine on a clinical trial with stable disease. He was then treated with MINE with the anticipation he would go on to an autologous transplant. He had progression of disease while receiving MINE. He then initiated therapy with brentuximab vedotin on a clinical trial. He reported complaints of numbness and tingling of his hands and feet with a sensitivity to cold and feeling “like his hands were always cold”. His dose was reduced after cycle 10. He had 4 delays of treatment. He received a total of 16 cycles of B. vedotin at which time his therapy was stopped (due to requirements of the study)-he was in a CR at the completion of therapy.
  • Follicular lymphomas account for at least one fifth of all non-hodgkins lymphoma diagnosed in the United States. NHL is typically a disease of older ages, with the median age at diagnosis being 60 years. For the average patient with follicular NHL, the goal of treatment is to control the disease with as little impact on quality of life as possible. In general, treatment is not curative. The median survival for a patients with follicular lymphoma is around 9 years and 4.5 years after first relapse. Approximately 30% of patients will experience disease transformation at some point in their disease course. Follicular lymphoma most commonly transforms into diffuse large b-cell lymphoma. References: Tilly H and Zelenetz A (2008) Treatment of follicular lymphoma: current status. Leukemia and Lymphoma, 49:1,7-17 Tan D and Horning S, Follicular lymphoma: clinical features and treatment. Hematol Oncol Clin N Am 22 (2008) 863-882 Vilolo U, Ferreri M and Montoto S. Follicular lymphomas. Critical Reviews in Oncology/Hematology 66 (2008) 248-261.
  • Follicular lymphomas are currently classified as Grades 1-3, based on the number of large cells present. Grade 1 FL is predominantly small calls. The clinical course is generally indolent. Grade 1 FL accounts for 40-45% of FL. Grade 2 FL contains a combination of small and large cells. It, too, typically progresses slowly and is an indolent disease. Grade 2 FL accounts for one third of all FL. Grade 3 FL is represented by a predominance of large cells and accounts for up to 20% of FL. It ’s course is typically aggressive and is therefore treated as a diffuse large b-cell lymphoma with the goal of treatment being cure. For the purposes of this presentation, we will focus on Grades 1 and 2 FL. Lastly, a small number of FL cases cannot be adequately classified and fall under the category Not Otherwise Specified. References: Tan D and Horning S. Follicular lymphoma: clinical features and treatment. Hematol Oncol Clin N Am 22 (2008) 863-882 Vilolo U, Ferreri M and Montoto S. Follicular lymphomas. Critical Reviews in Oncology/Hematology 66 (2008) 248-261 Lunning M and Armitage J. The curability of follicular lymphoma. Transfusion and Apheresis Science 37 (2007) 31-35 Bendandi M. Aiming at curative strategy for follicular lymphoma. CA Cancer J Clin 2008;58;305-317 Friedberg J, Taylor M Cerhan J et al. Follicular lymphoma in the United States: first report of the national lymphocare study. Journal of Clinical Oncology vol27 no 9 March 10,2009.
  • Patients with follicular grades I and II lymphoma typically present with advanced stage disease. Bone marrow involvement is more common in Grade I than in Grade II. Patients are typically asymptomatic at diagnosis. Although clinical courses are quite variable, the majority of patients can be expected to have an indolent disease course. Leukemic phase Grade I and II follicular lymphomas are rare but do occur in small numbers. References: Friedberg and Tan
  • Grade 3 FL is the least common subtype of FL. It is a poorly understood disease due to it ’s low volume and general exclusion from FL trials as well as diffuse large b-cell trials. Grade 3 FL is most often treated as diffuse large b cell lymphoma and up to half can be cured of their disease. References: Buske C, Gisselbrecht C, Gribben J et al. Refining the treatment of follicular lymphoma. Leukemia and Lymphoma. 2008. 49:1,18-26
  • NCCN guidelines, 2012 Vitolo u, Ferreri A, and Montoto S. Follicular lymphomas. Critical Reviews in Oncology/Hematology 66(208) 248-261. A diagnostic work up of FL starts with an adequate pathology sample. Because examination of architecture is required for proper classification, a fine needle biopsy is generally not suitable to for diagnosis. An excisional or incisional biopsy is the preferred method of tissue examination. Immunophenotyping commonly reveals CD 19, 20, 22 and 79 positivity. CD 10 and 23 may be positive or negative. CD 5 and 43 are negative and BCL-2 is positive in the majority of cases of FL. In addition molecular genetic analysis and cytogenetics or FISH studies may be useful in certain circumstances. There are reports showing Ki67 proliferation fraction of &gt; 30% may be associated with a more aggressive clinical behavior but no evidence shows this should guide treatment decisions.
  • Leich et al, 2009 Otake Y, Soundararajan S, Sengupta TK, Kio EA, Smith JC, Pineda-Roman M, Stuart RK, Spicer EK, Fernandes DJ (April 2007). &amp;quot;Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl2 mRNA&amp;quot; . Blood 109 (7): 3069–75. doi : 10.1182/blood-2006-08-043257 . PMID   17179226 .  Vaux DL, Cory S, Adams JM (September 1988). &amp;quot;Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells&amp;quot;. Nature 335 (6189): 440–2. doi : 10.1038/335440a0 . PMID   3262202 . Follicular lymphoma is genetically characterized by the presence of t(14;18) chromosomal translocation in approximately 90% of cases. This translocation results in the formation of the oncogene BCL2 (B-Cell Lymphoma 2). BCL2 interrupts apoptosis or programmed cell death, therefore allowing cells to live abnormally long periods of time. This is only one of the necessary immune system regulation errors necessary for FL to develop.
  • Once the diagnosis of FL is made, a staging work up should include physical exam, performance status, presence or absence of b-symptoms, comprehensive blood work, CT scanning of the chest, abdomen and pelvis and bone marrow aspirate and biopsy. In certain cases cardiac function studies, neck CT, beta 2 microglobulin, PET scan, additional labs and fertility assessment and planning should be considered. Hepatitis testing is indicated because of the risk of reactivation with immunotherapy when added to chemotherapy. NCCN guidelines
  • This slide depicts current recommendations on the utilization of PET scans in several subtypes of lymphoma. In FL being treated outside of a clinical trial, PET scan are not widely recommended.
  • This study demonstrates by several parameters why PET scans are not extremely useful in FL.
  • The IPI for diffuse large B-cell lymphoma was not an accurate predictor of outcomes in MCL, nor was it accurate for low-grade follicular lymphomas. This led to the development of the FLIPI (pronounce as “flippy”), which was shown to be superior to the IPI for determining prognosis in patients with follicular lymphoma. You can see that it varies from the IPI in the inclusion of a low hemoglobin at the expense of performance status and more than 4 involved nodes instead of more than 1 site of extranodal disease. The scale remains the same, with 1 point awarded for each factor encountered. You can see by the graph, taken from an external validation group derived from more than 1100 patients who were not used to establish the FLIPI criteria, that FLIPI does a nice job in segmenting risk among these patients. So let ’s apply the index to our patient. He is over 60 years old (*check*) with a normal LDH and hemoglobin, and has stage IV disease (*check*) with more than 5 nodal areas involved (*check*). This would give him a FLIPI score of 3, and places him at intermediate risk.
  • In 1998 a group of specialist collected data from 5000 patients with FL. The 5-year and 10-year overall survivals were determined by risk group. Reference Cartron G, &amp; Solal-Celigny PS (2007). Prognostic factors for lymphomas. In: R Marcus, JW, &amp; ME Williams (eds). Lymphoma: Pathology, diagnosis and treatment: pp. 32–55. New York: Cambridge University Press.
  • Abbreviations: FL, follicular lymphoma; OS, overall survival; TTF, time-to-treatment failure; FFP, freedom from progression; LDH, lactate dehydrogenase; PFS, progression-free survival; VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; IPI, International Prognostic Index; TNF, tumor necrosis factor; sICAM-1, soluble inter-cellular adhesion molecule-1. Relander, T et al Prognostic factors in Follicular Lymphoma. Journal of Clinical Oncology. Vol 28, Number 17, June 2010 There are many biomarkers under study in FL. To date, none have been shown to have accuracy and reliability that would influence treatment decisions. Many are familiar markers ordered in the setting of many disease states.
  • Indications for therapy in FL include progressive local disease or a change in disease progression tempo, symptoms, cytopenias, high tumor burden, leukemic phase disease, organ invasion, high risk disease based on FLIPI score, and transformation. Tan Vitolo
  • Initial therapy options for patients with advanced FL include single agent alkylators, single agent rituximab, multiple combination regimens and radioimmunotherapy. First-line therapy options differ based on overall health and age, with less aggressive regimens being appropriate for the elderly or those in poor health. All may be followed by rituximab maintenance, with recommendations to administer on a clinical trial whenever possible. Second-line and greater options include any regimen not utilized from the initial therapy choices, as well as more aggressive fludarabine-based therapy and any second-line DLBC regimen, such as ICE +R, ESHAP + R, DHAP + R, to name a few. Reference: NCCN guidelines
  • Bendamustine was FDA approved in 2008 for initial therapy in patients with CLL and for recurrent low grade B-cell lymphomas progressing less than or equal to 6 months after a rituximab-containing regimen. Bendamustine is an alkylating agent with purine analog properties, thus is a hybrid. Although it is new to us in the U.S., it has been used in Germany for over 30 years. In NHL patients, it is administered at a dose of 120 mg/m 2 IV over 60 minutes on Days 1 and 2 of 21 day cycles, although combination regimens commonly utilize lower doses. Since it is an alkylating agent, antiemetic premeds are appropriate. References: Robinson KS, et al. J Clin Oncol . 2008;26:4473-4479. Rummel MJ, et al. J Clin Oncol . 2005;23:3383-3389. Rummel MJ, et al. Blood . 2007;110: Abstract 385.
  • Exciting results were presented at the 2009 ASH Meeting in New Orleans in December by Rummel and colleagues. This trial randomized untreated follicular, indolent, or mantle cell lymphoma patients to receive either bendamustine and rituximab or CHOP and rituximab. Patients and Methods: 549 patients (pts) in need of treatment for their disease were randomized to receive Rituximab 375 mg/m 2 (day 1) plus either Bendamustine 90 mg/m 2 (days 1+2) every 28 days or the standard CHOP regimen every 21 days for a maximum of 6 cycles. The primary endpoint was progression-free survival (PFS). Patients characteristics, including age, stage, LDH, IPI, FLIPI, bone marrow infiltration and extranodal involvement were not statistically significant between the arms. The median patient age was 64 years (range 31-83) (64 yrs for B-R and 63 yrs for CHOP-R). Most patients were in stage IV (76.9% in BR and 77.5 in CHOP-R) and stage III (19.2% in B-R and 18.6% in CHOP-R). Histologies were distributed equally between B-R and CHOP-R: follicular 55% and 56%, mantle cell 18% and 19%, and other indolent lymphomas 27% and 24%, respectively. Prophylactic use of antibiotics or growth factors were not generally recommended in this protocol.
  • Of the 549 pts, 36 pts were not evaluable: 10 did not receive any study medication, 9 due to withdrawal of consent, 13 due to incorrect diagnosis (4 x DLBCL, 3 x CLL, 2 x MM, 1 x HD, 3 x solid tumors), and 4 for other reasons. 513 randomized pts are evaluable for the final analysis (B-R: n=260; CHOP-R: n=253). Out of these, 9 pts were not evaluable for response evaluation: 4 pts (3 x CHOP-R, 1 x B-R) due to early death in neutropenic sepsis, 3 pts due to a subsequent change of therapy after severe toxicity in 1st cycle of CHOP-R, 1 B-R pt due to progress of disease, and 1 B-R due to early death. All patients were counted for evaluation of PFS, overall survival (OS), event-free survival (EFS; an event was defined by a response less than a partial response, disease progression, relapse, or death from any cause), and for time to next treatment (TTNT). A median number of 6 cycles was given in both treatment arms each. 82% of B-R pts and 86% of CHOP-R pts received 6 cycles. At the time of analysis in August 2009, the median observation time was 32 months. Overall response rate for pts treated with B-R was similar to the CHOP-R group (93.8% vs 93.5%, respectively). The CR rate was significantly higher with 40.1% for B-R compared to 30.8% for CHOP-R (p=0.0323). The median PFS, EFS and TTNT were significantly longer after B-R compared to after CHOP-R: PFS 54.8 months for B-R versus (vs) 34.8 months for CHOP-R (p=0.0002), Hazard Ratio (HR) 0.5765 (95% confidence interval (CI) 0.4292 to 0.7683); EFS 54 months for B-R vs 31 months for CHOP-R (p=0.0002, HR 0.6014 (95% CI 0.4515 to 0.7845); and TTNT median not yet reached in the B-R group vs 40.7 months in the CHOP-R group (p=0.0002; HR 0.5416, 95% CI 0.3897 to 0.7491). OS did not differ between both groups at this point of time. Thus far, 67 deaths have been observed (B-R: 34; CHOP-R: 33).
  • Safety: R-Bendamustine vs R-CHOP in Patients With Untreated Follicular, Indolent and Mantle Cell Lymphomas Here is the safety profile of the regimens evaluated in the StiL study Serious AEs were higher in patients on R-CHOP and grade 3/4 neutropenia and leukopenia were seen in significantly more patients on R-CHOP versus R-bendamustine; although G-CSF use was not part of the protocol, more patients on R-CHOP received G-CSF to manage hematologic toxicities With respect to adverse events, R-bendamustine was also associated with significantly less infectious complications, peripheral neuropathy, stomatitis, and alopecia Based on the efficacy and safety data, R-bendamustine is poised to become the new standard of care for patients with follicular, indolent and mantle cell lymphomas Reference: Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect to progression free survival and CR rate when compared with CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of StiL (Study Group Indolent Lymphomas, Germany). ASH 2009:Abstract 405. For Slide and notes From previous slide deck; formatted and notes rewritten Rummel Abstract/Results/para 3 and conclusion
  • This slide demonstrates sensitization to chemotherapy and why rituximab is combined with essentially every chemotherapy regimen used in the treatment of FL. These are results of several Phase III trials randomizing patients to chemotherapy alone versus chemotherapy with rituximab. In 100% of studies, response rates are higher and remissions are longer in patients receiving rituximab with chemotherapy.
  • Although the Hainsworth maintenance rituximab schedule of 375mg/m2 weekly x 4 repeated every 6 months for 2 years (or disease progression) is likely the most widely utilized, several others are utilized and under study. The PRIMA study, which we will discuss in a moment, resulted in recent FDA approval of rituximab maintenance after immunochemotherapy on the schedule of one 375 mg/m2 dose every 2 months x 2 years.
  • The PRIMA study is the most mature randomized, multi-center trial investigating rituximab maintenance. 1217 patients were enrolled and 1019 were randomized (1:1) to receive 2 years of rituximab maintenance therapy (single dose every 8 weeks) or to observation, both following remission after rituximab plus chemotherapy. This trial is the largest randomised study ever in follicular lymphoma and is a huge accomplishment by the GELA lymphoma group. The patients were a high risk group, with almost 80% having intermediate-risk or high-risk scores on a validated follicular lymphoma international prognostic index (FLIPI). All had indications for therapy. Although three different chemotherapy regimens were used as induction therapy, most patients (75%) were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), rendering the results especially relevant to current practice.
  • Salles G, et al Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phas3 3 randomised controlled trial. Lancet 2010;377:42-51. ASH Abstract 768 Updated results of the PRIMA study confirms the benefit of 2-years rituximab maintenance in follicular lymphoma patients responding to immunochemotherapy. Salles, et al 2010 At 36 months of follow up, patients receiving every 2 month rituximab dosing had less disease progression and required less further therapy. We will continue to watch these results as they continue to mature.
  • Salles, 2010 Overall, adverse events were higher in the maintenance group than in the observation group. However, small numbers of patients in both arms had to discontinue treatment due to toxicity, making both arms well tolerated.
  • The strongest rationale favoring maintenance rituximab and the reason we all administer it so commonly is that rituximab maintenance has been demonstrated to result in better and longer remissions. That has led to lengthening time to next lymphoma therapy. However, those improvements have not yet demonstrated a clear survival benefit. Additionally, as seen in the previous slide, no standard maintenance schedule has been established. It can be given weekly x 4 every 6 months, in single doses every 2-3 months or repeated based on rituximab levels, to name a few approaches. Maintenance is typically stopped after 2 years due to an increased risk of infection. Many trials are ongoing to further study optimal maintenance schedules and doses. There is also a slightly greater risk of progressive multifocal leukoencephalopathy (PML), a rare, demyelinating disease of the CNS caused by reactivation of the JC polyomavirus in profoundly immunocompromised individuals, with more than 2 years of maintenance rituximab. Some researchers are also concerned that such regular and extended exposure to rituximab may lead to resistance, although this is a hypothetical concern at this time. Finally, the cost of maintenance rituximab is a consideration, especially without a clear survival benefit. Again, many trials are focusing on this very important topic.
  • Sehn et al. Ann Oncol . 2005;16:v69. Abstract 107. The administration schedule for rapid rituximab infusion is presented. Patients are premedicated with diphenhydramine 50 mg, acetaminophen 650-1000 mg, and daily prednisone dosed according to chemotherapy protocol. The first cycle of rituximab is infused according to product monograph, with rituximab 375 mg/m 2 IV being given. The subsequent cycles of rituximab are infused over a total of 90 minutes, with rituximab 375 mg/m 2 IV in 250 mL being given. Twenty percent of the dose was infused over the first 30 minutes, and the remaining 80% of the dose was infused over the last 60 minutes. Sehn et al, 2005 abstract 107
  • Montoto S, Davies AJ, Matthews J, et al: Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 25:2426-2433, 2007 Al-Tourah AJ, Gill KK, Chhanabhai M, et al: Population-based analysis of incidence and outcome of transformed non-Hodgkin ’s lymphoma. J Clin Oncol 26:5165-5169, 2008 Transformation is a real risk for every patient with FL. Transformation refers to the development of an aggressive NHL histology in the setting of an underlying low grade process. The most common histology of transformation is DLBC. In the literature, the frequency ranges from 10%-70%. The likely incidence is 3% per year or 30% over a 10 year disease course. Transformation should be confirmed with biopsy whenever possible and should be suspected in the setting of rapid localized nodal growth, new b symptoms, rapid rise in LDH or new hypercalcemia.
  • Montoto S, Davies AJ, Matthews J, et al:Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 25:2426-2433, 2007 ASBMT position statement: The role of cytotoxic therapy with hematopoietic stem cell transplant in the treatment of follicular lymphoma. 2010 doi:10.1016/j.physletb.2003.10.071 Although there is no accurate predictor of in whom and when transformation will occur, some high risk factors for predicting transformation include: advanced stage disease, high FLIPI/IPI at diagnosis, anemia, high LDH and high FLIPI at first recurrence. Despite aggressive treatment, along the lines of DLBC, including transplant approaches, the median survival after transformation is 1.2 years.
  • Tomblyn MR, et al. Autologous versus reduced-intensity allogeneic hematopoietic cell transplant for patients with chemosensitive follicular non-hodgkin lymphoma beyond first complete response or first partial response. Biol Blood Marrow Transplant: 1-8 (2011)
  • Tomblyn MR, et al. Autologous versus reduced-intensity allogeneic hematopoietic cell transplant for patients with chemosensitive follicular non-hodgkin lymphoma beyond first complete response or first partial response. Biol Blood Marrow Transplant: 1-8 (2011)
  • Ettinger, D.S.., Bierman, P.J., Bradbury, B., Comish, C.C., Ellis, G., &amp; Ignoffo, R.J. (2007). Antiemesis. Journal of the National Comprehensive Cancer Network, 5 (1),12-33.
  • Ettinger, 2007
  • Exkert, R.M. (2001). Understanding anticipatory nausea. Oncology Nursing Forum, 28 (10), 1553-1558. Stricker, C.T., &amp; Eanu. N. (2010). Chemotherapy induced nausea and vomiting. In C. Brown (Ed.), A guide to oncology symptom management (pp. 91-121). Pittsburgh, PA: Oncolgy Nur
  • * = all cycles
  • This slide was shown in the first talk and is presented again to point out that MCL in not one of the more common lymphomas, representing only about 6% of all lymphoma diagnoses. References: 1 Armitage JO, Weisenberger DD, et al. New approach to classifying non-Hodgkin&apos;s lymphomas: Clinical features of the major histologic subtypes. J Clin Oncol. 1998;16:2780-2795.
  • In the previous talk, there were a couple of cartoons showing the structure of a lymph node and where in that lymph node the various subtypes of NHL arise. Shown here is an actually pathology slide of a lymph node which gives you a more real world look at the lymph node. In the picture on the left, the arrow points to one of the many follicles that ring the cortex of the ymph node. It is these follicles, which may develop a germinal center when challenged with an antigen. On the right is a slide showing one of these germinal cell centers, and the homogeneous population of small- to medium-sized cells that surround it. It is from these cells that mantle zone lymphoma arises. REFERENCES: Andre Goy and Brad Kahl . Mantle cell lymphoma: The promise of new treatment options. Critical Reviews in Oncology/Hematology, 2011. 80: 69–86. Francesco Bertoni and Maurilio Ponzoni. The cellular origin of mantle cell lymphoma. The International Journal of Biochemistry &amp; Cell Biology . 2007.39 :1747–1753 Figures taken from: http://www.pathpedia.com/education/eatlas/histology/lymph_node/images.aspx http://www.pathpedia.com/education/eatlas/histology/lymph_node/images.aspx
  • As with most cancers and lymphoma in general, it is more commonly found in older individuals and, median age of diagnosis in 67 years. It has a male predominance and is more than twice as common among men compared with women. Among NHL subtypes, this is exceeded only by hairy cell leukemia (4:1) and Burkitt ’s lymphoma (3.5:1). At presentation, the majority of patients are symptomatic and the presence of B symptoms is common. Further, the vast majority of patients present with advanced stage disease. As such, extranodal involvement is common with bone marrow, spleen and the GI tract often involved. GI involvement with up to 90% of blind biopsies positive for disease. As such, it is not necessarily required in the initial work up but is necessary at restaging to confirm complete responses. References: Andre Goy and Brad Kahl . Mantle cell lymphoma: The promise of new treatment options. Critical Reviews in Oncology/Hematology, 2011. 80: 69–86. 2. Karin E. Smedbya and Henrik Hjalgrimb. Epidemiology and etiology of mantle cell lymphoma and other non-Hodgkin lymphoma subtypes. Seminars in Cancer Biology. 2011. 21: 293– 298
  • Mantle cell lymphoma is a subtype which generally carries a very poor prognosis. Overall, survival remains in the range of 4-5 years and there are few long terms survivors. Although MCL patients respond to initial therapy, a continuous pattern of relapse typically follows with the subsequent development of chemoresistant disease. However, like most lymphoma subtypes, there is a subset of patients who exhibit fairly indolent disease and enjoy a long survival of more than 7 – 10 years with little treatment. As the majority of patients present with symptomatic advanced stage disease, most patients require aggressive treatment at initial diagnosis. However, most of these patients will experience early and frequent relapses and the subsequent development of chemo-resistant disease. After first relapse, median survival is poor, generally in the range of 1-2 years. REFERENCES Andre Goy and Brad Kahl . Mantle cell lymphoma: The promise of new treatment options. Critical Reviews in Oncology/Hematology, 2011. 80: 69–86. 2. Karin E. Smedbya and Henrik Hjalgrimb. Epidemiology and etiology of mantle cell lymphoma and other non-Hodgkin lymphoma subtypes. Seminars in Cancer Biology. 2011. 21: 293– 298
  • The (11;14)(q13;q32) translocation is the hallmark cytogenetic abnormality of MCL. This involves an exchange of genetic material between chromosome 11 and chromosome 14 which puts expression of the bcl-1 gene under control of the IgH locus. The end result is an over-expression of Cyclin D1, the protein encoded by the bcl-1 gene. Cyclin D1 normally regulates progression of the cell cycle and is not normally expressed in resting cells. Thus, its increased expression leads to a increase in the rate of cell proliferation. In MCL, this is thought to be the first genetic hit necessary for malignant transformation, and in isolation, cells carrying this sole mutation may give rise to the rare indolent MCL phenotype. It appears that additional genetic lesions are necessary to have these cells transform to a more clinically aggressive phenotype that makes up the bulk of the patients with MCL. REFERENCES: Birgitta Sander. Mantle cell lymphoma. Seminars in Cancer Biology. 2011. 21: 291– 292 . Figure taken from: http://www.bio.davidson.edu/courses/immunology/Students/spring2006/Fried/mantelcell.htm#background
  • This progression from indolent MCL to aggressive MCL is depicted in this slide, whereby the initial genetic abnormality is the 11:14 translocation. Cells carrying only this mutation would have an indolent clinical course and survival would be very good. As more genetic changes occur, there is marked cell cycle dysregulation and the resistance to apoptosis. Clinically, these cells give rise to the more aggressive MCL lymphoma with greater chemotherapy resistance and shorter survival times. Predicting which patients will follow either the indolent or the aggressive course has been difficult, but a few clinical features are common to each subtype. REFERENCES: Birgitta Sander. Mantle cell lymphoma. Seminars in Cancer Biology. 2011. 21: 291– 292 . 2. Cristina Royoa, Itziar Salaverriaa, Elena M. Hartmannb et al. The complex landscape of genetic alterations in mantle cell lymphoma. Seminars in Cancer Biology. 2011. 21: 322– 334
  • As shown in the top table, there is a pattern of clinic findings that differs between patients with indolent and aggressive forms of MCL. Patients with indolent disease are more likely to have non-nodal disease, splenomegaly, a low LDH, and few symptoms at presentation. Gene profiling and immunohistochemical techniques have also identified molecular markers that can help distinguish between these two groups of patients. Compared to patients who follow an indolent clinical course, patients with aggressive disease are more likely to have a high proliferation rate (high ki-67), a complex karyotype (multiple mutations), and high levels of expression of Sox11, a nuclear transcription factor thought to be necessary for lymphoid cell proliferation. In routine practice, these markers are not used to make treatment decisions. Rather, symptoms and extent of disease determine the treatment plan. References: Verònica Fernàndez, Olga Salamero, Blanca Espinet, et al. Genomic and Gene Expression Profiling Defines Indolent Forms of Mantle Cell Lymphoma. Cancer Res; 2010. 70(4); 1408–18. Cristina Royoa, Itziar Salaverriaa, Elena M. Hartmannb et al. The complex landscape of genetic alterations in mantle cell lymphoma. Seminars in Cancer Biology. 2011. 21: 322– 334
  • Evaluating the New Patient With MCL As in my previous talk, I mention that this slide was presented in the first talk and I show it here only to bring up a few points that that should be stressed in the initial work up for MCL (and they are highlighted in bold this slide) Recall that the Mantle Cell Specific IPI utilizes 4 factors to group patients into risk categories and these include Age, PS, level of LDH, and total WBC. This information can be found in H &amp; P, CBC, &amp; LDH at initial presentation. The Ki-67, or proliferation index, can be a good measure of the aggressiveness of a particular lymphoma, and for MCL, this value should be noted on the Path report. Lastly, recall that in MCL, GI involvement is the norm rather than the exception. While not necessarily required for initial staging, it is a requirement for restaging and surveilence once treatment is completed. References: National Comprehensive Cancer Network Inc. NCCN Practice Guidelines in Oncology: Non-Hodgkin ’s Lymphomas Version.1.2012 .
  • While survival for patients with MCL is not particularly good, it has significantly improved over the past 30 years. As shown in this figure, survival in the group of patients diagnose in the decade from 1996-2004 have much better overall survival than those diagnosed in the decade from 1975-1986. While different patient selection may account for some of this improvement, the bulk of the increaed survival has been attributed to improved diagnosis, improved therapeutic choices, improved general supportive care, and the development of biologic therapy such as Rituxan. REFERENCES: Herrmann A, Hoster E, Zwingers T, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol. 2009;27:511-518.
  • There is no standard of care or consensus on best firs-line treatment for MCL. This lack of agreement has several causes. First, it can be difficult to predict the clinical course of mantle cell lymphoma on diagnosis and many providers do not want to risk the toxicities of overtreatment in this generally older population. Secondly, none of the recommended first line regimens have ever been compared head to head. Most of the regimens have very high response rates but, none appear to be curative all result in remissions that are shorter compared with other NHL subtypes. Very intensive regimens, including autologous and allogeneic stem cell transplantation, seem required to improve the outcome, but with the median age of diagnosis being 60 years or more, such approaches are feasible only in a limited number of patients. Many practices use a risk adapted approach to front line therapy, choosing therapy based on individual patient parameters and goals. The best therapy would rely on a combination of MIPI score, the proliferative index, a patient ’s transplant eligibility, their age, PF, and comordiites, and of course, the expected toxicity profile of the chosen regimen. An algorithm outlining this risk adapted approach is shown in the next slide. REFERENCE: Thomas J. Harris, Heather Brooks and Michael E. Williams, MD. Mantle cell lymphoma: an overview of diagnostic and therapeutic advances. Commun Oncol 2008;5:465–472.
  • A schema for a risk-adapted approach is shown in this slide. Aggressive regimens and consolidation with ASCT are reserved for younger, healthier patients with a good performance status. For older patients, less aggressive treatment regimens are recommended. And for frail patients with multiple comorbidities, treatment options include monotherapy such as single agent Rituxan or low intensity chemotherapy regimens. REFERENCES: Thomas J. Harris, Heather Brooks and Michael E. Williams, MD. Mantle cell lymphoma: an overview of diagnostic and therapeutic advances. Commun Oncol 2008;5:465–472. National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin ’s Lymphomas Version.1.2012
  • Shown is this slide are the initial treatment regimens for MCL as recommended by the NCCN. Radiation therapy may be added to the first-line regimens for patients with early stage disease, but this is a very rare occurrence. No randomized trials have studied the initial therapy regimens head-to-head, and the regimens are simply listed alphabetically. In most institutions however, the R-HyperCVAD regimen is commonly utilized when an aggressive treatment approach is required. For those patients who are eligible, NCCN recommends consolidation with HDT and ASCT in first remission. Many patients will receive induction with an aggressive regimen prior to consolidation but less aggressive regimens followed by consolidation with HDT and ASCT may also result in good long-term outcomes. REFERENCE: National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin ’s Lymphomas Version.1.2012. Kahl BS, Longo WL, Eickhoff JC, et al. Maintenance rituximab following induction chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: A pilot study from the Wisconsin Oncology Network. Ann Oncol . 2006; 17:1418-1423.
  • Why do patients with MCL undergo autologous transplant in first This graph demonstrates the results of the Nordic MCL-2 trial. This single arm, sequential study examined 160 newly diagnosed patients with MCL who were treated with 6 cycles of intensive induction immunochemotherapy using alternating cycles of R-CHOP and rituximab plus high-dose cytarabine; responders received HDTfollowed by autologous stem cell support. Of the 145 responders who completed treatment, there was a median 4-year PFS of 73%; OS was also high with plateaus emerging in all both curves at 5 years, suggesting that this regimen may curative. References: Geisler CH, Kolstad A, Laurell A, et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo–purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood . 2008; 112:2687-2693. 44
  • This is the general outline for the Rituxan-HyperCVAD regimen. It is a somewhat complex, in patient regimen that combines alternating cycles of an infusional/fractionated CHOP like regimen (the odd cycles) with a cycle of high dose methotrexate and cytarabine (the even cycles). If a patients blood counts recover, these cycles are given every 21 days for a total of 6 (3 of each). This is a regimen with many side effects and all patients will require aggressive supportive care to get them ready for each successive cycle and to keep them from being hospitalized between cycles.
  • A few of the common and more severe side effects of HyperCVAD are listed here: The incidence of myelosuppression is very high and growth factor support is required in nearly every patient. While cycles are generally delayed until counts recover, platelet and WBC targets are generally lower than with conventional chemotherapy (plt counts 75,000 and total WBC 3,000). Because of myelosuppression, the rate of infection can be very high and prophylaxis for pneumocystis pneumonia, fungal infections and viral reactivation is generally recommended. We will discuss a common infection in the case study at the end of this talk. In this regimen, the rate of mucositis can be very high and is an easy source for septic infection. Good oral hygiene is absolutely required. Vincristine-associated neurotoxicity is not uncommon and may require dose modifications of vincristine. Hyperglycemia has been reported and may be related to the high dose steroids given in the odd cycles. *Available at: www.clinicaltrials.gov, protocol NCT00500240.
  • Despite the use of more aggressive first-line treatment regimens, most patients still relapse at about 3 years. Shown is this slide are second-line treatment regimens for MCL as recommended by the NCCN. Of these, only Bortezomib is FDA approved. However, all of the regimens listed here have shown activity against recurrent or relapsed MCL. As with first line therapy, the choice will be individualized to the patient and the goal of treatment. Regardless, recurrent disease is incurable with conventional chemotherapy. Most patients will continue through several treatment regimens until their disease becomes completely chemoresistant. If a patient does achieve a complete response, an allogenic stem cell transplant may be an option. References: National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin ’s Lymphomas V.4.2011. Maris, MB, Sandmaier BM, Storer BE, et al. Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma. Blood. 2004;104:3535-3542. Tam CS, Bassett R, Ledesma C, et al. Mature results of the MD Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma. Blood . 2009;113:4144-4152
  • If a patient has not had an autologous stem cell transplant, this an option in second remission although it has not been shown to be successful. This is likely probably because of the selection of chemoresistant lymphoma clones during initial chemotherapy, with these clones subsequently reconstituting the disease bulk at relapse. HDT chemotherapy is not able to overcome this chemoresistance. There have been several studies that have shown benefit for an allogenic transplant in second remission. In these studies, the graft versus lymphoma effect was associated with increased survival, even in patients who had previously undergone an atuolougous stem cell transplant. However, to be effective, these patients must have chemosensitve disease an attain a second remission. In this setting, fully myeloablative transplants have an unacceptable transplant related mortality of up to 50% and has led to the use of non-myeloablative strategies. With these transplants, up front mortality was dramatically reduced and 3 year survival were well above 50%. And, while the graft versus lymphoma effect is critical for the curative potential of aloogenic transplants for these patients, chronic graft versus host disease remains a significant source of morbidity and mortality. Finally, as MCL is generally considered a disease of the elderly, many of patients who are diagnosed with MCL are too old or have significant comorbidities which make them ineligible for an allogenic transplant. References: Khouri IF, Lee M-S, Saliba RM, et al. Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphomas. J Clin Oncol. 2003;21:4407-4412. Maris MB, Sandmaier BM, Storer BE, et al. Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma. Blood. 2004;104:3535-3542. Tam CS, Bassett R, Ledesma C, et al. Mature results of the MD Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma. Blood . 2009;113:4144-4152.
  • In summary, MCL is an NHL subtype with one of the poorest survival rates, averaging around 2 -3 years. However, there is a subset of patients who present with very indolent disease who have survival rates up to 10 years. The hallmark of the disease is a translocation of material between chromosomes 11 and 14 that results in an upregulation of the protien Cyclin D1. This protein regulates cell growth, and its increased expression causes cells to proliferate and divide. There is currently no standard of care for the treatment of MCL and NCCN guidelines recognize a number of treatment regimens that vary in their level of aggressiveness and toxities. A risk adapted approach is often used to choose the best regimen for each patient. More aggressive regimens are chosen for younger healthy patients with a good performance status while less aggressive regimens are used for older patients with a poorer perfromance status. HyperCVAD is an aggressive regimen that is commonly used. It can be very toxic with many side effects. Regardless of the regimen chosen, none of them are likely to cure the disease and HDT with ASCT is recommended in first remission for all patients who are eligible. Relapse is common and for these patients, survival is often very short. For patients who get back into remission, allogenic transplant may be an option for potential long term survival
  • IFI is associated with significant morbidity and mortality and can cause delays in or cancellation of treatment of the underlying disorder. Candida and Aspergillus species are the leading cause of IFI in patients with hematologic malignancy. However, epidemiology has shifted with the adoption of antifungal prophylaxis and previously rare pathogens such as Fusarium species and the Zygomycetes are emerging. Candida species can affect even relatively non-immunocompromised patients while Aspergillus species are much more opportunistic, and these infections are found mainly in severely immunocompromised patients. Aspergillus species are common in the environment and are found widely in soil, dirt, dust, compost or decaying matter RESOURCES: George J. Alangaden. Nosocomial Fungal Infections: Epidemiology, Infection Control, and Prevention. Infect Dis Clin N Am 25 (2011) 201–225. Laura Zitella. Invasive Aspergillosis in an Allogeneic Hematopoietic Cell Transplant Patient. ONCOLOGY Nurse Edition. Vol. 25 No. 7 (2011) 16-20.
  • In general, the likelihood of IFI depends on a variety of factors. Most important is the patient ’s state of immunocompetence and Neutropenia is one of greatest risk factors and risk increases with the duration and severity of neutropenia. Stem cell transplant patients, both auto and allo recipients, are at the greatest risk due to their prolonged immunocompromised status. For allogeneic transplant patients, this may continue long after transplant with the chronic use of immunosuppressant medications. In addition, certain chemotherapy agents, such as fludarabine and alemtuzumab can be more crippling to the immune system often months after receiving the agents. In particular, these two agents cripple the function of T-cell which are important components of the immune system for clearing fungal spores. Organ damage and the presence of invasive devices provides entry for fungal spores beyond the normal physical pathways such as through inhalation or ingesting. . Finally, the degree of exposure to the IFI spores, whether at home or in the medical setting, add to a patients risk of developing an IFI.
  • Early diagnosis and prompt IFI treatment improve patient outcome. However, diagnosis is difficult because IFI symptoms are nonspecific and often indistinguishable from those of bacterial or viral infection. Microbiologic culture techniques typically have low sensitivity for detecting mold infection and identification of the specific pathogen can be difficult and time consuming. General IFI management strategies include (1) directed treatment of an established infection once the pathogen is identified, (2) empiric therapy for at-risk patients with persistent fever despite broad-spectrum antibacterial therapy; and (3) prophylaxis, in which antifungal treatment is designed to prevent infection in an at-risk population. Because untreated IFIs can be rapidly fatal , it is not feasible to await identification of the pathogen before initiating therapy and empiric therapy is started when fungal infections are suspected. Directed therapy is useful for focusing antifungal therapy after empirical therapy has been initiated and the pathogen has been identified. Prophylaxis is useful in high-risk groups and has been in widespread use since the 1980 ’s. Prophylaxis is credited with reducing the rates of IFI over that time by 50% Robenshtok E, Gafter-Gvili A, Goldberg E, et al. Antifungal prophylaxis in cancer patients after chemotherapy or hematopoietic stem-cell transplantation: systematic review and meta-analysis. J Clin Oncol. 2007; 25(34): 5471-5489. Mauricette Michallet and James I. Ito. Approaches to the Management of Invasive Fungal Infections in Hematologic Malignancy and Hematopoietic Cell Transplantation. J Clin Oncol (2009) 27:3398-3409.
  • The most common presentation of an IFI is persistant fever in a patient with prolonged neutropenia in spite of 3-5 days of antibiotic and antiviral therapy. Symptoms of invasive aspergillus symptoms manifest as fever, cough, dyspnea, pleuritic chest pain, and hemoptysis, but these often present late in the course of the infection
  • While blood cultures readily identify Candidia infections, Aspergillus is generally not found on routine blood cultures. Newer seriologic tests that identify components of the Aspergillus cell wall components are available, such as 1) the Aspergillus g alactomannan assay and the D-glucan serum assay but these are not yet completely reliable and are subject to both false positives and false negative results. High-resolution CT scans can be helpful to identify the characteristic radiologic findings: halo sign (an area of ground-glass infiltrate surrounding nodular densities), crescent sign (crescent of air surrounding nodules, indicative of cavitation). Tissue specimens obtained by biopsy or bronchoscopy helpful in at most, 50% of cases. Because of these diagnostic difficulties, empiric therapy is typically started when there is a suspicion of fungal infection. James I. Ito, Jane Kriengkauykiat, Sanjeet S. Dadwal. Approaches to the early treatment of invasive fungal infection. Leukemia &amp; Lymphoma, September 2010; 51(9): 1623–1631 Hope WW, Walsh TJ, Denning, DW: Laboratory diagnosis of invasive aspergillosis. Lancet Infect Dis 5(10):609622, 2005.
  • Shown here is the standard diagnostic and treatment approach for immunocompromised patients with suspected fungal infections. James I. Ito, Jane Kriengkauykiat, Sanjeet S. Dadwal. Approaches to the early treatment of invasive fungal infection. Leukemia &amp; Lymphoma, September 2010; 51(9): 1623–1631 National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Prevention and Treatment of Cancer-Related Infections. Version.1.2012
  • In selecting an antifungal agent, several factors need to be weighed, including whether use is intended for prophylaxis, empiric treatment, or preemptive therapy. Factors include the patient ’s underlying disease state, co-morbidities, renal and hepatic function, nutritional status, prior antifungal exposure, site of infection, and the infecting organism. The main classes of antifungal agents used in the setting of IFI in patients with hematologic malignancy and HCT are the polyenes, azoles, and echinocandins National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Prevention and Treatment of Cancer-Related Infections. Version.1.2012
  • National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Prevention and Treatment of Cancer-Related Infections. Version.1.2012
  • National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Prevention and Treatment of Cancer-Related Infections. Version.2.2011
  • James I. Ito, Jane Kriengkauykiat, Sanjeet S. Dadwal. Approaches to the early treatment of invasive fungal infection. Leukemia &amp; Lymphoma, September 2010; 51(9): 1623–1631 Hope WW, Walsh TJ, Denning, DW: Laboratory diagnosis of invasive aspergillosis. Lancet Infect Dis 5(10):609622, 2005. National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Prevention and Treatment of Cancer-Related Infections. Version.2.2011
  • DA is a 61 year old active white male with a past medical history of hypertension and reflux. His hypertension is well controlled with daily HCTZ but his reflux did not respond to OTC omeprazol. He has no known drug allergies. DA presented to his primary care provider with continued complaints of reflux and he was sent for an EGD. During the procedure, the gastroenterologist noted both gastric polyps and erosions and took multiply biopsies that returned the diagnosis of MCL. Initial staging studies with CT scans and a PET/CT scan identified bilateral axillary, mediastinal and retroperitoneal lymphadenopathy. A bone marrow biopsy was positive for MCL. He is, therefore, Ann Arbor Stage IVA, MIPI High Risk (7 points based on age, LDH, PS, and WBC). His path showed a high proliferation rate with a Ki-67 of 85%. DA wanted to be very aggressive with his treatment and therefore, he was started on Rituxan-HyperCVAD with the intent to have High Dose Therapy and an autologous stem cell transplant in first remission. What prophylactic agents would you initiate prior to starting HyperCVAD therapy ?
  • Six days following the start of his 5 th cycle of HyperCVAD he comes to your clinic with mucositis, a fever of 101⁰F, and an ANC of 0.2. What is your detailed plan for treating his fever? While hospitalized, he continues to have fevers in spite of negative blood cultures and the appropriate antimicrobial therapy. What additional diagnostic studies would you order? What changes would you make to his antimicrobial therapy?
  • Answer = 2. t(11,14): prolonged cell cycle
  • Answer = 6. Only 1 &amp; 4
  • Although there are no environmental or external factors directly responsible for the development of CLL, there is sufficient evidence to support an association between Agent Orange and CLL. White males are the most commonly diagnosed patients. Familial CLL is rare and not well understood. Families with CLL should be referred for laboratory based clinical trials of familial CLL.
  • Before focusing on CLL, it is important to point out the detail that CLL and SLL (small lymphocytic lymphoma) are pathologically idential diseases. If mainly bone marrow involvement is present, the clinical diagnosis is CLL; if mainly nodal disease is noted, the clinical diagnosis is SLL. This is an important teaching point for patients, as therapy may be indicated in the same patient over time for both daignoses and many have mention of both diseases in their medical records.
  • Rozman &amp; Montserrat, 1995; Oscier et al, 2004 CLL is an incidental finding in the vast majority of patients and in the absence of symptoms. For those presenting with CLL signs or symptoms, they commonly include fatigue, malaise, dyspnea on exertion, palpable lymphadenopathy, complaints related to splenomegaly, infection or fevers, night sweats or unexplained weight loss
  • Cramer, IWCLL guidelines The diagnosis of CLL is made in the setting of over 5K clonal circulating b-lymphocytes with peripheral blood smear revealing small mature lymphocytes and flow cytometry notable for CD5, CD19, CD20 and CD23 positivity and either kappa or lambda light chains
  • Rozman &amp; Montserrat, 1995; Oscier et al, 2004, NCCN guidelines
  • Rozman &amp; Montserrat, 1995; Oscier et al, 2004, NCCN guidelines
  • Tadmor et al, 2010) Immune dysfunction is a significant challenge in managing patients with CLL. Multiple components of the immune system are involved and result in widespread immune dysfunction. Both the cells themselves and the communication with other parts of the immune system are impaired.
  • Rai et al, 1975; The Rai staging system includes 5 stages of CLL; Stages 0-4. Stage 0 disease is represented by lymphocytosis only and carries the best survival prediction. Stages I and II are intermediate risk with shorter survival than low risk, Stage I disease. They are represented by lymphocytosis plus lymphadenopathy and/or organomegaly. Stages III and IV are high risk with short survival and carry the presence of lymphocytosis with anemia and/or thrombocytopenia.
  • Cramer, nccn guidelines
  • Moreno &amp; Montserrat, 2008 Pittner, BT, Shanafelt, TD, Kay, NE and Jelinek, DF. CD38 expression levels in chronic lymphocytic leukemia B cells are associated with activation marker expression and differential response to interferon stimulation. Leukemia (2005) 19, 2264-2272. Hamblin, TJ, David, Z, Gardiner, A, Oscier, DG and Stevenson, FK. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999 94: 1848-1854 Several prognostic biomarkers exist for CLL. Beta-2 microglobulin is a small protein found on the surface of many cells, including lymphocytes. May be elevated for a variety of reasons but in CLL, elevated levels may be associated with high disease burden. Serial values may be useful in monitoring disease progression and response to therapy. Immunuoglobulin heavy chains (IgVH) mutational status separates CLL into 2 subsets: Mutated (40% of cases in the US) and unmutated (60% of cases in the US). There is no evidence to date that this status changes over the course of an individual patient ’s disease, unlike genomic parameters discussed in the previous slide. Unmutated disease is that which occurs in a naïve b-cell, one which is likely young and has not come into contact with antigen. Mutated disease arises in a b-cell which has been exposed to antigen and has “mutated” into a cell with memory. Unmutated disease is 3 times more common in males, while mutated disease is equal among men and women. The two groups have separate and distinct natural histories. Early stage patients with unmutated disease have a median survival of 8 years, while early stage patients with mutated disease have a median survival of 25 years. It is likely that all cases of smoldering CLL are associated with mutated disease. IgVH mutational status is tested by gene sequencing or reverse transcription-polymerase chain reaction (RT-PCR), which are both expensive and not readily available, making the discovery of accurate surrogate markers the focus of much research. At this time, there has been no 100% accurate surrogate marker discovered. CD38 is a protein found on the surface of many immune cells, including B-lymphocytes. Expression increases upon normal b-cell activation and when elevated in the setting of CLL, may suggest a more aggressive disease course and inferior response to therapy. It has not been determined whether CD38 plays a direct physiologic role in B-cell CLL or whether it is merely a surrogate marker of disease aggressiveness. It is measured by flow cytometry, so is a fast and easy test to order and result. Zeta-associated peptide of 70 kilodaltons (Zap70) is a cytoplasmic tyrosine kinase whose expression has been associated with a poor CLL prognosis. Cells with germline IgV H often have an increased expression of Zap70; however, studies have shown discordance rates of 10-20% between IgV H mutational status and Zap70 expression levels. Elevated levels of Zap70 are believed to decrease the threshold for signaling through bcl2 , thereby facilitating the antiapoptotic effects of bcl2.
  • Cramer and NCCN guidelines, 2011. Common indications for therapy include eligibility for a clinical trial, disease related symptoms, threatened end-organ function, bulky disease, short lymphocyte doubling time, progressive cytopenias due to bone marrow involvement and progressive high risk disease. Patients without an indication for therapy are typically observed without intervention.
  • NCCN guidelines, 2011 If watch and wait is utilized, at the time an indication for therapy is noted, repeat testing of genomic parameters and disease burden should be considered and performed, as clinically indicated.
  • The aggressiveness and toxicity profiles of each regimen are reflected in this stratified approach to therapy in patients with CLL. Less aggressive options are recommended in the elderly or infirm, while aggressive approaches are indicated in the young or those with unfavorable disease. Allogeneic transplant should be considered in first (or subsequent) remission in patients with unfavorable risk disease.
  • Eichhorst B and Hallek M. Revision of the guidelines for diagnosis and therapy of chronic lymphocytic leukemia (CLL). Best Practice &amp; Research Clinical Haematology, 2007;20:469-477 Lymph node size, organomegaly, symptoms, hematologic parameters and bone marrow findings are all factors in the current CLL response criteria.
  • Sorensen, 1997, Fludara package insert, Keating, 1993 Fludarabine is the “gold standard” for treating CLL. It is the oldest nucleotide analog, with FDA approval in 1991. Initial studies began in humans in the mid 1980’s. Initial studies were plagued with significant myelotoxicity and neurotoxicity, eventually found to be dose-dependent. In lower, less toxic doses, response rates of 80% were seen in untreated patients.
  • Reynolds, C, et al. Phase III trial of fludarabine, cyclophosphamide, and rituximab vs. pentostatin, cyclophosphamide and rituximab in b-cell chronic lymphocytic leukemia. Blood (ASH Annual meetings Abstracts) 2008 112: Abstract 327. Fludarabine is frequently utilized in combination regimens. Heightened toxicity profiles are seen in these combination regimens. Several Phase II studies suggested more favorable hematologic and non-hematologic toxicity profiles with pentostatin but in a randomized trial, there was no significant difference when comparing PCR to FCR. Overall response rates and survival also showed no significant differences between the reigmens.
  • Knauf 2009 Bendamustine is a novel hybrid alkylator with purine analog properties. Although approved in 2008, it was orginally engineered in the late 1960 ’s in communist Germany. The drug’s success was uncovered during German reunification in the mid 1990’s and modern clinical trials led to it’s FDA approval in 2008.
  • Relapsed/refractory treatment options are stratified by disease risk, length of remission and age
  • Alemtuzumab Package insert Alemtuzumab is a humanized anti CD52 monoclonal antibody, FDA approved for use in B-CLL in 2001. It utilized a stepped up dosing schedule to attempt to minimize infusion reactions. It is commonly administered 3 times per week for 12 weeks with premedications. Response rates are higher in untreated patients but the drug is still active in previously treated patients.
  • Package insert Alemtuzumab is associated with several severe complications, including cytopenias, including autoimmune cytopenias, infusion reactions and infections.
  • This slide is meant to depict why such significant immunosuppression is anticipated with alemtuzumab. While infections are rarely an issue with rituximab, which targets CD20 and b-cells only, CD52 is present on several immune system cells, making alemtuzumab significantly more immunosuppressive and therefore carrying a much higher infection risk/rate. More verbiage below to be tailored to the audience. Monoclonal antibodies used in B-cell disorders target cell surface molecules found on various blood cells. These so-called clusters of differentiation, or CDs, are given numbers for identification. Clusters of differentiation are called “antigens,” because antibodies can be raised against them, and they are called “markers,” because they identify and discriminate or “mark” different cell populations. CD20 is a predominant B cell surface antigen that appears during B-cell maturation. CD20 represents the perfect antigen for a monoclonal antibody targeted at B-cell disorders because; It is expressed on most mature B cells as well as on 90% of B-cell lymphomas It first appears on the pre-B cell, and continues to be present on immature B cells and mature or activated B cells, but is not found on hematopoietic stem cells, normal antibody-secreting plasma cells, or other normal tissues. It is a stable target antigen that does not shed or become internalized, nor does it modulate or mutate. It triggers apoptosis which lessens its dependence on ADCC or CDC. Rituximab, ibritumomab tiuxetan, and tositumomab target CD20. CD52 is found on thymocytes, T and B cells, monocytes, macrophages, NK cells, granulocytes, and spermatozoa. Alemtuzumab targets CD52. References: Abbas et al, pp. 19, 21[Box 2-1], 463-466. Campath® (Alemtuzumab) Full Prescribing Information Cheson, Blood, 2003 Janeway et al, Immunobiology, pp. 579-572. Leffel et al, Handbook of Human Immunology, p. 21 Rituxan® (Rituximab) Full Prescribing Information, February 2002 Zevalin™ (Ibritumomab Tiuxetan) Full Prescribing Information, January 2002
  • Ofatumumab package insert Targets the CD20 antigen at a unique target when compared to all current anti-CD20 therapy (Rituxan, Zevalin, Bexxar) Consider reducing and discontinuing corticosteroid as tolerated with subsequent infusions
  • Premedicate, monitor blood counts, monitor for neurologic changes, discontinue if noted, screen high risk patients for hepatitis . Favorable response rate in a heavily pre-treated population. Wierda, eta al recently reported interim analysis results of a 183 patient study with refractory CLL Package insert and coffier, 2008 and Wierda 2010
  • AJN, American Journal of Nursing: February 2010 - Volume 110 - Issue 2 - p 59 Package insert Lemery, 2008 doi: 10.1097/01.NAJ.0000368057.72729.22 Drug Watch New Drugs For Kidney Cancer And Chronic Lymphocytic Leukemia Aschenbrenner, Diane S. MS, APRN, BC And package insert www.arzerra.com Neutropenia is the most commonly noted adverse event with ofatumumab
  • Reference: García-EscobarI,etal.Therapeuticmanagementofchroniclymphocyticleukaemia.Stateoftheartand future perspectives.CritRevOncol/Hematol(2010),doi:10.1016/j.critrevonc.2010.10.006 Autologous BMT is controversial in CLL. One of the major challenges is in clearing the bone marrow sufficiently of disease to qualify for this approach. To date, studies have shown prolonged remissions in carefully selected patients.
  • García-EscobarI,etal.Therapeuticmanagementofchroniclymphocyticleukaemia.Stateoftheartand future perspectives.CritRevOncol/Hematol(2010),doi:10.1016/j.critrevonc.2010.10.006
  • García-EscobarI,etal.Therapeuticmanagementofchroniclymphocyticleukaemia.Stateoftheartand future perspectives.CritRevOncol/Hematol(2010),doi:10.1016/j.critrevonc.2010.10.006
  • García-EscobarI,etal.Therapeuticmanagementofchroniclymphocyticleukaemia.Stateoftheartand future perspectives.CritRevOncol/Hematol(2010),doi:10.1016/j.critrevonc.2010.10.006
  • NCCN guidelines, 2012 CLL-related complications are a significant part of the management of these patients. Autoimmune disorders, infection and transformation are among the most challenging complications.
  • Hamblin TJ, Oscier DG, Young BJ. Autoimmunity in chronic lymphocytic leukemia. J Clin Pathol. 1986;39:713-716. 2. Rozman C, Montserrat E. Chronic lymphocytic leukemia. N Engl J Med. 1995;333:1052-1057. 3. Fauro FR et al. Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic and prognostic features. Blood, 1 May 2000. Vol 95, Number 9 Autoimmune complications have been noted in patients with CLL for over 100 years and continue to be poorly understood. AIHA and ITP are the most common diagnoses, with red cell aplasia being less common and autoimmune granulocytopenia being a rare diagnosis. Independently, these complications carry no independent prognostic significance and may occur in patients with all stages of CLL. They can occur as single entities or in combination.
  • García-EscobarI,etal. Therapeutic management of chronic lymphocytic leukaemia. State of the art and future perspectives. CritRevOncol/Hematol(2010),doi:10.1016/j.critrevonc.2010.10.006 Many novel agents are currently under study in CLL. They include monoclonal antibody, kinase inhibitors, Bcl-2 inhibitors, and many others.
  • Although there are many potential etiologies for cytopenias in patients with CLL, the most common causes in this population are a result of reduced production of bone marrow stem cells or accelerated removal of hematopoeitic cells. Reference: Kumar V, Abbas A, Fausto N, Kumar:Robbins and Coltran Pathologic Basis of Disease, 7 th 3ed. Elsevier Saunders, Philadelphia, PA, 2005. Chapter 13 and 14.
  • Appropriate management of cytopenias in CLL patients due to decreased bone marrow production is varied. If due to bone marrow infiltration, systemic therapy is the treatment of choice to eradicate or reduce tumor involvement. The goal is to allow normal, healthy bone marrow tissue to grow and produce normal cells. If other drugs with the possibility of decreasing bone marrow production are being taken, discontinue or replace with less marrow toxic agents whenever possible. Growth factors and transfusion support are appropriate. If viral etiology is present, treat with anti-virals whenever possible. Kumar Ferri
  • These are only a small number of examples of the possible etiologies of cytopenias in patients with follicular lymphoma. Due to the wide varieties of causes, it is essential to determine the most likely etiology and treat appropriately. However, given the complexity of these patients, it is highly likely that multiple causes may be present in the same patient, requiring various interventions.
  • ITP is an autoimmune hematologic disorder in which the body raises antibodies that tag platelets for destruction by macrophages that reside in the spleen and liver. Sequencing suggests that these autoantibodies originate from a small number of B-cell clones. ITP is classified as either primary (idiopathic) ITP or secondary ITP. Secondary ITP is associated with underlying disorders (e.g., NHL, CLL, rheumatoid arthritis, and systemic lupus erythematosus) or use of certain drugs (e.g., heparin). ITP may occur either in young children (age 2 to 6 years) or in adults (most common in adults age 18 to 40); childhood-onset and adult-onset ITP also differ in the course of their disease. This presentation will focus on adult-onset disease. Adult-onset ITP is frequently insidious in its presentation and is often a chronic condition. Spontaneous remission is rare. ITP is characterized by a low platelet count that interferes with blood clotting and creates a risk of fatal hemorrhage. The American Society of Hematology estimates that the lifetime risk of fatal hemorrhage for patients with ITP is approximately 5%, with rates increasing with age (from 0.4% for patients less than 40 to 13% for patients over 60) and with decreases in platelet count. Increased morbidity and mortality are also associated with persistently low platelet counts (&lt;30,000/ μ L) after primary therapy. References: Cines and Blanchette, N Engl J Med, 2002 Cohen et al, Arch Intern Med, 2000 George et al, Blood, 1996
  • Hamblin TJ, Oscier DG, Young BJ. Autoimmunity in chronic lymphocytic leukemia. J Clin Pathol. 1986;39:713-716. 2. Rozman C, Montserrat E. Chronic lymphocytic leukemia. N Engl J Med. 1995;333:1052-1057 3. Visco C, et al. Impact of immune thrombocytopenia on the clinical course of chronic lymphocytic leukemia. Blood. 2007 Nov 6. ITP involved self destruction of platelets and occurs in up to 5% of patients with CLL. Patients with unmutated disease, a positive Coombs or clinically active AIHA had the highest incidences of ITP. Patients with ITP typically present with rapid (occurring in a 2 week or less period), profound (half of the initial level and below 100x10(9)/L) thrombocytopenia. It is important to rule out other causes of thrombocytopenia, such as splenic sequestration or treatment effect. The hallmark of ITP is the presence of normal platelet precursors (megakariocytes) in the bone marrow.
  • Hamblin TJ, Oscier DG, Young BJ. Autoimmunity in chronic lymphocytic leukemia. J Clin Pathol. 1986;39:713-716. 2. Rozman C, Montserrat E. Chronic lymphocytic leukemia. N Engl J Med. 1995;333:1052-1057 3. Visco C, et al. Impact of immune thrombocytopenia on the clinical course of chronic lymphocytic leukemia. Blood. 2007 Nov 6. 4. Diehl, LF, Ketchum LH. Autoimmune disease and chronic lymphocytic leukemia: autoimmune hemolytic anemia, pure red cell aplasia and autoimmune thrombocytopenia. Seminars in Oncology. 1998 Feb;25(1):80-97 Autoimmune disorders are most commonly treated with corticosteroids, IV IgG, rituximab, chemotherapy and cyclosporin. These agents may be administered sequentially or concurrently. Management of these disorders and the impacts of treatment options are often a challenge for the entire health care team.
  • Asymptomatic (favorable) Early stage disease (favorable) 11q deletion (unfavorable) Unmutated disease (unfavorable) Unfavorable overall While being watched the following CBC results were noted. Although from diagnosis to 6 months after diagnosis, there was a 6 month doubling of the ALC, in general, this rule is not meant to be widely enforced if the WBC is &lt; 100K. The patient remained completely asymptomatic and declined all therapy discussion until 12 months, when he began to experience minor fatigue. By 15 months the fatigue had worsened to the point where the patient is agreeable to treatment. He is having no s/sx of bleeding or any infectious complications.
  • Yes, he has progressive disease with worsening cytopenias and symptoms. A bone marrow examination is the gold standard for sorting out cytopenias in CLL. Antiplatelet antibody testing is helpful but a bone marrow gets directly to the root of whether the defect is in adequate production. A direct Coombs is also appropriate to evaluate for AIHA. Evans Syndrome is characterized by the occurrence of both ITP and AIHA simultaneously.
  • Patients with CLL on steroids for any reason should be considered for PCP and herpes virus prophylaxis. Depending on the dose and schedule, H2 blockers may be appropriate. In this case, with a high WBC, allopurinol for TLS prophylaxis and aggressive oral hydration should also be initiated. The WBC initially drives upward as an effect of steroids before the antineoplastic impact of prednisone kicks in and drives the WBC down.
  • Yes, the patient still needs systemic therapy. AIHA is an indication for treatment of CLL. Let ’s review initial therapy options for this now 71 yo with no treatment-limiting comorbidities and in good overall physical condition.
  • Slide 5 The translocation of chromosomes 9 and 22 is pictured. The reciprocal exchange of genetic material occurs between the long arms of chromosomes 9 and 22. The translocation results in the juxtaposition of the ABL proto-oncogene with the BCR gene. Reference : Savage DG, Antman KH. N Engl J Med 2002;346:683-693.
  • Unlike other leukemias, CML seldom presents with bacterial or fungal infection because neutrophil function is preserved.
  • Transcobalamin I is produced by granulocytes so serum B12 levels are increased in CML
  • Slide 9 FISH is a DNA mapping technique that uses fluorescent molecules to mark the BCR-ABL gene. In normal cells, two red and two green signals indicate the location of the normal ABL and BCR genes, respectively. In abnormal cells, the BCR-ABL fusion product is visualized through the fusion of the red and green signals, which is frequently detected as a yellow fluorescence. At diagnosis when 90% of cells are BCR-ABL positive, FISH is highly accurate diagnostic test –false negative results are uncommon. However, in low disease burden, FISH is less useful. Reference: Faderl S, et al. Hematol Oncol Clin N Am 2004;18:657-670.
  • The reduction of CML burden and the sensitivity of assays. Routine cytogenetics will fail to detect the Ph (a CCyR) after a 1-2 log reduction in CML burden. The detection limit of RT-PCR is approximately a 5-6 log reduction of disease burden. Radich, 2009. Figure 1. Disease burden and tests. The reduction of CML burden and the sensitivity of assays (plot not to scale). Thus, routine cytogenetics will fail to detect the Ph (a CCyR) after a 1 to 2 log reduction in CMLburden. The detection limit of RT-PCR is approximately a 5 to 6 log reduction of disease burden. Professional illustration by Marie Dauenheimer.
  • Cytogenetic response and MMR have prognostic significance Studies with dasatinib used cytogenetic response and MMR as primary end point.
  • Cytogenetic response and MMR have prognostic significance Studies with nilotinib used cytogenetic response and MMR as primary end point.
  • Myelosuppression from TKIs is probably a therapeutic effect since the majority of hematopoiesis in CML is derived fro Ph chromosome-positive cells. There is minimal suppression of normal hematopoiesis by imatinib, nilotinib and dasatinib. Dose reductions are unlikely to assist in the revcovery of normal hematopoiesis.
  • He was started on imatinib Monitoring: Repeat CBC 1 wk later indicated a WBC of 1.0 with an ANC of &lt; 500 He reports not having a fever that he has noticed
  • Excess over production of a normal immunoglobulin Plasma cells turn malignant “ M” protein (monoclonal), or “M- Spike” Heavy chains involved: IgG, IgA, IgD, IgE Light chains: Kappa or lambda Presentation: Protein in serum, urine, non-secretory Not everyone who presents with a monoclonal protein has myeloma Monoclonal gammopathy of Unknown Significance (MGUS) is an asymptomatic condition and the majority of patients will not progress to MM, amyloid, WM or other disorders Figure: MM cells are inherently drug resistant; fail to undergo apoptosis, and uncontrolled cell growth occurs which is similar to many different types of cancer. Basically, The pluripotent bone marrow stem cell differentiates into the myeloid and lymphoid lineage. On the lympohid lineage, mature B cells form healthy, normal plasma cells (1). (2,3,4) However, through a series of genetic changes, mutations and chromosomal aberrations, the pre-B cell becomes damaged and creates the malignant plasma cell, or myeloma cell (5).
  • Multiple Myeloma Disease is now recognized to be a continuum— MGUS and Smoldering Multiple Myeloma (SMM) are asymptomatic premalignant conditions. MGUS is relatively common: prevalence is 3% of 50+ year olds and 5% of 70+ year olds but has a low liklihood of progression: 1% per year. Smoldering MM has a much higher risk of progression. Watchful waiting is the current approach to MGUS and SMM treatment, although that might be changing. Mateos et al demonstrated that Lenalidomide/Dexamethasone treatment prevented disease progression of SMM patients. TRANSITION: Multiple Myeloma is generally symptomatic. Unlike with MGUS or SMM, there is end organ damage—CRAB criteria-- C alcium elevation (serum calcium &gt;11.5 mg/dL) R enal insufficiency (serum creatinine &gt;2 mg/dL) A nemia (hemoglobin &lt;10 g/dL or 2 g/dL &lt;normal) B one disease (lytic lesions or osteopenia)
  • Immunoglobulins contain 2 types of smaller molecules: heavy chains and light chains There are 5 types of heavy chains (IgG, IgA, IgM, IgD, and IgE) and 2 types of light chains (kappa [ κ ] and lambda [ λ ]) Each plasma cell produces only 1 type of heavy chain and 1 type of light chain Patients may also produce incomplete immunoglobulins, which contain only the light chain portion of the protein (known as Bence Jones myeloma or proteinuria ). Excess light chains are very small and enter the blood stream as free light chains and can freely pass into the urine, depositing in and blocking the small tubules and vessels in the kidney Roughly 30% of myeloma patients produce excess light chains and have Bence Jones proteinuria Normal levels of kappa free light chains are between 3.3 and 19.4 mg/L, and normal lambda light chains are between 5.71 and 26.3 mg/L References: Durie BGM. Multiple myeloma: cancer of the bone marrow. Concise review of the disease and treatment options. North Hollywood, CA: International Myeloma Foundation; 2006. Available at: www.myeloma.org/main.jsp?source=tab&amp;type=tab&amp;tab_id=13. Accessed 2/13/07. Multiple Myeloma Research Foundation. Intro to Myeloma . Available at: www.multiplemyeloma.org/about_myeloma/index.html. Accessed 07/16/07.
  • As mentioned in the past few slides, most patients with active Multiple Myeloma are symptomatic. In contrast to patients with MGUS or SMM, patients with MM have “end organ damage” by CRAB criteria C alcium elevation (serum calcium &gt;11.5 mg/dL) R enal insufficiency (serum creatinine &gt;2 mg/dL) A nemia (hemoglobin &lt;10 g/dL or 2 g/dL &lt;normal) B one disease (lytic lesions or osteopenia)
  • Prevalence data 54,930 first invasive myeloma were diagnosed in the 26-year period, 1975–2000 (SEER data) 2 Risk factors Age (rarely occurs before age 45; 66% of cases diagnosed at ≥60 year). Median age of diagnosis from SEER data 2 Gender (slightly more prevalent in men) Race (affects twice as many African Americans as white Americans) Exposure to ionizing radiation Exposure to environmental toxins: pesticides, herbicides, dioxin, petroleum products, Agent Orange (herbicide used in Vietnam War) Immune system disorders Most causes unclear but first degree relatives are being investigated First Case: Sarah Newbury was a housewife who fell ill one winter in the 1840 ’s with spontaneous fractures of femur, humerus. After an infusion of orange peel, rhubarb pills she passed. Autopsy revealed destruction of femur, humerus and sternum with tumor. It wasn’t, however, until years later when the disease was termed “multiple myeloma” because it caused multiple bone (myel) tumors (omas). First effective treatment was melphalan in 1962 American Cancer Society. Available at: http://www.cancer.org/downloads/STT/CAFF2005f4PWSecured.pdf Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader N, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Cronin K, Chen HS, Feuer EJ, Stinchcomb DG, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2007, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2007/ , based on November 2009 SEER data submission, posted to the SEER web site, 2010.
  • Chromosomal changes are present in many patients with myeloma as mentioned on the previous slide. Changes detected by interphase fluorescence in situ hybridization (FISH), define subtypes of multiple myeloma (MM), each with different biology and prognosis and needing tailored management approaches. Two genetic categories deserve special mention: t(4;14)(p16;q32) and 17p13 deletions. T(4;14) is a primary genetic aberration in MM, is observed in 15% of cases and is consistently associated with an unfavorable outcome (irrespective of treatment modality) Patients with t(4;14)(p16;q32) have short disease control with high-dose chemotherapy and urgently need development of alternative therapeutic strategies Patients with 17p13 deletions ( P53 locus), a genetic progression event in MM, represent the highest risk of all MM genetic categories. These patients have a short survival and lower likelihood of response, and frequently will develop extramedullary disease, hypercalcemia, and plasmacytomas One study reported that translocation of immunoglobulin heavy-chain (IgH) locus (14q32) and deletion of chromosome 13 were found in 75% and 45% of patients with plasma cell disorders, respectively, and were not randomly distributed but rather interconnected References: Avet-Loiseau H, Facon T, Grosbois J, et al: Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood 99:2185-2191, 2003. Fonseca, R. (2007). Multiple myeloma and FISH (but no CHIPS). Blood , 15 April 2007, Vol. 109, No. 8, pp. 3132-3133.
  • The early stages of multiple myeloma are often asymptomatic and the disease may be discovered on routine laboratory testing When myeloma is suspected (ie, older patients with unexplained pain, fracture, anemia), the diagnostic evaluation should include: Laboratory tests of both serum and urine Radiographic imaging Bone marrow biopsy The alterations associated with myeloma are listed here Quantitative immunoglobulins measure the antibodies IgG, IgA, IgM, IgE, and IgD with normal ranges: (IgG 650-1500 mg/dL; IgA (76-390 mg/dL; IgM 40-345 mg/dL; IgE 0-380 IU/ml) Beta 2 microglobulin is a standard measure of tumor burden for myeloma (normal range, 2.0–2.5 µg/mL) Albumin is a surrogate marker for IL-6, a growth factor for myeloma cells. When low, increased myeloma activity may be taking place A 24-hour urine protein electrophoresis (UPEP) measures the presence and amount of myeloma protein in the urine A serum-based assay (Freelite™) detects and quantifies free light chains, which may help predict the risk of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma. This test is also easier for patients to complete than a 24-hour urine collection Emerging evidence suggests that use of magnetic resonance imaging (MRI) is more sensitive and specific than x-ray and scintigraphy for detecting bone metastases in multiple myeloma patients. Thus, MRI may also be used for initial assessment of multiple myeloma. References: Abella HA. MR tops x-ray and scintigraphy for detecting bone mets. Oncology News International. 2007;16(12):27. Barlogie B, Shaughnessy J, Epstein J, et al. Plasma cell myeloma. In: Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT, eds. Williams Hematology . 7th ed. New York, NY: McGraw-Hill; 2006:1501-1533. Durie BGM, Kyle RA, Belch A, et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation Hematol J . 2003;4:379-398. [erratum Hematol J . 2004;5:285]. Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood . 2005;106(3):812-817. Weininger M, Lauterbach B, Knop S, et al. Whole-body MRI of multiple myeloma: comparison of different MRI sequences in assessment of different growth patterns. Eur J Radiol. December 2007 [Epub ahead of print; Doi: 10.1016/j.ejrad.2007.10.025].
  • Anemia is a common presenting symptom and may be present throughout the disease. This slide highlights various differential diagnoses of anemia in patients with myeloma. Cytokine mediated or from crowded bone marrow microenvironment (MM related) Blunted erythropoiesis and shortened red cell survival (treatment related) Bleeding/Blood loss Renal disease (decreased erythropoeisis) Macrocytic anemia (B12 deficiency) Myelodysplastic syndrome (rare in MM, but occurs in older patients which is the demographic of MM. Hence, older patietns with anemia are often evaluated for the possiblility of MDS)
  • Renal Failure The patient in the case study also presented with renal failure (creatinine 3.9). Renal failure can be reversed if prompt intervention and treatment of underlying cause! Overproduction of light chains  tubular capacity for reabsorption is exceeded Filtered light chains &amp; immunoglobulins then bind Tamm-Horsfall glycoprotein (secreted in the medullary TAL of the loop of Henle) Cast formation &amp; obstruction in the distal nephron subsequently results Bence Jones proteinuria is a particular risk factor for ongoing renal injury as light chain immunoglobulins are small enough to pass into urine and block the kidneys; especially incomplete immunoglobulins such as light chains Deterioration of kidney function may result from precipitation of calcium salts in the setting of hypercalcemia Many factors may affect renal function in myeloma patients including: Metabolic conditions such as volume depletion and elevations in serum calcium or uric acid References: Durie BGM, Kyle RA, Belch A, et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation Hematol J . 2003;4:379-398. [erratum Hematol J . 2004;5:285]. Chanan-Khan AA, Kaufman JL, Mehta J, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood. Mar 15 2007;109(6):2604-2606 Rajkumar SV, Kyle RA. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc . 2005;80(10):1371-1382. Sanders, PW et al. Pathobiology of cast nephropathy from human Bence Jones proteins. J Clin Invest 1992; 89:630 Dimopolous et al (2010). Renal impairment is not an independent adverse prognostic factor in MM in patients treated with upfront novel –based agents. Abstract 3033. ABSTRACT: The adverse prognosis of renal impairment in patients with multiple myeloma (MM) has been reported in several series. However, the prognostic impact of renal dysfunction on the survival of ΜΜ patients who are treated upfront with novel agents has not been clearly defined. Τo address this question we studied 180 consecutive patients who received upfront novel agent (thalidomide, bortezomib or lenalidomide)-based regimens, in a single center in Athens, Greece. Many of these patients had been included in clinical trials; however, several patients who were ineligible because of poor performance status, significant renal impairment or comorbidities were also treated with novel agent-based regimens. Thus, these patients are more representative of the general myeloma population. Renal function, estimated by the glomelural filtration rate (eGFR) was assessed using the simplified Modification of Diet in Renal Disease (MDRD) formula (eGFR in mL/min/1.73 m2 = 186 x (Serum Creatinine)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if African-American). Patients were divided into 5 groups according to the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (KDOQI) chronic kidney disease (CKD) classification. According to this classification, stage 1 includes patients with eGFR ≥90 ml/min, while stage 2 includes patients with eGFR between 60-89 ml/min, stage 3 with eGFR between 30-59 ml/min, stage 4 with eGFR between 15-29 ml/min and stage 5 includes patients with eGFR below 15 ml/min or patients who undergo dialysis.  Eighty-five patients (47%) had stage 3-5 CKD and 95 (53%) had stage 1 or 2 CKD. One half of our patients (51%) were 70 years of age or older. Advanced age (p=0.001), anemia (p&lt;0.001), low serum albumin (p=0.017), hypercalcemia (p&lt;0.001), elevated beta2-microglobulin (p&lt;0.001) and Bence Jones proteinuria &gt;2 g/day (p&lt;0.001) were associated with stage 3-5 CKD. The majority of patients with International Scoring System (ISS)-3 myeloma had advanced renal disease (stage 3-5 CKD in 76%) in comparison with ISS-2 (33%) or ISS-1 (10.5%) patients (p&lt;0.001). Eighty-one percent of our patients received upfront an IMiD-based therapy, while 19% received bortezomib-based regimens. The dose of lenalidomide was adjusted according to renal function. The frequency of advanced CKD was similar among patients treated with IMiDs- or bortezomib-based regimens (47% vs. 48.5%, p=0.843). Response to primary treatment was similar between patients with stage 3-5 CKD and patients with stage 1 or 2 CKD (72.6% vs. 78.7%, respectively; p=0.343). In the univariate analysis, variables associated with worse survival were: stage 3-5 CKD (median survival 39 months vs. not reached in stage 1 or 2 CKD; p=0.001), age ≥70 years (p&lt;0.001), anemia (p=0.005), hypercalcemia (p=0.012), ISS stage (p&lt;0.001) and LDH ≥300 IU/L (p=0.007). However, in the multivariate analysis, the presence of renal dysfunction (stage 3-5 CKD) or the degree of renal dysfunction (evaluating each CKD stage separately) was not independently associated with survival.  Age &gt;70 years (p&lt;0.001), corrected serum calcium ≥11.5 mg/dl (p=0.04) and elevated LDH ≥300 IU/L (p=0.001) were the only independent factors associated with worse survival. The same results were obtained when we assessed renal function as a continuous variable. We also evaluated the effect of CKD staging on the survival of patients within each ISS stage and we did not find any statistically significant correlation. We conclude that the presence οr the degree of renal dysfunction has no independent prognostic impact on the survival of multiple myeloma patients who are treated upfront with novel agent-based regimens.
  • Hypercalcemia One of the most common reasons for reversible renal failure is hypercalcemia Hypercalcemia is found in 25% of patients at diagnosis. Increased ca ++ levels can lead to dehydration which can further precipitate renal failure but this is generally reversible if detected early. Treatment includes Pamidronate for hypercalcemia of malignancy, hydration, and treatment of the underlying disease Pathobiology: malignant cells produce osteoclast- activating factors that destroy bone cells Osteoclast stimulation leads to extensive osteolysis, severe bone pain, and pathologic fractures Spinal cord compression is rare in myeloma but must be ruled out if neurologic compromise is suspected. Plasmacytoma with significant bone destruction may also occur. Bone damage related to myeloma is often the most visible aspect of myeloma as it leads to kyphotic deformities of the spine and height loss. At least 85% of patients develop bone disease. References: Oyajobi, BO. (2007). Multiple myeloma/hypercalcemia. Arth Res Ther, 9(Suppl 1): 54. Roodman, G. D. (2008). Skeletal imaging and management of bone disease. Retrieved June 4, 2009, from http://asheducationbook.hematologylibrary.org/cgi/content/full/2008/1/313
  • Most patients present with a measurable m protein noted on serum protein electrophoresis or urine protein electrophoresis. Patients must have a serum and urine evaluation as if the patient is not secreting an intact monoclonal protein (i.e IgA kappa or IgG Lambda) in the serum, you could miss patients with hypogammaglobulinemia who may not be secreting measurable proteins. As a percentage of patients will only secrete un-intact free light chains in their serum or urine, a serum free light chain assay may be useful. This test is a nephelometric assessment of free serum light chains in the blood. Increased levels of serum free light chains (kappa or lambda) can be used to diagnose and monitor disease status. Light chain escape has been described recently and refers to a phenomenon in which a patient with myeloma had been previously treated and at relapse, does not show an increase in serum or urine m spike but only increased serum free light chains. Therefore, intermittent monitoring of sFLC is recommended
  • In recent years a nephelometric assay of the serum free light chains (sFLC) has been proposed as a quantitative marker of disease activity that may be used in the diagnosis and evaluation of patients with non- secretory MM. Patients with non-secretory MM or those with light chain escape fail to secrete measurable amounts of monoclonal protein in the serum and/or urine which provides a challenge for the monitoring of disease status. The sFLC assay relies on an imbalance between kappa and lambda light chains and is a surrogate marker for monoclonality that correlates with myeloma disease activity. Several studies have evaluated the validity of the sFLC assay since its inception, and one suggests that abnormal sFLC ratios have been linked to a higher risk of progression from smoldering or asymptomatic myeloma to active MM The table to the left describes normal and abnormal sFLC levels The table to the right illustrates the upward trend in this patient with kappa light chain multiple myeloma. She had mildly abnormal sFLC levels at diagnosis but throughout the years has progressed to a rather abnormally elevated sFLC level of 3089.0 mg/L. References: Faiman and Licata (2010) New tools for detecting occult monoclonal gammopathy, a cause of secondary osteoporosis. Cleveland Clinic Journal of Medicine, 77 (4), 273-278. Dispenzieri A, Kyle RA, Katzmann JA, et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood. 2007. Drayson M, Tang LX, Drew R, Mead GP, Carr-Smith H, Bradwell AR. Serum free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma. Blood. 2001; 97:2900-2902 Kühnemund A; Liebisch P; Bauchmüller K; zur Hausen A; Veelken H; Wäsch R; Engelhardt M. &apos;Light-chain escape-multiple myeloma&apos;-an escape phenomenon from plateau phase: report of the largest patient series using LC-monitoring. Journal of cancer research and clinical oncology,  2009;135(3):477-84.
  • Skeletal xrays are the gold- standard for diagnosing myeloma related bone damage. These are relatively inexpensive and easily obtained compared with other tests. (The patient in our case study had evidence of myeloma –related bone damage on xray.) Bone x rays are less sensitive than MRI, PET or CT scans to detecting bone loss. It is estimated that as 30-40% must be present before damage is visible on xray MRI or CT: evaluate suspicious lesions found on xray. MRI is best used to image spine, muscles, tendons or nerves. CT scans are sensitive to determine bone damage. Bone scan imaging is not performed in MM patients (absent osteoblastic response). Basically, osteoclastic (bone destruction) and osteoblastic (bone rebuilding) activity is essential to healthy bone turnover. This process is uncoupled in myeloma as the degree of bone destruction and osteoblastic stimulation far outweighs osteoblastic activity. In fact, osteoblastic activity is nearly absent in myeloma. Tests such as bone scan (which are performed to detect metastatic disease such as in patients with prostate, breast and lung cancer) rely on osteoblastic activity to detect osteoblastic or osteolytic lesions from metastatic bone disease. Hence, a normal bone scan does not mean that a MM patient does not have bone disease, it just may have not been detected.
  • How does bone disease in patients with multiple myeloma occur? Malignant cells produce osteoclast-activating factors that destroy bone cells which leads to osteolysis, bone pain, and increased risk of pathologic fracture. Osteoclastic (bone destruction) and osteoblastic (bone rebuilding) activity is essential to healthy bone turnover. This process is uncoupled in myeloma as the degree of bone destruction and osteoblastic stimulation far outweighs osteoblastic activity. In fact, osteoblastic activity is nearly absent in myeloma. Bisphosphonates such as pamidronate and zoledronic acid are potent inhibitors of bone resorption. Acute phase reactions – flulike symptoms, tylenol before and the evening of infusion may diminish Renal dysfunction – monitor for albuminuria which suggests renal tubular damage over time, dose reduction and longer infusion time Osteonecrosis of the jaw Current ASCO 2007 guidelines recommend bisphosphonate treatment for up to 2 years with bisphosphonates but recent data from ASH suggests that there is an anti-myeloma benefit from BPs such as zoledronic acid.
  • Predisposition to infection is the single most dangerous complication of myeloma Although the exact mechanism for the increased risk of infection is not fully understood, the presence of active myeloma in the bone marrow causes an impairment of normal immune functions including a decreased response to antigen stimulation and a decrease in antibody production Infection risk is further increased by therapies used to treat myeloma, such as cytotoxic drugs, autologous or allogeneic stem cell transplantation, and glucocorticoids Patients with myeloma should be instructed to report symptoms of infection immediately In the case of life-threatening infection, IV immunoglobulin may be required Prophylactic treatment with low-dose acyclovir can reduce herpes simplex virus (HSV) and treatment with trimethoprim-sulfamethoxazole (TMP-SMX) is used to prevent Pneumocystis carinii Myeloma patients have a poor antibody response to pneumococcal and influenza vaccines References: Barlogie B, Shaughnessy J, Epstein J, et al. Plasma cell myeloma. In: Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT, eds. Williams Hematology . 7th ed. New York, NY: McGraw-Hill; 2006:1501-1533. Durie BGM. Multiple myeloma: cancer of the bone marrow. Concise review of the disease and treatment options. North Hollywood, CA: International Myeloma Foundation; 2007. Available at: http://myeloma.org/main.jsp?source=link&amp;source_link_id=775&amp;type=article&amp;tab_id=13&amp;menu_id=0&amp;id=941. Accessed January 8, 2008. Durie BGM, Kyle RA, Belch A, et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation Hematol J . 2003;4:379-398. [erratum Hematol J . 2004;5:285]. Malpas JS, Bergsagel DE, Kyle R, Anderson K. Myeloma Biology and Management . 3rd ed. Philadelphia, PA: Saunders; 2004;261. Multiple Myeloma Research Foundation (MMRF). Symptoms. Norwalk, CT: Multiple Myeloma Research Foundation; 2005. Available at: www.multiplemyeloma.org/about_myeloma/index.html. Accessed January 8, 2008.
  • Bone marrow biopsy is indicated at diagnosis for tissue diagnosis and to quantify abnormal plasma cell clone and percentage. (The patient depicted in our case presentation had increased bone marrow plasma cells and abnormal cytogenetic findings). Not routinely performed as in other malignancies but only if on study and clinically indicated Cytogenetics and FISH are becoming more important to assess for in patients with MM Metaphase cytogenetics may not harbor as many responses as interphase “FISH” analysis . This is most useful to detect translocations and structural abnormalities (particularly of the heavy chain locus) in MM Several ASH abstracts reported the addition of novel agents will reduce poor prognosis of chromosomal abnormalities such as deletion of 13 chromosome Gene expression profiling is not widely available but may be the wave of the future. This technique defines patterns of gene expression in high- risk types of myeloma Abstract 3056: Incorporation of Bortezomib Into Frontline Treatment of Multiple Myeloma According to Risk Stratification Shifts the Most Significant Prognostic Indicator From Cytogenetics to the Quality of Induction Response Abstract 1942: Jakubowiak et al: Responses and Survival Are Not Affected by Cytogenetics In Patients with Relapsed and Refractory Multiple Myeloma (R/R MM) Treated with Single-Agent Carfilzomib Abstract #2985: Gene Expression Profiling (GEP) of CD138-Purified Plasma Cells: Modeling for High LDH and Cytogenetic Abnormalities as Independently Adverse Features of Multiple Myeloma (MM) In Total Therapy (TT) Protocols
  • International Staging System The Durie-Salmon staging system has been around for 35 years but more commonly used today is ISS. Recent data at ASH 2010 show the ISS remains a robust prognostic tool independent of renal function (Dimopoulos et al, Abst 3036, 2010) The International Prognostic Index (IPI) for MM was introduced in 2002 to supersede the Durie-Salmon system introduced in 1975 The IPI staging brochure is available online 2 In 2004, the IPI was renamed the International Staging System or ISS, which was subsequently published 1 For ISS, clinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia. Potential prognostic factors were evaluated by univariate and multivariate analysis. Three modeling approaches were then explored to develop a staging system, including 2 non-tree and 1 tree survival assessment methodologies A combination of serum  2 -microglobulin and serum albumin provided a simple, powerful, and reproducible 3-stage classification The ISS was further validated by demonstrating effectiveness in patients in these 3 continents, either &lt;65 or ≥ 65 years of age, with standard therapy or autotransplantation, and in comparison with the Durie-Salmon staging system Greipp PR et al. J Clin Oncol . 2005;23:3412 International Staging System. Available at: http://www.myeloma.org/pdfs/IPI_TipCard_2003.pdf ABSTRACT #3036: The ISS introduced by Greipp et al (J Clin Oncol 2005) represents today the most widely used staging system for patients with multiple myeloma (MM) because it is based on two readily available variables: serum albumin and beta2-microglobulin. Serum beta2-microglobulin not only reflects myeloma tumor load but it is also increased in patients with renal dysfunction. Thus, there have been concerns that ISS-3 stage may include MM patients with renal impairment in whom elevated beta2-microglobulin does not reflect tumor burden but rather the degree of renal dysfunction. To address this issue, we assessed the impact of patients ’ renal function on the prognostic performance of ISS. Our analysis included data from 1516 patients with symptomatic MM that had been entered into the database of the Greek Myeloma Study Group. Renal function was assessed by the estimated GFR (eGFR), which was calculated using the modified MDRD formula (eGFR in mL/min/1.73 m2 = 186 x (Serum Creatinine)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if African-American) and the degree of renal dysfunction was staged according to the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (KDOQI) classification of chronic kidney disease (CKD) as follows: stage 1 eGFR ≥90 ml/min; stage 2 eGFR of 60-89 ml/min; stage 3 eGFR of 30-59 ml/min; stage 4 eGFR of 15-29 ml/min and stage 5 eGFR &lt;15 ml/min or under dialysis. At the time of treatment initiation, 788 patients had stage 1 or 2 CKD and 728 patients had stage 3-5 CKD. According to ISS, 29% patients had ISS-1, 38% patients had ISS-2 and 33% ISS-3.  Renal impairment was significantly more common in ISS-3 patients: 76% of ISS-3 patients had stage 3-5 CKD compared to 42% and 27% for ISS-2 and ISS-1, respectively (p&lt;0.001). Similarly, the incidence of stage 4 or 5 CKD was higher in ISS-3 (23% and 20%, respectively) than in patients with ISS-2 (6% and 1.5%, respectively) or ISS-1 (4% and 1%, p&lt;0.001). In the univariate analysis, which included all patients, stage 3-5 CKD was associated with inferior survival (31 months vs. 51 months for those with stage 1 or 2 CKD, p&lt;0.001). However, CKD stages had not an independent prognostic value in the multivariate analysis. Subsequently, we analyzed the prognostic significance of renal function in each ISS group separately. ISS-1 patients with stage 1 or 2 CKD had a median survival of 76 months vs. 56 months for patients with stage 3-5 CKD (p=0.053). In ISS-2, the respective median survival was 49 months and 29 months for stage 1-2 CKD vs. stage 3-5 CKD (p=0.02). In contrast, in patients with ISS-3 the median survival was similar (30 vs. 24 months, p=0.292) for patients with stage 1-2 CKD and stage 3-5 CKD. Multivariate analysis performed in each ISS subgroup revealed that renal function (either as a dichotomous or as a continuous variable) was not an independent prognostic factor in any of ISS stages: HR=1.031, p=0.873 for ISS-1; HR=0.996, p=0.123 for ISS-2 and HR=1.09, p=0.6 for ISS-3. We conclude that ISS is a simple, yet powerful prognostic staging system. The robustness of ISS remains unaffected by the degree of renal function. In patients with ISS-3, which includes many patients with renal dysfunction, elevated beta2-microglobulin reflects tumor burden, despite its increase due to renal impairment. Our data in a large population of myeloma patients indicate that adjustment for renal function will not improve the prognostic performance across all ISS stages.
  • The optimal administration and schedule of novel agents used in the treatment of MM is unknown. However, based on previous clinical trials there are several recommended schedules and regiments for transplant and non=transplant candidates. Bortezomib is generally administered for 8 cycles and lenalidomide is ongoing outside of transplant. There are many regimens and too many to list the appropriate dose and schedule, but here are a few of the most common and FDA approved regimens you will see given to patients with newly diagnosed MM&gt; Bortezomib containing regimens are commonly given to transplant – eligible patients and do not impair stem cell harvest. Dexamethasone dosing varies per trial but is generally given day of and after bortezomib. Lenalidomide (Rajkumar et al, 2007) is not FDA approved for newly diagnosed MM but is included in the NCCN guidelines based on the preponderance of phase III trial data to support its safety and efficacy in this population. Thalidomide is not often given by itself but more commonly in combination with bortezomib or PLD. Nontransplant candidates are often administered any of the above treatments yet each regimen can contain melphalan. Prednisone is better tolerated in the elderly population and is preferred steroid over dexamethasone (ludwig et al, 2008) MP+ Thalidomide, MP+ Revlimid and MP+ Velcade are all reasonable options but MPV is the only fda approved combination for Newly dx MM in elderly patients. Here is the dosing schema. Maintenance is controversal but lenaliomide and bortezomib are all commonly used these days (to be discussed later today)
  • Due to our patient ’s young age, SCT should be considered an option Transplant candidates: Age, performance status, desire, insurance, prior treatment history) Depth of response is a prognostic factor for long-term survival Complete remission (CR), very good partial remission (VGPR) Autologous SCT: infusion of patient ’s own HSCs Allogeneic SCT: infusion of donor HSCs Graft vs myeloma effect can be beneficial Tumor-free grafts Reduced risk of relapse vs autologous SCT
  • This slide lists most common side effects of newer therapies. In subsequent slides we will discuss these and proceed with ASH treatment updates during the final portion of this presentation.
  • Peripheral neuropathy, even mild, can be particularly devastating to the individual. This is a challenging event which can impair ones ’ QOL. Drugs such as thalidomide and bortezomib place patients at risk and up to 80% will develop even mild PN symptoms if previously treated. Vincristine and cisplatin are less commonly used but can cause PN as well Small fiber nerve endings can be damaged from the disease or treatment and produce a variety of sensations that range from mild , moderate to severe. Small fibers are most responsible for sensory changes and sensory, small –fiber neuropathy is the most common side effect of treatment. Muscle weakness and motor neuropathy can lead to paralysis if severe, and although uncommon should be monitored for in all patients receiving bortezomib and thalidomide.
  • Consider for all MM patients What is the risk of VTE? (IMWG guidelines) Increased if prior VTE, receiving lenalidomide, thalidoimide, combination chemotherapy. Also increased if BMi &gt;30, surgery, hospitalization, sedentary Bone health: Do they require bisphosphonates if widespread osteopenia or bone lesions, most recommend aredia or zometa monthly for at least 12-24 mos after baseline dental exam ID: Is your patient at high risk for infection (myelosuppression from disease, treatment) Weekly CBCdiff for 8 weeks with lenalidomide Acyclovir prophylaxis with bortezomib IVIG for recurrent infections and hypogammaglobulinemia Prophyllactic antibiotics for prolonged neutropenia is generally not recommended by infectious disease society of america (IDSA) GI: Anti-emetic prior to bortezomib, doxorubicin Assess for diarrhea, constipation (more common to have diarrhea with bortezomib, long – term lenalidomide; constipation with doxil and especially with opioids) PN: Review increased risk of PN with bortezomib and thalidomide Prompt intervention of holding the bortezomib/thalidomide and decreasing the dose can prevent irreversible PN symptoms. SubQ bortezomib and weekly dosing can prevent incidence of painful grade 3 PN symptoms Monthly monitoring of disease parameters SPEP, UPEP, 24-hr urine, serum free light chains should be performed monthly and at least every 3 mos after remission has been obtained
  • Background: Lenalidomide (Revlimid ® ) is an oral immunomodulatory agent with clinical efficacy in patients with multiple myeloma (MM). In patients with relapsed/refractory MM, lenalidomide plus dexamethasone improved time to progression (TTP) and overall survival (OS) in comparison with dexamethasone alone. In newly diagnosed MM patients, the current study compares the efficacy and safety of melphalan, prednisone and lenalidomide (MPR) with that of MP alone.   From Abstract 475, Palumbo et al 2011 “ Conclusions : Continuous Len treatment with MPR-R significantly reduced disease progression risk compared with MP and MPR in pts aged 65-75 yrs. MPR induction significantly extended PFS vs MP. To date, MPR-R has provided one of the longest median PFS (31 mos) among other available regimens (bortezomib, melphalan, prednisone: 24-27 mos; melphalan, prednisone, thalidomide: 28 mos; bortezomib, melphalan, prednisone, thalidomide: 37 mos). The PFS benefit in the landmark analysis supports continuous treatment to suppress disease in all patient age groups. Management of toxicities is essential to allow pts to continue therapy and receive full benefits. Although hematologic SPMs were imbalanced, the risk of PD/death clearly outweighs the risk of SPMs. MPR-R should be considered a standard of care in transplant-ineligible NDMM pts aged 65-75 yrs. “
  • 477 Maintenance Therapy with Bortezomib Plus Thalidomide (VT) or Bortezomib Plus Prednisone (VP) In Elderly Myeloma Patients Included In the GEM2005MAS65 Spanish Randomized Trial Program: Oral and Poster Abstracts Type: Oral Session: 653. Myeloma - Therapy, excluding Transplantation I Monday, December 12, 2011: 10:30 AM Ballroom 20D (San Diego Convention Center) María-Victoria Mateos, MD, PhD 1* , Albert Oriol 2* , Ana-Isabel Teruel 3* , Enrique Bengoechea 4* , Montse Pérez 5* , Javier López 6* , Joaquín Díaz-Mediavilla 7* , Jose Mariano Hernández 8* , Felipe de Arriba 9* , Yolanda Gonzalez 10* , Joan Bladé, MD 11* , Juan José Lahuerta 12* and Jesús F. San Miguel 13 1 Hospital Clinico Universitario, Salamanca, Spain 2 PETHEMA Group. Spanish Society of Hematology, Badalona, Spain 3 Hospital Clinico Universitario de Valencia, Valencia 4 Hematology, Hospital Osakidetza, San Sebastian, Spain 5 Hematology, Hospital Virgen de la Concha, Zamora, Spain 6 Hematology, hospital ramón y cajal, Madrid, Spain 7 Hematology, Hospital Clinico de Madrid, Madrid, Spain 8 Hospital General de Segovia, Segovia, Spain 9 Hospital Morales Messeguer, Murcia, Spain 10 ICO Dr Josep Trueta, Girona, Spain 11 Hospital Clinic, Barcelona, Spain 12 Hospital 12 de Octubre, Madrid, Spain 13 Hematology, Hospital Universitario de Salamanca, Salamanca, Spain In 2005, Spanish Myeloma Group (GEM/Pethema) activated a two-stage, randomized trial including 260 elderly untreated myeloma patients. In the first stage, patients received induction therapy based mainly on a once per week dosing of bortezomib in combination with prednisone plus either melphalan (VMP) or thalidomide (VTP). The results of this first stage were already published (Mateos et al. Lancet Oncology 2010) and among all the 260 patients included in the trial, VMP and VTP as induction regimens yielded similar overall responses rate (80% and 81%, respectively). Patients completing the six induction cycles, in absence of disease progression or toxicity, moved to the second stage, in which each of the arms were equally randomly assigned to maintenance therapy with bortezomib plus prednisone (VP) or bortezomib plus thalidomide (VT). Maintenance consisted of one conventional cycle of bortezomib (1.3 mg/m 2 on days 1, 4, 8 and 11) every 3 months, plus either oral prednisone 50 mg every other day or oral thalidomide 50 mg daily, for up to 3 years. We report the results of this second stage of the trial comparing VT with VP for up to three years as maintenance following induction with VMP or VTP. 178 out of 260 patients were randomized to receive VT or VP. Concerning baseline characteristics, both groups were well balanced, including the response status at the moment of randomization to maintenance (23% of patients were in CR in VT arm and 20% in VP arm). Median follow-up after randomization to maintenance therapy was 34 months (8-54). Overall, maintenance therapy resulted in an improvement of the depth of response and the IF-CR rate was increased from 24% after induction up to 42%. Although no significant differences were observed between VT and VP, the IF-CR rate was slightly higher for VT versus VP (46% versus 39%). For all patients receiving maintenance therapy, the median progression free survival (PFS) from initiation of treatment was 35 months (95% CI 29-39) and the median overall survival (OS) 60 months (95%C CI 51-69). From the randomization to maintenance therapy, the median PFS was 30 months (95% CI 21–39) for patients receiving VT and 24 months (95% CI 15–33) for those receiving VP (p=0·1). The slight benefit of VT versus VP as maintenance was independent of the type of induction therapy (VMP or VTP) (p=0·9). No differences in overall survival from this timepoint for VT and VP arms were observed (HR 1·4, 95% CI 0·8–2·4). Concerning safety profile, grade 3 or higher hematological toxicity was recorded only as neutropenia in one patient (1%) in each arm and grade 1-2 occurred in less than 5% of patients (3% and 2% of patients in VT arm developped neutropenia and thrombocytopenia, respectively; and 1% of anemia in VP arm). Concerning non-hematological toxicity, although more of the side effects were of grade 1-2 in both arms, their incidence was superior for VT as compared with VP arm (p=0·0001). Of note, seven patients (7%) in VT arm developped cardiac events, consisting on bradycardia (2 pts), tachycardia (2 pts), heart attack (2 pts) and cardiac failure (1 pt), while only one patient in VP arm. Gastrointestinal toxicity, as constipation or paralitic ileus, was reported in 11 patients (11%) in VT and 3 patients (3%) in VP arm. Grade 3-4 peripheral neuropathy was observed in 9 patients (9%) in VT and 3 (3%) in VP arm. In summary, VT or VP as maintenance therapy resulted in a substantial increase in complete response rate, from 24% after induction to 42%, which can not be attributed to thalidomide or prednisone single agents but to their combination with bortezomib. In terms of CR, PFS and OS, although no significant differences between VT and VP were observed, a trend to better outcome for VT patients was observed, with a PFS that is one of the longest so far reported for elderly MM patients (39 months from diagnosis). However, VT arm was also associated with a higher incidence of non-hematological toxicity. These regimens, including bortezomib-based induction schemes that use weekly dosing of bortezomib, followed by bortezomib-maintenance schemes represent a platform for further optimisation of the treatment for elderly patients with multiple myeloma through use of lenalidomide instead of thalidomide by reducing adverse events and potentially improving the efficacy. Disclosures: Mateos: Celgene: Honoraria; Janssen-Cilag:  
  • Study results demonstrated that the efficacy of bortezomib in patients with relapsed multiple myeloma was similar with SC and IV administration with respect to complete and partial response rates, time to disease progression, progression-free survival, one-year survival, time to response and duration of response. The data highlight the efficacy of bortezomib irrespective of its route of administration. Median progression-free survival was 10.2 months in the SC arm compared to 8.0 months in the IV arm, and one year overall survival was 72.6 percent in the SC group and 76.7 percent in the IV arm.
  • Introduction: Carfilzomib is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target, resulting in sustained inhibition absent of off-target effects relative to bortezomib. Carfilzomib has demonstrated durable anti-tumor activity and an acceptable tolerability profile in patients with multiple myeloma (MM). Final results will be presented for the bortezomib-naïve group of PX-171-004, a phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory MM. Herein we report the most recent data analysis available at time of abstract submission. Updated final results for the bortezomib-naïve group of PX-171-004, including OS data, will be presented at the meeting. Methods: Patients received either 20 mg/m 2 for all treatment cycles (Cohort 1) or a stepped-up dose-escalating regimen of 20 mg/m 2 for Cycle 1 and 27 mg/m 2 for all treatment cycles thereafter (Cohort 2). Carfilzomib was administered over 2–10 minutes on Days 1, 2, 8, 9, 15, and 16 of every 28-day cycle, for a maximum of 12 cycles. The primary endpoint was the best overall response rate (ORR; [CR + VGPR + PR]) determined according to the IMWG Uniform Response Criteria. Secondary endpoints included the clinical benefit response rate (CBR; [ORR + MR per EBMT criteria]), progression-free survival (PFS), time to progression (TTP), duration of response (DOR), OS, and safety. The result of efficacy analysis from disease assessment by the Independent Review Committee is presented in this abstract. Results: 127 of 129 enrolled bortezomib-naïve patients were evaluable for response. Prior therapies included thalidomide (59%), lenalidomide (59%), alkylating agents (81%), and stem cell transplant (73%). Patients had received a median of 2 prior regimens (1 in 54 patients, 2 in 40 patients, 3 in 28 patients, and ≥4 in 7 patients). 84 patients (65%) were disease refractory to their most recent therapy, defined as ≤25% response or progression during or within 60 days after completion of therapy. The median duration of carfilzomib treatment is 7 cycles (range 1−12) in Cohort 1; 8 patients were receiving drug as of February 2011 in Cohort 2 with a median treatment of 6.5 cycles (range 1−13) at that time. Best ORR was 42% in Cohort 1 and 52% in Cohort 2. Median TTP was 8.3 months and median DOR was 13.1 months in Cohort 1. The median TTP and DOR for Cohort 2 have not been reached at the time of this interim analysis; the lower bound of the 95% CI for the median TTP was 10.2 months, and 84% were estimated to have DOR ≥1 year at the time of data cutoff. Higher response rates for Cohort 2 compared with Cohort 1 do not appear to be associated with higher toxicities. Patients with unfavorable cytogenetic characteristics (≥1 abnormality) per mSMART criteria had an ORR of 37% and CBR of 42% compared with 50% and 65%, respectively, for patients with no abnormality. The most common treatment-emergent adverse events (AEs), regardless of relationship to carfilzomib in Cohorts 1 and 2, respectively, were fatigue (71%, 54%), nausea (54%, 43%), anemia (46%, 37%), and dyspnea (49%, 33%). These were primarily ≤Grade 2 in severity. The most common Grade 3/4 AEs were anemia (15%), lymphopenia (15%), thrombocytopenia (13%), pneumonia (12%) and neutropenia (12%). Treatment-emergent peripheral neuropathy (PN) was mild and infrequent (16%). Only 1 case of Grade 3 PN (0.8%) was observed. Overall, 38 patients (30%) completed 12 cycles and 22 of these patients continued to receive carfilzomib therapy under a safety extension protocol (PX-171-010), an ongoing, multicenter, open-label phase 2 study to monitor long-term use of single-agent carfilzomib. Conclusions: To date we have seen robust and durable single-agent activity for carfilzomib in bortezomib-naïve patients with relapsed and often refractory MM with an ORR of 42−52% and a CBR of 59−63% from 2 separate dose cohorts in a population wherein 92% received an immunomodulatry drug and 73% had undergone an autologous stem cell transplant previously. These data are suggestive of a dose–response relationship and are being further evaluated in the exploratory phase 1b/2 study PX-171-007. Carfilzomib was associated with minimal PN and excellent long-term tolerability, with nearly one-third of patients completing 12 cycles and 22 of these continuing treatment beyond 1 year in the extension protocol PX-171-010.
  • 634 Randomized, Open Label Phase 1/2 Study of Pomalidomide (POM) Alone or in Combination with Low-Dose Dexamethasone (LoDex) in Patients (Pts) with Relapsed and Refractory Multiple Myeloma Who Have Received Prior Treatment That Includes Lenalidomide (LEN) and Bortezomib (BORT): Phase 2 Results Program: Oral and Poster Abstracts Type: Oral Session: 653. Myeloma - Therapy, excluding Transplantation: Combinations Therapy for Myeloma Monday, December 12, 2011: 2:45 PM Ballroom 20D (San Diego Convention Center) Paul G. Richardson, MD 1 , David S. Siegel, MD, PhD 2 , Ravi Vij, MD 3* , Craig C. Hofmeister, MD 4 , Sundar Jagannath, MD 5* , Christine Chen, MD 6 , Sagar Lonial, MD 7 , Andrzej J Jakubowiak, MD, PhD 8 , Nizar J Bahlis, MD 9 , Rachid Baz, MD 10 , Gail Larkins, RN 11* , Min Chen, PhD 11* , Mohamed Zaki, MD, PhD 11* and Kenneth C. Anderson, MD 1 1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 2 John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ 3 Division of Oncology, Washington University School of Medicine, Saint Louis, MO 4 Internal Medicine, Division of Hematology, The Ohio State University Medical Center, Columbus, OH 5 St. Vincent&apos;s Comprehensive Cancer Center, New York, NY 6 Hem. and Medical Onc., Princess Margaret Hospital, Toronto, ON, Canada 7 Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 8 University of Michigan, Ann Arbor, MI 9 Division of Hematology, University of Calgary, Calgary, AB, Canada 10 Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Reseach Institute, Tampa, FL 11 Celgene Corporation, Summit, NJ Background: Pts with relapsed/refractory multiple myeloma (RRMM), resistant to LEN and BORT, have poor outcomes. POM (2 or 4 mg/d for 28 d of each 28-d cycle) is an immunomodulatory compound with activity in pts refractory to both LEN and BORT (Lacy MQ et al. Blood 2011;doi:10.1182). This multicenter phase 1/2 study investigated the safety and efficacy of POM alone or in combination with LoDex (POM+LoDex) for treatment of pts with RRMM who had received both BORT and LEN. Phase 1 identified 4 mg/d of POM as the recommended dose for phase 2 (Richardson PG et al. Blood 2010;116:Abs 864). Phase 2 results are presented. Methods: Pts with RRMM after ≥ 2 prior regimens, including ≥ 2 cycles of LEN and BORT separately or in combination, were eligible. Pts had to have progressed ≤ 60 d of their last treatment prior to study entry (refractory disease). This analysis evaluated the efficacy and safety of POM+LoDex (POM 4 mg/d 1–21 d of each 28-d cycle; Dex 40 mg/wk) and POM alone in a randomized open-label study. Results presented here were based on investigator assessed responses for the intent-to-treat population. Responses were independently adjudicated. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response (partial response [PR] or ≥ PR), duration of response (DOR), overall survival (OS), and safety. All pts received daily low-dose aspirin thromboprophylaxis. Results: A total of 221 pts were enrolled in phase 2 (POM+LoDex n = 113; POM n = 108); 219 received ≥ 1 cycle of study treatment and 191 pts were evaluable for response. Baseline characteristics were comparable between the two arms with a median of 5 (range 2–13) prior therapies in both arms; 74% of pts in POM+LoDex and 76% of pts in POM alone had prior autologous stem-cell transplantation (ASCT). The remaining pts were elderly (aged &gt; 75 yrs) or ineligible for ASCT; all pts were exposed to corticosteroids and 84% in the POM+LoDex and 95% in POM alone arms were exposed to alkylators. Pts were refractory to LEN (POM+LoDex 77% and POM alone 79%), BORT (73% and 69%), or both drugs (61% and 59%). Among pts who were randomized to receive POM alone, 61 (56%) subsequently went on to receive POM+LoDex due to progressive disease (PD) per protocol. A median of 5 (range 1–17) treatment cycles were received by pts in both arms. Median treatment duration was 5.0 mos. Response of ≥ PR was seen in 34% of pts in the POM+LoDex arm and 13% in the POM alone arm, including 1% complete response (CR) in each arm; ≥ minor response (MR) was 45% vs 29%, respectively. Median DOR was 7.7 mos with POM+LoDex and 8.3 mos with POM alone, and median PFS was 4.6 mos and 2.6 mos, respectively (Fig 1). Median OS was comparable for both arms (14.4 and 13.6 mos). Results from independent adjudication were similar, with ≥ PR in 30% of pts in the POM+LoDex arm and 9% in the POM alone arm, including 1% and 0% CR, respectively, in each arm. ≥ MR was achieved with POM+LoDex in 45% and with POM alone in 25%; PFS was 3.8 mos and 2.5 mos, respectively. In the subgroup of pts refractory to both LEN and BORT, 30% and 16% of pts treated with POM+LoDex or POM alone, respectively, achieved ≥ PR; ≥ MR was 45% and 30%, respectively. Median PFS was 3.8 mos for POM+LoDex and 2.0 mos for POM alone; median OS showed a similar trend (13.5 and 10.8 mos, respectively). The main reason for treatment discontinuation was PD in both arms (POM+LoDex 51%; POM alone 44%); discontinuations due to adverse events (AEs) were 7% and 12%, respectively. Grade 3/4 AEs in POM+LoDex vs POM alone, respectively, were: neutropenia 38% and 47%; febrile neutropenia 2% and 2%; thrombocytopenia 19% and 21%; anemia 21% and 17%; pneumonia 19% and 8%; and fatigue 10% and 8%. All grades of peripheral neuropathy, deep vein thrombosis, and renal failure occurred in 7% and 10%, 2% and 1%, and 2% and 1% of pts for POM+LoDex vs POM alone, respectively. Conclusions: POM (4 mg/d 1–21 d of each 28-d cycle) with or without LoDex demonstrates clinical activity and is generally well tolerated in pts with advanced MM who have received multiple prior therapies and are refractory to both LEN and BORT. Prospective comparison indicates that POM+LoDex is associated with greater clinical benefit and no increased toxicity vs POM alone. This is supported by high response rates, long DOR, and PFS benefit achieved with POM+LoDex. The regimen is now being investigated both in phase 3 trials, and as part of combination treatment including with BORT. Figure 1. PFS for pts treated with POM+LoDex vs POM alone.
  • Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, an antigen highly and uniformly expressed on multiple myeloma (MM) cells but with restricted expression on normal cells. Elotuzumab exhibits significant antimyeloma activity in vitro and against MM xenografts, and its antitumor activity is enhanced independently by both lenalidomide and dexamethasone. In a dose-escalation phase 1 study that evaluated the combination of elotuzumab (5, 10, and 20 mg/kg), lenalidomide, and dexamethasone, the maximum tolerated dose was not reached, and the combination showed encouraging clinical activity (82% response rate) in patients with advanced MM. The most frequent infusion-related adverse events (AEs) were headache (21%), nausea (21%), and dizziness (11%), with 7% (2/28) of patients experiencing 3 serious infusion-related AEs during cycle 1 (1 with a grade 4 hypersensitivity reaction and 1 with 2 grade 3 stridor events). Key objectives of this dose randomized, open-label, multicenter, phase 2 study in patients with relapsed MM were to select the optimum dose of elotuzumab and to evaluate an enhanced premedication regimen to minimize the occurrence of infusion reactions. Methods : Patients with confirmed relapsed and/or refractory MM who had received 1–3 prior therapies were enrolled; prior lenalidomide therapy was excluded. Patients were randomized 1:1 to receive elotuzumab either 10 or 20 mg/kg (IV infusion on days 1, 8, 15, and 22 of a 28-day cycle in the first 2 cycles and then days 1 and 15 of subsequent cycles), along with lenalidomide 25 mg PO daily on days 1 to 21 and dexamethasone 40 mg PO weekly. Patients were treated until disease progression or unacceptable toxicity, if earlier. To control potential infusion reactions, patients received methylprednisolone (50 mg IV), diphenhydramine (25–50 mg PO or IV) or equivalent, ranitidine (50 mg IV) or equivalent, and acetaminophen (650–1000 mg PO) 30 to 60 minutes prior to each elotuzumab infusion. Objective responses (OR) were assessed according to the International Myeloma Working Group (IMWG) criteria. Results : As of July 8, 2010, a total of 59 patients were randomized (intent to treat population); 47 patients received at least 1 dose of study medication (safety population); and 26 patients completed or progressed prior to completing 2 cycles of treatment (efficacy population). Median age was 64 years; 36 (61%) had received ≥2 prior therapies; 28 (48%) and 31 (53%) had received bortezomib or thalidomide, respectively, and 40 (68%) had undergone transplantation. Among efficacy evaluable patients, 22/26 (85%) had a confirmed or an unconfirmed response (≥ PR) including 31% VGPR/CR. The remaining 4/26 (15%) had stable disease (Table). Treatment-emergent AEs were reported in 36/47 patients (77%); the most common events were fatigue (26%) and nausea (21%). Serious treatment-emergent AEs were reported in 22% of patients; 2 events, nausea and febrile neutropenia with thrombocytopenia, were considered to be related to elotuzumab and lenalidomide. The most common infusion-related AEs within 24 hours of elotuzumab infusion were dizziness (15%), nausea (15%), and headache (9%). These decreased in frequency after the first treatment cycle. There were no severe AEs associated with infusion reactions. Conclusion : The combination of elotuzumab, lenalidomide, and dexamethasone resulted in a high response rate in patients with advanced MM and was generally well tolerated. These results are consistent with the results previously reported from the phase 1 study. The revised premedication regimen appeared to be more effective in controlling infusion reactions, which were generally mild to moderate with no severe infusion reactions reported to date. Updated response and safety data on all patients by dose level will be presented at the meeting.
  • 811 Vantage 088: Vorinostat in Combination with Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma: Results of a Global, Randomized Phase 3 Trial Program: Oral and Poster Abstracts Type: Oral Session: 653. Myeloma - Therapy, excluding Transplantation: Novel drugs in relapsed/refractory myeloma patients Monday, December 12, 2011: 4:30 PM Ballroom 20D (San Diego Convention Center) Meletios Athanasios Dimopoulos, MD 1 , Sundar Jagannath, MD 2 , Sung-Soo Yoon, MD, PhD 3 , David S. Siegel, MD, PhD 4 , Sagar Lonial, MD 5 , Roman Hajek, MD, PhD 6 , Thierry Facon, MD 7 , Laura Rosiñol, MD 8* , Hilary Anne Blacklock, MD 9* , Hartmut Goldschmidt, MD 10* , Vania Hungria, MD 11 , Andrew Spencer, MD 12 , Antonio Palumbo, MD 13 , Donna E. Reece, MD, FRCPC 14 , Thorsten Graef, MD, PhD 15 , Jennifer Houp 16* , Linda Sun, PhD 17* , Joseph E. Eid, MD 15 and Kenneth C. Anderson, MD 18 1 Department of Therapeutics, University of Athens, Athens, Greece 2 Mount Sinai Hospital, New York, NY 3 Seoul National University Hospital, Seoul, South Korea 4 John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ 5 Department of Hematology and Medical Oncology, Emory University School of Medicine 6 Department of Internal Medicine and Hematooncology, University Hospital Brno and Masaryk University, 625 00 Brno, Czech Republic 7 Service des Maladies du Sang, Hopital Claude Huriez, Lille, France 8 Hematology, Hospital Clínic, Barcelona, Spain 9 Haematology, Middlemore Hospital, Auckland 6, New Zealand 10 Medizinische Klinik V, Universitaetsklinikum Heidelberg, Heidelberg, Germany 11 Santa Casa de São Paulo , Sao Paulo, Brazil 12 Alfred Hospital-Monash University, Melbourne, Australia 13 Myeloma Unit, Division of Hematology, University of Torino, AOU S. Giovanni Battista, Torino, Italy 14 Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, ON, Canada 15 Merck Research Laboratories, Upper Gwynedd, PA 16 Merck &amp; Co, Inc, North Wales, PA 17 Merck &amp; Co., Inc., North Wales, PA 18 Medical Oncology, Dana-Farber Cancer Institute, Boston, MA Introduction: Vorinostat (VOR), an oral inhibitor of histone deacetylase class I and class II proteins, regulates genes and proteins involved in tumor growth and survival. The synergistic effects of VOR and bortezomib (BTZ) have been shown in preclinical studies and were confirmed in independent phase 1 trials in patients with relapsed/refractory multiple myeloma (MM), producing objective response rates (ORRs) of up to 42% and overall clinical benefit of up to 90%. Materials and methods: Eligible patients were aged ≥ 18 years, had measurable secretory MM, had received 1 to 3 prior systemic anti-myeloma regimens, and had an Eastern Cooperative Oncology Group status ≤ 2. Previous exposure to BTZ and the presence of extracellular plasmacytoma were allowed per protocol, but patients with prior resistance to BTZ were excluded. Patients were randomized 1:1 to receive 21-day cycles of BTZ (1.3 mg/m 2 intravenously; days 1, 4, 8, and 11) in combination with oral VOR 400 mg/d, or matching placebo, on days 1 to 14. Additional use of corticosteroids for the treatment of MM was not allowed during the trial. Patients were treated until disease progression, unacceptable toxicities, or withdrawal from the study. The primary endpoint for this trial was progression-free survival (PFS; occurrence of 412 PFS events). Secondary and exploratory endpoints included ORR (≥ partial response), clinical benefit response (ORR + minimal response), overall survival, time to progression, patient-reported outcomes questionnaires (QLQ-C30, QLQ-MY20), and safety/tolerability of this novel drug combination. Responses and progression were determined according to the European Bone and Marrow Transplantation Group criteria and will be confirmed by an Independent Adjudication Committee. Results: Between January 2009 and January 2011, 637 patients were enrolled from 174 centers in 33 countries across the globe making this trial one of the largest studies conducted in patients with relapsed/refractory myeloma. Median age of the study population was 62 years (range, 29–86 years). Of the enrolled patients, 59% were male and 56% were Caucasian. Patients had received a median of 2 prior regimens (range, 1–3). Prior anti-myeloma agents included BTZ (24%), thalidomide (56%), lenalidomide (13%), melphalan (56%), and stem cell transplantation (35%). As of July 2011, 635 patients had received study medication, with a median exposure of 7 cycles (mean: 7.6 cycles; range 1–30 cycles). Reported median exposure to BTZ monotherapy in previous phase 3 trials was approximately 5 cycles. Based on the full analysis of 417 PFS events in 637 patients, patients treated with ZOLINZA (n= 317) and bortezomib (n= 320) had a 23 percent reduction in the risk of progression compared to bortezomib alone with a hazard ratio of 0.774 (p=0.01). The observed median PFS was 7.6 months in the ZOLINZA and bortezomib arm, and 6.8 months in the bortezomib arm. In addition to the improvement in PFS, significant improvement in overall response rate (ORR) was also observed in the combination arm (ZOLINZA and bortezomib, 56 percent; bortezomib and placebo, 41 percent; p&lt;0.0001). The duration of response was 8.5 months in the combination arm and 8.4 months in the control arm. A trend in favor of overall survival (OS) was observed in the ZOLINZA and bortezomib arm, but the difference was not statistically significant (hazard ratio = 0.86; ZOLINZA and bortezomib vs. bortezomib and placebo; p=0.35).
  • No adjustments to bortezomib dose are required but administer after . May reverse renal failure Dialysis can be stopped if kidneys recover in some. Some hemodialysis filters can dialyze light chains and help to reverse renal failure Plasmapheresis is controversial. Idea is to filter heavy chain proteins such as IgA, IgG or IgM (whatever clone is elevated) to “offload” the kidney. Several small studies have been inconclusive. 3974 An International Study of High Cut-off Hemodialysis for the Management of Myeloma Kidney Program: Oral and Poster Abstracts Session: 653. Myeloma - Therapy, excluding Transplantation: Poster III Monday, December 12, 2011, 6:00 PM-8:00 PM Hall GH (San Diego Convention Center) Colin A Hutchison, MB, CHB 1*, Anne Bevins, BMedSc2*, Graham Mead, PhD3 and Mark Cook4* 1Renal Unit, University Hospital Birmingham, Birmingham, United Kingdom 2IDRL, The Binding Site Group Ltd, Birmingham, United Kingdom 3The Binding Site Ltd, Birmingham, United Kingdom 4Department of Haematology, University Hospital Birmingham, Birmingham, United Kingdom Background: An early reduction in serum free light chains (FLC) improves outcomes for patients with myeloma kidney. The purpose of this study was to assess how high cut-off (HCO) dialysers are being used internationally to achieve this target. Methods: Data was collected for 54 patients, from 18 centers in 10 countries. Clinical presentation and treatment parameters, including details of removal of FLCs with high cut off hemodialysis and chemotherapy treatment, were captured using a web-based collection database. Demographics: All patients were Caucasian, median age of 65 years (range 43-81). Median biochemistry at presentation was: GFR of 8mls/min/1.73m2 (1-27). creatinine 633.5µmol (168-2263); calcium 2.3mmol/L (0.91-3.83); albumin 34g/L (14-46) and β2M 9.45mg/L (0-55.7). Baseline monoclonal κ and λ FLCs levels were: 5070mg/L (range 2250-20200) and 4200mg/L (range 300-13300), respectively. Of the patients who received a renal biopsy, 81% had myeloma kidney as their primary diagnosis. For initial chemotherapy prescriptions: 78% received bortezomib and 34% received thalidomide. 68.75% of the patients were treated with the Theralite HCO dialyzer; the other 31.25% received treatment with the HCO1100 dialyzer. There was a total of 626 HCO dialysis sessions recorded, with each patient receiving on average 13 session each (median, range 3-35) treatments per patient. Of the 54 patients, only 3 were treated with HDF. Results: 73.2% of patients demonstrated a decreased serum FLC level over the course of treatment, with 86.7% of these patients demonstrated decreased levels by day 12. The median FLC reduction achieved was 72.96% (15.09-99.62%) by day 12 and 93.03% (40.23-99.96%) by the last dialysis treatment. There was no difference in the percentage FLC reduction achieved between bortezomib (median: total 94.09%, day 12 79.14%) and thalidomide (median: total 77.65%, day 12 66.51%) treatment groups (total p=0.179, day 12 p=0.300). FLC removal was significantly increased in patients receiving Theralite treatment over those receiving HCO1100 at both day 12 (p=0.030) and by the end of treatment (p=0.031) Dialysis independence occurred in 68.2% of patients, median time 32 days (10-249). Patients who became independent of dialysis had significantly greater reductions in serum FLC by day 12 (p=0.032). No significant adverse events related to the study device were reported. Conclusion: Reducing FLC in patients with myeloma kidney is associated with increased levels of dialysis independence. This study adds further evidence that a combination of chemotherapy and FLC removal by HCO hemodialysis improves patient outcomes following acute kidney injury secondary to multiple myeloma.
  • Preventing Fractures with Bisphosphonates Two bisphosphonates, pamidronate and zoledronic acid, have been approved for patients with multiple myeloma to prevent progression of skeletal events Pamidronate 90 mg is administered IV once a month and zoledronic acid 4 mg is also administered IV monthly The NCCN and ASCO guidelines recommend these agents for at least 1 year and for not more than 2 years Patients with MM must be evaluated for renal insufficiency; in case of renal insufficiency, bisphosphonates must be administered at reduced doses Because of the risk for osteonecrosis of the jaw, baseline dental examination is essential prior to infusion In some instances, albuminuria may develop, which can suggest tubular renal damage Oral calcium and Vitamin D supplementation is suggested for patients taking either pamidronate or zoledronic acid Weight-bearing exercise increases muscle strength and bone mass and decreases the risk for falls References: Aredia ® (pamidronate) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2011. Berenson JR, Hillner BE, Kyle RA, et al. American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2002;20:3719-3736. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol . 2007;25:2464-2472. National Comprehensive Cancer Network Inc. NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma v.1.2011 . Zometa ® (zoledronic acid) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2011.
  • Balloon kyphoplasty and vertebraplasty: Both Minimally invasive surgical procedures Inject cement into collapsed vertebral body Goal: decrease pain, stability of vertebrae
  • Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial Dr James Berenson MD a , Robert Pflugmacher MD b, Peter Jarzem MD c, Jeffrey Zonder MD d, Kenneth Schechtman PhD e, John B Tillman PhD f, Prof Leonard Bastian MD g, Talat Ashraf MD f, Prof Frank Vrionis MD h, for the Cancer Patient Fracture Evaluation (CAFE) Investigators‡ Summary Background Non-randomised trials have reported benefits of kyphoplasty in patients with cancer and vertebral compression fractures (VCFs). We aimed to assess the efficacy and safety of balloon kyphoplasty compared with non-surgical management for patients with cancer who have painful VCFs. Methods The Cancer Patient Fracture Evaluation (CAFE) study was a randomised controlled trial at 22 sites in Europe, the USA, Canada, and Australia. We enrolled patients aged at least 21 years who had cancer and one to three painful VCFs. Patients were randomly assigned by a computer-generated minimisation randomisation algorithm to kyphoplasty or non-surgical management (control group). Investigators and patients were not masked to treatment allocation. The primary endpoint was back-specific functional status measured by the Roland-Morris disability questionnaire (RDQ) score at 1 month. Outcomes at 1 month were analysed by modified intention to treat, including all patients with data available at baseline and at 1 month follow-up. Patients in the control group were allowed to crossover to receive kyphoplasty after 1 month. This study is registered with ClinicalTrials.gov , NCT00211237 . Findings Between May 16, 2005, and March 11, 2008, 134 patients were enrolled and randomly assigned to kyphoplasty (n=70) or non-surgical management (n=64). 65 patients in the kyphoplasty group and 52 in the control group had data available at 1 month. The mean RDQ score in the kyphoplasty group changed from 17·6 at baseline to 9·1 at 1 month (mean change −8·3 points, 95% CI −6·4 to −10·2; p&lt;0·0001). The mean score in the control group changed from 18·2 to 18·0 (mean change 0·1 points; 95% CI −0·8 to 1·0; p=0·83). At 1 month, the kyphoplasty treatment effect for RDQ was −8·4 points (95% CI −7·6 to −9·2; p&lt;0·0001). The most common adverse events within the first month were back pain (four of 70 in the kyphoplasty group and five of 64 in the control group) and symptomatic vertebral fracture (two and three, respectively). One patient in the kyphoplasty group had an intraoperative non-Q-wave myocardial infarction, which resolved and was attributed to anaesthesia. Another patient in this group had a new VCF, which was thought to be device related. Interpretation For painful VCFs in patients with cancer, kyphoplasty is an effective and safe treatment that rapidly reduces pain and improves function.
  • 46-year-old male Lower back pain rated 8/10. Ibuprofen 4x/day did not help Severe pain prompted an urgent care visit History of mild high blood pressure and “blood sugar problems”, was told “if I lose weight my blood sugar would be ok” ROS: Lower than normal urine output Fatigue and shortness of breath when walking
  • Note the anemia, hypercalcemia an elevated creatinine which is commonly noted in patients presenting with MM This slide shows an abnormally elevated M spike noted on SPEP. See the high spike in the gamma region and M spike 9.20g/dL. You will not often find an mspike so high. This correlates with the IgG and Kappa found on MPA.
  • Note the serum free lambda light chains are extremely high and is characteristic for patients with light chain MM
  • These key features of the pathobiology of MDS will be describe in detail in the next slide. References: Kurtin SE: Advances in the management of low to intermediate risk myelodysplastic syndrome: Integrating the National Comprehensive Cancer Network Guidelines. Clin J Oncol Nurs 10(2):197–208, 2006. List AF: New approaches to the treatment of myelodysplasia. Oncologist 7(suppl 1):39–49, 2002. List, A. F., Vardiman, J., Issa, J-P., DeWitte, T. M. (2004). Myelodysplastic Syndromes. Hematology, The Education Program of the American Society of Hematology, 297-317.
  • Treatment-related MDS is associated with a poor prognosis and will require specific approaches to treatment that are adapted from strategies used to treat high-risk acute myeloid leukemia Incidence of MDS in a population served by one district hospital between 1981 and 1990 in Bournemouth, England.
  • In addition, methylation status may be investigated. Hypermethylation (p15) is observed in 32%-58% of MDS patients.
  • Cytogenetic, morphological, and clinical data from 7 retrospective risk-based studies were combined. Patients who previously received intensive chemotherapy and those with secondary MDS were excluded. Patients who previously received short courses (&lt;3 months) of low-dose oral chemotherapy (N=43) or hemopoietic growth factors (N=20) were included. N=816 AML Progression and IPSS MDS Risk Classification 25% AML Evolution of MDS Patients within the IPSS subgroups: Low – 9.4 years Int-1 – 3.3 years Int-2 – 1.1 years High – 0.2 years Greenberg P, et al. Blood . 1997;89:2079-2088.
  • High mortality rate 80%-90% of RAEB/RAEB-T patients succumb to bone marrow failure due to MDS or AML 60%-75% of RA/RARS patients succumb to bone marrow failure due to MDS or AML
  • IPSS Classification Patients are stratified into 4 well-defined risk groups based on predicted survival and time to AML transformation Overall prognostic score based on the following: Number of cytopenias Bone marrow blasts (%) Cytogenetics (karyotype) The FAB and WHO classifications are useful for the diagnostic categorization of patients with MDS, but their prognostic value are limited An International MDS Risk Analysis Workshop was convened and they developed the International Prognostic Scoring System (IPSS) for patients with primary MDS who were untreated The IPSS was based upon the cytogenetic, morphological, and clinical data from 816 patients with primary MDS who had been evaluated in prior individual risk-based studies for clinical outcomes Of these patients, 759 were analyzed for AML evolution The prognostic variables, chosen both on clinical and statistical grounds, used for the IPSS were percentage of BM blasts, number of cytopenias, and cytogenetic subgroup AML Progression and IPSS MDS Risk Classification 25% AML Evolution of MDS Patients within the IPSS subgroups: Low – 9.4 years Int-1 – 3.3 years Int-2 – 1.1 years High – 0.2 years
  • IPPS-R is still being modified by the International Working Group for Prognosis in MDS (IWG-PM) including assignment of scores and the final attributes of each category It will include five risk categories with refinement of the cytogenetic risk groups and consideration of additional factors such as fibrosis, transfusion burden, and thrombocytopenia at presentation. It will also be adapted to allow application throughout the disease trajectory. References Greenberg et al. Leuk Res. 2011;35:S6. Abstract 14. Greenberg et al. J Natl Compr Canc Netw. 2011;9:30-56.
  • Best supportive care
  • Treatment options for MDS include best supportive care (eg, transfusions, antibiotics, CSFs), bone marrow transplant, and/or chemotherapy and other novel agents How to Evaluate When to Use Erythropoietin + G-CSF for the Treatment of Anemia in MDS When the Serum-EPO level was ≥ 500 U/L or there was ≥ 2 U/m transfusion need there was a lower rate of response. If both of these factors were present, there was an even lower chance of response
  • This is a flow chart depicting the current NCCN guidelines for treatment of IPSS Int-1 and Low MDS. Treatment should take age, performance status, and coexisting medical conditions into consideration.
  • This is a flow chart depicting the current NCCN guidelines for treatment of IPSS Int-2 and High MDS. Treatment should take age, performance status, and coexisting medical conditions into consideration.
  • Epigenetics refers to heritable changes in gene expression that are not coded in the primary DNA sequence.1 Three systems are used to initiate and sustain epigenetic silencing1: DNA methylation Histone modification RNA-associated silencing Any disruption in one of these systems can lead to inappropriate expression or silencing of genes, resulting in epigenetic disease such as MDS. Epigenetic changes are potentially reversible2 and represent a promising target for therapy. DNA Methylation DNA methyltransferase methylates cytosine (C) in DNA, turning genes &amp;quot;off&amp;quot; or silencing them. This is a normal process during development but is abnormal in MDS.1 Treatments that inhibit hypermethylation, such as VIDAZA, have the potential to manage MDS. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation3 Hypomethylation can occur only when cells are actively dividing3 Thus, these agents must be administered for an extended period of time before achieving results4 Gene expression typically reverses when treatment ceases4 Prolonged treatment may be required to achieve and/or maintain inhibition of DNA methylation in patients with MDS.4
  • Deletion 5q is the Most Common Cytogenetic Abnormality Found in MDS Chromosomal abnormality involving 5q is present in 20% to 30% of all MDS Patients who have deletion 5q can be grouped into 3 distinct categories with variable prognoses: Based on IPSS, patients with an isolated deletion 5q (no additional cytogenetic abnormalities): prognosis is good A subgroup of isolated deletion 5q patients comprise a distinct clinical syndrome with separate favorable prognosis, called “5q- syndrome” 99/148 (67%) patients achieved Transfusion Independence in Phase II Study Evaluating REVLIMID® (lenalidomide) in the Treatment of Transfusion-Dependent Low- or Int-1 Risk MDS with a deletion 5q Chromosomal Abnormality with or without Additional Cytogenetic Abnormalities Study Schema 148 patients were enrolled and 94 patients were verified to be RBC-transfusion dependent for 16 weeks prior to study entry The median transfusion requirement was 5 units in 8 weeks Initial study starting dose was a cycled dose of 10mg po qd x 21 of 28 days Shortly after study initiation, the protocol was amended for the dose of newly enrolled patients to be 10mg daily Label recommended starting dose is 10mg po daily The study required a wash-out period for patients on growth factors Recombinant erythropoietin was not permitted on the study G-CSF was permitted for patients who developed neutropenia or fever in association with neutropenia RBC transfusions were allowed if Hgb reached 8.0gm/dL or lower (or if Hct ≤ 25%) or if levels fell below the pre-study baseline Hgb levels This phase 3, randomized, double-blind study assessed the efficacy and safety of lenalidomide in 205 red blood cell (RBC) transfusion-dependent patients with International Prognostic Scoring System Low-/Intermediate-1-risk del5q31 myelodysplastic syndromes. Patients received lenalidomide 10 mg/day on days 1-21 (n = 69) or 5 mg/day on days 1-28 (n = 69) of 28-day cycles; or placebo (n = 67). Crossover to lenalidomide or higher dose was allowed after 16 weeks. More patients in the lenalidomide 10- and 5-mg groups achieved RBC-transfusion independence (TI) for ≥ 26 weeks (primary endpoint) versus placebo (56.1% and 42.6% vs 5.9%; both P &lt; .001). Median duration of RBC-TI was not reached (median follow-up, 1.55 years), with 60% to 67% of responses ongoing in patients without progression to acute myeloid leukemia (AML). Cytogenetic response rates were 50.0% (10 mg) versus 25.0% (5 mg; P = .066). For the lenalidomide groups combined, 3-year overall survival and AML risk were 56.5% and 25.1%, respectively. RBC-TI for ≥ 8 weeks was associated with 47% and 42% reductions in the relative risks of death and AML progression or death, respectively ( P = .021 and .048). The safety profile was consistent with previous reports. Lenalidomide is beneficial and has an acceptable safety profile in transfusion-dependent patients with Low-/Intermediate-1-risk del5q myelodysplastic syndrome. This trial was registered at www.clinicaltrials.gov as # NCT00179621 .
  • Study 9221 was a randomized, open-label, phase III study of subcutaneous VIDAZA ® (azacitidine for injection) plus supportive care versus supportive care alone. 53 US sites were included in the study. Study included patients with any of the 5 FAB subtypes of MDS; patients with AML were excluded from analysis (N=19). Primary endpoint was response rate (CR + PR). Per protocol, patients achieving CR with VIDAZA therapy were to receive 3 additional treatments before completing the study. The use of all hematopoietic growth factors was prohibited. Patients with secondary MDS were included if they were cancer free for at least 3 years and had not received chemotherapy or radiotherapy for 6 months. Patients were stratified by FAB subtype and randomly assigned to receive VIDAZA or supportive care. Transfusions and antibiotics were used as needed. Patients who were randomized to receive supportive care were allowed to cross over if their disease progressed after a minimal interval of 4 months. N=191 For the best supportive care arm Minimum duration of supportive care=4 months unless transformation to AML; death or platelets &lt;20 x 109/L at week 8 or later Growth factors were prohibited Considered to have failed if Advanced to high-risk category (RAEB or RAEB-T) or AML Remained blood transfusion dependent before and during study Developed progressive bone marrow failure
  • All trials have been consistent Trend towards survivial
  • Doubling of survival 9.5 mos
  • 2 mjr ph 3 studies and neither have shown survival advantage Lübbert, M., S. Suciu, et al. (2011). &amp;quot;Low-Dose Decitabine Versus Best Supportive Care in Elderly Patients With Intermediate- or High-Risk Myelodysplastic Syndrome (MDS) Ineligible for Intensive Chemotherapy: Final Results of the Randomized Phase III Study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group.&amp;quot; Journal of Clinical Oncology, 29 (15), 1987-1996. Decitabine administered in 6-week cycles is active in older patients with higher-risk MDS, resulting in improvements of OS and AMLFS (nonsignificant), of PFS and AML transformation (significant), and of QOL. Short MDS duration was an independent adverse prognosticator.
  • 5-Day IV Low-Dose Decitabine Schedule in in Intermediate or Advanced MDS Low-Dose Decitabine Well Tolerated and Effective in Intermediate or Advanced Myelodysplastic Syndrome Summary of Key Conclusions The overall response rate among all participants was 72%, with the highest marrow CR rate of 39% reported in the 5 days IV dosing arm. Low-dose decitabine has pronounced activity against myelodysplastic syndrome (MDS) Optimal decitabine dose 20 mg/m2 intravenously (IV) over 1 hour for 5 days – resulted in improved epigenetic reactivation. Decitabine treatment generally well tolerated Estimated survival significantly better for decitabine-treated patients vs historical group treated with intensive chemotherapy References: O&apos;Brien S, Issa J, Ravandi-Kashani, F, et al. Decitabine low-dose schedule (100 mg/m2/course) in myelodysplastic syndrome (MDS): comparison of 3 different dose schedules. Program and abstracts of the 41st Annual Meeting of the American Society of Clinical Oncology; May 13-17, 2005; Orlando, Florida. Abstract 6545. Kantarjian H, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood; 2007,109(1):52-57. Kantarjian H, et al. ASH 2007. Abstract 115
  • Inhibits DNA methylation Dosing and administration Recommended dose from registration trial: 15 mg/m 2 /h over 4 hours every 8 hours for 3 days, every 6 weeks for up to 10 cycles Alternative dosing schedules being utilized and evaluated Daily IV administration using 20 mg/m 2 over 1 hour has been evaluated in more recent trials Dose-limiting toxicity: myelosuppression Other common toxicities GI toxicities, pyrexia, edema, hyperbilirubinemia
  • 969 Validation of a Prognostic Model and the Impact of SF3B1 , DNMT3A , and Other Mutations in 289 Genetically Characterized Lower Risk MDS Patient Samples Program: Oral and Poster Abstracts Type: Oral Session: 633. Myelodysplastic Syndromes: Advances in Prognostic Models in MDS Tuesday, December 13, 2011: 7:30 AM Room 6CF (San Diego Convention Center) Rafael Bejar, MD, PhD 1, Kristen Stevenson2*, Bennett Caughey1*, Omar Abdel-Wahab, MD3, Naomi Galili, Ph.D.4*, Guillermo Garcia-Manero5, Hagop M Kantarjian5*, Azra Raza, MD6, David P. Steensma, MD7, Ross L Levine, MD8, Donna Neuberg, ScD9 and Benjamin L. Ebert, MD, D.Phil1 1Division of Hematology, Brigham and Women&apos;s Hospital, Boston, MA 2Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 3Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York City, NY 4Irving Cancer Research Center, Columbia University Medical Center, New York, NY 5University of Texas, MD Anderson Cancer Center, Houston, TX 6Columbia Presbyterian Medical Center, New York, NY 7Hematologic Oncology, Dana Farber Cancer Institute, Boston, MA 8Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY 9Dana-Farber Cancer Institute, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA Selection of the appropriate therapy for patients with myelodysplastic syndromes (MDS) depends heavily on the predicted prognosis of each afflicted individual. Prognostic scoring systems help stratify patients into risk groups, but outcomes can be highly variable even within these groups. Of particular concern are patients predicted to have lower risk disease that go on to progress more rapidly than expected. Such patients may not be offered risk-appropriate therapy at a time when it might be of greatest benefit. A prognostic model that better predicts survival in patients believed to have lower risk disease has been proposed by investigators at the MD Anderson Cancer Center, but not yet validated in an independent cohort. Acquired genetic mutations can also identify patients with higher-than-predicted disease risk. We have previously demonstrated that mutations in any of five genes ( TP53 , EZH2 , ETV6 , RUNX1 , and ASXL1 ) predict a poorer prognosis independently of the International Prognostic Scoring System (IPSS). In this study, we examined 289 MDS patients with Low or Intermediate-1 IPSS risk for mutations in 21 genes, including two genes that have recently been reported to be frequently mutated in MDS: DNMT3A and SF3B1 . We validate the ability of the Lower-Risk MD Anderson Prognostic Scoring System (LR-PSS) to more finely risk-stratify patients using an independent cohort and identify gene mutations independently associated with clinical features and overall survival. Patients were stratified into one of three risk categories using the LR-PSS shown in the Table. The 58 patients (20%) assigned to Category 1 had a median survival of 5.19 years (95% confidence interval in years [CI] 3.05-10.34), compared to 2.65 years (CI 2.18-3.30) for the 160 patients (55%) in Category 2, and 1.11 (CI 0.82-1.51) for the 71 patients (25%) in Category 3. Differences in survival were significant between all three categories (p &lt; 0.001 for all comparisons). Point mutations were identified in 63% of samples, including 64% of those with a normal karyotype. The 10 most frequently mutated genes were TET2 (23% of cases), SF3B1 (21%), ASXL1 (15%), DNMT3A (14%), RUNX1 (9%), EZH2 (8%), JAK2 (3%), NRAS (3%), TP53 (2%), and ETV6 (2%). Mutations of SF3B1 were highly enriched in cases of refractory anemia with ring sideroblasts (RARS; 32 out of 43, 74%), associated with normal blast percentages (p = 0.04) and neutrophil counts (p = 0.002), and more likely to be present in cases with platelet counts greater than 450,000/µl (p &lt; 0.001). We extended our analysis of SF3B1 mutations by adding a separate cohort of 98 RARS patients with Low or Intermediate-1 IPSS risk for a total of 141 cases. In this extended RARS set, SF3B1 mutations were associated with improved survival even after adjustment for IPSS risk group or LR-PSS category (hazard ratio [HR]=0.49; CI 0.29-0.81, HR=0.35; CI 0.21-0.58, respectively). SF3B1 is the first gene mutation independently associated with a favorable prognosis in non-CMML MDS. In contrast, DNMT3A mutations were not associated with differences in overall survival in the 289 patients with lower IPSS risk MDS. In a model generated from stepwise Cox regression analysis that considered LR-PSS risk categories and the mutation status of the 13 most frequently mutated genes as candidates, only EZH2 mutations emerged as a LR-PSS-independent risk factor associated with a poor prognosis (HR=2.90; CI 1.86-4.53). In a similar model using IPSS risk groups, EZH2 (HR=2.85; CI 1.78-4.57), NRAS (HR=2.78; CI 1.35-5.72), and ASXL1 (HR=1.60; CI 1.09-2.34) were significant IPSS-independent risk factors. Mutations in genes such as ASXL1 , RUNX1 , NRAS , and ETV6 , which are associated with poor survival in unselected MDS patients, were most common in patients assigned to the LR-PSS risk Category 3, indicating that this prognostic model may capture more clinically relevant information associated with adverse gene mutations. In conclusion, this study validates the LR-PSS &apos;s ability to identify higher risk MDS patients among those with lower IPSS risk and demonstrates that point mutations are common in this cohort, associate with specific clinical features, and independently provide both favorable and adverse prognostic information.
  • 2776 Impact of Iron Chelation Therapy on Overall Survival and AML Transformation in Lower Risk MDS Patients Treated At the Moffitt Cancer Center Program: Oral and Poster Abstracts Session: 633. Myelodysplastic Syndromes: Poster II Sunday, December 11, 2011, 6:00 PM-8:00 PM Hall GH (San Diego Convention Center) Rami S. Komrokji, MD 1, Najla H Al Ali, M.S1*, Eric Padron, MD1, Jeffrey E. Lancet, MD1 and Alan F. List, MD2 1Malignant Hematology, H. Lee Moffitt Cancer Center &amp; Research Institute, Tampa, FL 2Moffitt Cancer Center, Tampa, FL Background :Elevated serum ferritin levels and red blood cell transfusion dependence are associated with poor outcome in patients with lower risk myelodysplastic syndromes (MDS). Few retrospective and observational studies suggest that iron chelation therapy (ICT) may favorably impact outcome in lower risk MDS. The vast majority of patients in those studies were treated with deferoxamine (Desferal). Two studies reported that oral deferasirox (Exjade) significantly decreases ferritin level over time in MDS. An ongoing randomized placebo-controlled trial (TELESTO) is designed to address the impact of deferasirox on overall survival (OS) in lower risk MDS. We examined the impact of ICT predominantly deferasirox in lower risk MDS patients treated at the Moffitt Cancer Center (MCC).   Methods :Patients were retrospectively identified from the MCC database and individual patients’ records reviewed. Inclusion criteria included lower risk MDS patients defined as low or intermediate-1 (int-1) risk disease by the international prognostic scoring system (IPSS) and serum ferritin level ≥ 1000 ng/ml. Patients were divided into two comparator groups: ICT vs. no ICT. Baseline characteristics were compared between the two groups; chi square test was used for categorical variables and t-test for continuous variables. The primary endpoint was overall survival compared between the two groups using Kaplan-Meier estimates. Cox regression was used for multivariate analysis. All analyses were conducted using SPSS version 19.0 statistical software.  Results : Between July 2001 and July 2009, 97 patients with lower risk MDS and serum ferritin ≥ 1000 ng/ml were identified. Forty five (46.4%) received ICT and 52 did not. The ICT included deferasirox in 35 patients and deferoxamine in 10 patients. The baseline characteristics between the two groups (ICT and no ICT) are summarized in (table-1). No statistically significant difference in baseline characteristics was observed except more patients in the ICT group were transfusion dependent. The median duration of follow up was 85.7 month from time of diagnosis. The median OS was 59 months (95%CI 22-48) for patients who received ICT compared to 33.7 months (95%CI 38-80) for patients who did not receive ICT (P= 0.013). After adjustment for age and cytogenetics in Cox multivariable analysis, ICT was associated with better OS (HR 0.52, 95%CI 0.31-0.87, P= 0.013). The rate of AML transformation was 21.2% in patients who did not receive ICT compared to 15.6% in those who had ICT. (p=0.33).  Conclusion :ICT in lower risk MDS patients with elevated serum ferritin ≥ 1000 ng/ml was associated with improved overall survival and a trend to lower AML transformation. Results of ongoing randomized clinical study with deferasirox are needed to confirm the retrospective data. Table-1 : Baseline characteristics   ICT No ICT P-value Age (mean, years) 67 65.5 0.54 Serum Ferritin (mean, ng/ml) 2680 3038 0.77 Caucasian Race (%) 97.8% 92.3% 0.43 Male gender (%) 73.3% 63.5% 0.3 WHO subtype RA RARS RCMD Del 5q RAEB-1 RAEB-II CMML MDS,nos 8 (17.8%) 11 (24.4%) 17 (37.8%) 2 (4.4%) 6 (13.3%) 0 1 (2.2%) 0 14 (26.9%) 10 (19.2%) 14 (26.9%) 1 (1.9%) 9 (17.3%) 2 (3.8%) 1 (1.9%) 1 (1.9%) 0.6 IPSS Low Int-1 15 (33.3%) 30 (66.7%) 9 (17.3%) 43 (82.7%) 0.07 MDAS Low Int-1 Int-2 High 7 (15.6%) 25 (55.6%) 9 (20%) 4 (8.9%) 10 (19.2%) 21 (40.4%) 16 (30.8%) 5 (9.6%) 0.48 Karyotype Good Intermediate poor 38 (84.4%) 5 (11.1%) 2 (4.4%) 44 (86.3%) 7 (13.7%) 0 0.3 ECOG PS 0 1 2 3 12 (26.7%) 31 (68.9%) 2 (4.4%) 0 7 (13.5%) 34 (65.4%) 10 (19.2%) 1 (1.9%) 0.06 RBC Transfusion 45 (100%)   43 (82.7%)   0.003
  • 2613 Phase I Study of the Combination of 5-Azacitidine Sequentially with High-Dose Lenalidomide in Higher-Risk Myelodysplastic Syndrome (MDS) and Acute Myelogenous Leukemia (AML) Program: Oral and Poster Abstracts Session: 615. Acute Myeloid Leukemia - Therapy, excluding Transplantation: Poster II Sunday, December 11, 2011, 6:00 PM-8:00 PM Hall GH (San Diego Convention Center) Guillermo Garcia-Manero1, Naval G. Daver, MD1, Gautam Borthakur1, Marina Konopleva, M.D., Ph.D.2, Farhad Ravandi, MD1, William G. Wierda, MD, PhD1, Zeev Estrov1, Stefan Faderl, MD1, Tapan Kadia1, Kristy Rey, MS, RN1*, Cora Cheung, RN1* and Hagop M. Kantarjian1 1Leukemia, MD Anderson Cancer Center, Houston, TX 2mdacc, Houston, TX The hypomethylating agents are standard of care in patients with higher risk MDS and used frequently in older AML. A number of strategies, including combination approaches, are being developed to improve results of single agent hypomethylating agent. For instance the combination of 5-azacitidine and lenalidomide (LEN) has been shown to be safe and active in a phase I trial (Sekeres JCO 2010; 28:2253-8). Recently the use of high dose LEN (50 mg orally daily) has been reported to have significant activity in older AML (Vij Blood. 2011;117:1828-33). We hypothesized that sequential combination of 5-azacitidine followed by LEN could be safe and active in patients with higher risk MDS and AML. To test this concept, we developed a phase I/II protocol of such combination. Here, we present results from the completed phase I portion of the study. Patients with refractory or relapsed AML and MDS (bone marrow blasts more than 10%) of any age or untreated patients older than 60 years with AML or MDS who refused or were not eligible for frontline therapy were eligible. Adequate performance status, liver function and renal function were requiered. All study participants were registered into RevAssist® program. Females of childbearing potential were required to have a negative pregnancy test. 5-azacitidine was administered at 75 mg/m2 IV daily for 1 to 5 day on a 28 day cycle. LEN was administered on day 6 for 5 or 10 days. The phase I portion of the study design followed a classic “3+3” design and only LEN was dose escalated. 28 patients were registered in the study. The following doses of LEN were used: 10 (N=5), 15 (N=3), 20 (N=3), 25 (N=3), 50 (N=4), 75 mg (N=3) orally for 5 days and 75 for 10 days (N=7). Median age was 65 (range 31 to 79); 19 patients had AML and 9 had MDS or CMML. Median baseline WBC was 1.95 K/µL (range 0.1 to 19.1), median platelet count 68 K/µL (4 to 328), median bone marrow blasts 23% (range 11% to 84%),  8 had diploid cytogenetics and 20 others including 5q- (8 patients), monosomy 5 (5 patients) and monosomy 7(7 patients), del 17 (4 patients), t(9:11)(2 patients) and t(3;5)(2 patients). FLT-3 and N-RAS mutations were seen in 2 patients each and NPM-1 mutation in 1 patient. 22 patients had received prior therapy. A total of 88 cycles of therapy have been administered with a median of 1.5 cycles (range 1 to 10). No dose limiting toxicity was documented and the maximal tolerated dose was therefore not reached. At the 75 mg x 10 days dose, one patient died unexpectedly and subsequently 6 additional patients were treated with no additional severe toxicities observed. Common non-hematological toxicities were fatigue, loss of appetite, constipation, skin rash, fevers and weight loss.  Of 6 patients that had not received prior therapy, 5 were evaluable for response and 3 (60%) achieved a  complete response at doses of 25 and 50 mg of LEN. No response was observed in previously treated patients but 9 (47%) had stable disease. In conclusion, the combination of 5-azacitidine with high dose LEN up to 75 mg orally x 10 days is safe in patients with AML/MDS. The study continues now in a phase II extension of N=40 patients with LEN at a dose of 50 mg daily x 10 days.  2774 Azacitidine Treatment of Lenalidomide-Resistant Myelodysplastic Syndrome with Deletion 5q Program: Oral and Poster Abstracts Session: 633. Myelodysplastic Syndromes: Poster II Sunday, December 11, 2011, 6:00 PM-8:00 PM Hall GH (San Diego Convention Center) Rami S. Komrokji, MD , Najla H Al Ali, M.S*, Eric Padron, MD, Jeffrey E Lancet, MD and Alan F List, MD Malignant Hematology, H. Lee Moffitt Cancer Center &amp; Research Institute, Tampa, FL Background :Lenalidomide is a highly effective treatment for lower risk transfusion dependent myelodysplastic syndrome (MDS) patients with deletion 5q [del(5q)]. Approximately two thirds of patients become transfusion independent for a median duration of 2 years or longer (List et al, NEJM). Effective treatment alternatives after lenalidomide treatment failure are limited. We examined the response to treatment with azacitidine in del(5q) MDS patients after lenalidomide treatment failure.   Methods :MDS patients with del(5q) who were treated with azacitidine after lenalidomide failure were identified through the Moffitt Cancer Center (MCC) MDS database and individual charts reviewed. Data collected included demographics, disease baseline characteristics, duration of response to lenalidomide, responses to azacitidine by international working group (IWG) 2006 criteria, transformation to acute myeloid leukemia (AML), and overall survival (OS). Descriptive statistics were used for analysis and Kaplan Meier estimates were used for OS and AML transformation. All analysis was conducted using SPSS version 19.0 statistical software.  Results :Between July 2005 and June 2011, 18 del(5q) MDS patients treated with azacitidine were identified. The median age was 66 years (50-83), all patients were Caucasian, and male predominance (67%; 12 patients). ECOG performance status was 0-1 in 94% of the patients. The median duration of follow up from date of azacitidine initiation was 645 days. According to the WHO classification, 7 patients (38.9%) had MDS with isolated del(5q), 7 patients (38.9%) refractory cytopenia with multilineage dysplasia (RCMD), 2 patients (11.1%) refractory anemia with excess blasts 1 (RAEB-1), and 2 patients (11.1%) refractory anemia (RA).The international prognostic scoring system (IPSS) risk category was low in 2 (11.2%), intermediate 1 (int-1) in 14 (77.8%), and int-2 in 2 (11.2%) patients. Based on karyotype, 7 patients (38.9%) had isolated del(5 q), 9 (50%) del 5q +1 abnormality, and 2 (11.2%) with del 5q +2 or more cytogenetic abnormality. All patients were transfusion dependent.  The median number of lenalidomide cycles prior to azacitidine was 12 (1-38), with median duration of response 319 days (17-1169). The median number of azacitidine cycles administered was 6 (2-23). The median duration of treatment was 183 days (43-592). The best response to azacitidine by IWG 2006 criteria was one (7.1%) complete response (CR), 2 (5.6%) marrow CR (mCR), 7 (38.9%) hematological improvement (HI), 4 (22.2%) had stable disease, and 4 (22.2%) had progressive disease (PD). The overall response rate was 56%.The HI cell lineage responses were 9 out of 18 (50%) erythroid, 3 out of 13 (23%) HI-P (Platelets), and 2 out 9 (22.2%) HI-N (neutrophils). The median OS was 749 days (95%CI 435-1063) from the time of starting azacitidine. The rate of AML transformation was 27.8% (n=5); median time to AML transformation from azacitidine start was 864 days (95%CI 360-1368). Conclusion:  To our knowledge this is the first report demonstrating the activity of azacitidine in patients with del(5q) MDS after lenalidomide treatment failure. Response rates are similar to those reported in non-del(5q) patients providing azacitidine as an effective option for salvage treatment. Larger cohort of patients is needed to confirm these findings.
  • 607 Final Results From the Phase 2 Continuation Study of the Lenalidomide and Azacitidine Combination in Patients with Higher-Risk Myelodysplastic Syndromes (MDS) Program: Oral and Poster Abstracts Type: Oral Session: 633. Myelodysplastic Syndromes: Advances in the Therapy of MDS Monday, December 12, 2011: 2:45 PM Room 6CF (San Diego Convention Center) Mikkael A. Sekeres, MD, MS 1, Rami S. Komrokji, MD2, Jeffrey E. Lancet, MD2, Ramon V. Tiu, MD3, Anjali S. Advani, MD4, Manual Afable3*, Ricki Englehaupt3*, Joyce Juersivich3*, David Cuthbertson, M.S.5*, Jennifer Paleveda2*, Ronald Paquette, MD, PhD6*, April Smith3*, Lori Strozniak3*, Alan F. List, MD7 and Jaroslaw P. Maciejewski, MD, PhD3 1Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 2Malignant Hematology, H. Lee Moffitt Cancer Center &amp; Research Institute, Tampa, FL 3Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 4Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 5Pediatrics Epidemiology Center, University of South Florida, Tampa, FL 6UCLA Medical Hematology &amp; Oncology, Los Angeles, CA 7Moffitt Cancer Center, Tampa, FL Background: Lenalidomide (LEN) and azacitidine (AZA) have activity in lower- and higher-risk MDS patients (pts), where both microenvironment and cell regulatory mechanisms play a role. The LEN/AZA combination was well-tolerated in the Phase 1 study (Sekeres JCO 2010) that established Phase 2 dosing, with an overall response rate (ORR) of 67%. Methods: The primary objectives for this multicenter, Phase 2 trial were to determine the efficacy and safety of combination therapy, with AZA 75mg/m2 daily x 5 days, and LEN 10mg daily x 21 days of a 28-day cycle (maximum of 7 cycles), in pts with higher-risk MDS (IPSS score ≥1.5, or World Health Organization (WHO) classification with ≥5% myeloblasts) not previously treated with AZA or LEN. Adverse Events (AEs) were assessed per NCI CTC v.3.0, with median decrease in absolute neutrophil count (ANC) or platelets (plt) calculated for the first 8 weeks of therapy. Subjects were enrolled to the Phase 1 study from 5/05 through 5/08, and to the Phase 2 continuation from 3/09 through 4/11, with results reported through 7/11. Bone marrow biopsies were performed after the 4th and 7th cycles, and pts could continue on AZA monotherapy off-study. Responses were assessed per modified International Working Group criteria as complete or partial response (CR, PR), or hematologic improvement (HI), and validated centrally. Time to progression was from date of CR, and overall survival (OS) from date of study enrollment. Results: A total of 36 pts were enrolled at 3 centers (18 Phase 1, 18 Phase 2); median age was 68 years (range 47-78), 13 pts (36%) were female, median interval from diagnosis was 8 weeks (range, 2-106), and median follow-up was 15 months (range 2-60). Prior MDS therapies included growth factors (19%), immunosuppressants (14%), and chemotherapy (17%). Median baseline hemoglobin was 9.7 g/dL, platelet count 65 k/uL, neutrophil count 840 k/uL, erythropoietin level 108 MIU/mL, and bone marrow blast percentage was 11%. IPSS categories were Int-1 (5 pts), Int-2 (20 pts), and High (11 pts); 8 pts had RAEB-1, 21 had RAEB-2, and 3 had CMML. Only 1 pt had a chromosome 5q deletion. Pts received a median of 5 cycles of therapy on-study. Grade 3/4 non-hematologic AEs (related or unrelated) included cardiac (11%), febrile neutropenia (31%), other infection (8%), pulmonary (11%), vascular access-related thrombosis (6%), CNS hemorrhage (6%), or other (11%). Three pts (8%) died while on-study. The most common grade ≤2, non-hematologic AEs related to treatment included constipation (47%), dermatologic (rash or injection site reaction) (44%), fatigue (39%), diarrhea (39%), nausea (19%), dizziness (19%), and dyspnea (19%). Median decrease from baseline in ANC was 35% and in plts was 18%. Of 35 patients evaluable, the ORR was 71%: 14 pts (40%) had a CR and 11 (31%) had HI, of whom 3 had bi- or tri-lineage HI. Median time to response was 3 months (range, 1-7). Three patients had progressive disease while on-study. Among pts achieving a CR, 7 (50%) continue to receive therapy; median age was 68 years (range, 50-76); IPSS was Int-1 (n=3), Int-2 (n=9), and High (n=2); WHO was RAEB-1 (n=5) and RAEB-2 (n=9); cytogenetic profiles were: 9 (64%) normal; 1 (7%) del (5q); 1 (7%) +8, 1 (7%) -7, 1 (7%) complex, and 1 (7%) unknown; median CR duration at last study assessment  was 16 months (range, 3-36) and median OS at last assessment among CR pts was 27 months (range, 7-55). Seven CR pts (50%) evolved to AML a median of 20 months from achieving CR (range, 9-31); 10 (71%) remain alive at last study assessment. Conclusions: The LEN/AZA combination is well-tolerated and highly active in treating higher-risk MDS. The ORR seen in the Phase 1 study was supported by Phase 2 data, with good OS, even among progressing pts. Subsequent randomized studies will compare the LEN/AZA combination to AZA monotherapy and other AZA-based combinations. 609 Low-Dose Clofarabine Has Significant Activity in High-Risk Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia Post-MDS (sAML) After Azacitidine (AZA) Failure: Interim Results of the GFM Clo08 Dose Escalating Phase I/II Study (NCT0106325) Program: Oral and Poster Abstracts Type: Oral Session: 633. Myelodysplastic Syndromes: Advances in the Therapy of MDS Monday, December 12, 2011: 2:45 PM Room 6CF (San Diego Convention Center) Thorsten Braun 1*, Emmanuel Raffoux, MD, PhD2*, Thomas Prebet, MD, PhD3, Sabine Brechignac1*, Aspasia Stamatoullas4*, Francois Dreyfus5*, Zehaira Hebibi6*, Lionel Ades1, Norbert Vey, MD3*, Hervé Dombret2*, Pierre Fenaux, MD, PhD1 and Claude Gardin1* 1Hematology Department, Avicenne Hospital APHP University Paris XIII, Bobigny, France 2Hematology Department, Saint-Louis Hospital APHP University Paris VII, Paris, France 3Hematology Department, Institut Paoli Calmettes, Marseille, France 4Hematology Department, Centre Henri Becquerel, Rouen, France 5Hematology , APHP, Cochin Hospital, University Paris Descartes, Paris, France 6Groupe Francophone des Myelodysplasies (GFM), Bobigny, France Background: Clofarabine (CLO) alone has shown antileukemic activity in MDS and AML, including sAML, at doses ranging from 15 to 40 mg/m2, although with significant myelosuppression and toxicity. Patients with high-risk MDS or sAML who failed AZA have a median OS of only 5 months (Prébet, JCO, online ), and no established drug therapy is available for such patients. In this Phase I/II dose escalating study (NCT0106325), we explored safety and activity of CLO at lower dosing levels (DLs), in such patients. Methods: A standard IV, D1-5 and an extended D1, 3, 5, 8 and 10, administration schedules were studied in parallel, using a standard 3+3 design. Three DLs (CLO 5, 7.5 and 10 mg/m2, daily) were planned. Dose limiting toxicities (DLTs) were defined as any grade &gt;3 non-hematological toxicity, excluding bleeding, infections or febrile neutropenia, or as any delayed cytopenias past D56, defined here as blood counts less than 50% of baseline counts. Responses were evaluated according to IWG 2006 MDS criteria or AML IWG criteria after courses 1 and 2, administered within 56 days. Patients in CR/PR after course 1 could receive up to 7 maintenance courses with only 3 daily infusions at same dosing. Patients in CR/PR or with stable disease after course 2 could receive up to 6 maintenance courses.  If DLTs after course 1 were observed in less than 1 of 3 or 2 of 6 patients, dose escalation was permitted. If 2 or more DLTs were observed after course 1, exploration of lower intermediate DLs was planned. Patients with de novo MDS or sAML who failed at least 6 courses of AZA were eligible, if not candidates to intensive chemotherapy. Exclusion criteria included renal dysfunction (MDRD&lt;50 ml/mn), bilirubin&gt;1.5 ULN, liver function tests &gt;2.5 ULN, ECOG score &gt;2, and uncontrolled infection. Patients: Between November 2009 and July 2011 , 19 Patients (10F, 9M) were enrolled, at DL1 (5 mg/m2, N=9) and DL2 (7.5 mg/m2, N=10), Median age was 72 years (62-90), WHO diagnosis were: RAEB 1 (N=1), RAEB 2 (N=8), sAML (N=10), including 7 patients with &lt;30% marrow blasts). Cytogenetics was normal in 4 (3 RAEB, 1 AML), complex or with abn chr. 7 in 11 (8 sAML, 3 RAEB), and inv3, +8, 5q and 11q, del9q in 4 patients. Median duration of MDS phase, before entry, was 20 months (9-161).  Responses to prior treatment with AZA included 6 CR, 2 marrow CR (mCR) and 4 stable with HI-E, 6 failures and 1 stable w/o HI, after a median number of AZA cycles of 10 (6-34), 11 (6-26) and 6 (6-8) respectively. Eleven patients had only received AZA and eight AZA and 1 to 3 other treatment lines, excluding growth factors. Results: (Table 1) All patients were evaluable for DLTs and response after one cycle. In the D1-5 cohort: one DL1 patient was classified as failure and non-hematological DLT (due to likely unrelated sudden death on D55, before evaluation), and one DL2 patient with mCR as DLT, due to prolonged thrombocytopenia beyond D56. One sAML patient was classified as failure due to early death linked to sepsis, but not as DLT per protocol. In the D1-10 cohort, no DLT was observed after cycle 1. Fifteen patients were eligible for an identical second course, as 2 patients had early death and 2 CR/PR. Twelve patients received a second course, with only 1/8 evaluable for response after course 2, improving response. This patient with mCR obtained durable HI-E and P after course 2. No significant liver or renal toxicity was observed in both cohorts. Seven patients were hospitalized after first course for fever or bleeding (3/9 in DL1/5mg/m2 and 4/10 in DL2/7.5mg/m2 cohorts). Overall, 6 of the 19 patients (32%) had a response after a single course including 2CR/PR and 4 of the 6 responses were seen at the 7.5 mg/m2 dose level. Conclusion: In this dose escalating study in MDS or sAML patients who had failed azacitidine, low-dose clofarabine had significant activity and was administered as an outpatient therapy in most, although hospitalization due to myelosuppression was frequent, even at this low dosing. The extended alternate day (D1-10) schedule may be better tolerated and at least as efficient as the standard D1-5 schedule, although a larger number of patients is required to conclude. Dose escalation in the trial is continuing. Table 1
  • 1529 Determination of the Maximum Tolerated Dose of Panobinostat in Combination with a 5-Day Schedule of Azacitidine in High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia: Planned Interim Analysis of a Phase Ib/II Study Program: Oral and Poster Abstracts Session: 615. Acute Myeloid Leukemia - Therapy, excluding Transplantation: Poster I Saturday, December 10, 2011, 5:30 PM-7:30 PM Hall GH (San Diego Convention Center) Peter T. Tan, MBBS 1*, Kate Reed, BSc1*, Patricia A. Walker, MBBS, FRACP, FRCPA1, Sharon Avery, MBBS1, Sushrut S. Patil, FRACP FRCPA1, Andrew Grigg, MBBS, FRACP, FRCPA2*, Peter Mollee, MBBS, FRCPA, FRACP, MMSc3, Othon L Gervasio, DDS, MS, PhD4*, Ivo J. Winiger, MD5, Dirk Hönemann, MD6*, Andrew H Wei, MBBS, PhD7 and Andrew Spencer, MD8 1Department of Clinical Haematology, The Alfred Hospital, Melbourne, Australia 2Haematology, Austin Health and Northern Health, Heidelberg 3Dept. of Haematology, Princess Alexandra Hospital, Brisbane, Australia 4Novartis Pharmaceuticals, Sydney, Australia 5Novartis Pharma AG, Basel, Switzerland 6Celgene Pty Ltd, Melbourne, Australia 7Clinical Hematology, The Alfred Hospital, Monash University, Melbourne, Australia 8Alfred Hospital-Monash University, Melbourne, Australia Background: The management options for patients with high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who are not eligible for intensive chemotherapy remain limited. The combination of hypomethylating agent and deacetylase inhibitor (DACi) has been shown to be synergistic, both in terms of leukaemia cell killing and gene reactivation in vitro. Aim: To investigate the safety, tolerability and preliminary efficacy of combining the oral pan-DACi panobinostat (LBH589) with azacitidine in previously untreated MDS or AML, not fit for standard induction therapy. Methods: Phase Ib/II multi-center open label dose-escalation and expansion study. Inclusion criteria: untreated IPSS intermediate-2 or high risk MDS, or AML (marrow blasts ≥20%), not eligible for standard induction therapy. Patients received azacitidine 75 mg/m2 SC on days 1-5 of each 28-day cycle with 10, 20, 30 or 40mg panobinostat orally 3 days per week (M/W/F) for 7 doses per cycle commencing on day 5. The safety and tolerability of the combination was assessed. Results: This preliminary analysis includes 26 patients (M 17, F 9), median age 69 years (36-81).  18 AML patients had intermediate (11/18) or poor cytogenetic risk (7/18); 8 MDS patients with intermediate-2 (7/8) or high risk (1/8) IPSS. Patients were enrolled into panobinostat dose-escalation cohorts of 10mg (4 patients), 20mg (7), 30mg (6) or 40mg (6); and expansion study 30mg (3). All grade non-hematologic adverse events regardless of relatedness to study treatment (&gt;10%) were: subcutaneous injection site redness or pain (57%), fatigue (48%), nausea (30%), anorexia (22%), diarrhoea (22%), dyspnoea (13%), fever (13%), hyperbilirubinemia (13%), hyperglycaemia (13%), hyponatremia (13%), leg oedema (13%) and light headedness (13%).  There were no unexpected adverse events or drug reactions. The principal dose-limiting toxicity (DLT) was fatigue, as haematological toxicity was not considered dose-limiting. In the dose-escalation phase, the grade 3/4 DLTs were: panobinostat 10mg cohort (0/4 DLT), panobinostat 20mg cohort (1/7 DLT; grade 3 fatigue), panobinostat 30mg cohort (1/6 DLT; grade 3 fatigue), panobinostat 40mg (4/6 DLTs; all grade 3: fatigue (1), syncope (1), hyponatremia (1) and somnolence/reduced level of consciousness (1)). Therefore, in combination with the 5-day schedule of azacitidine, the maximum tolerated dose (MTD) of panobinostat was defined at 30mg; this dose level has been selected for expanded accrual. At present 10/26 patients (38%) remain on combination study therapy. The panobinostat dose has been reduced by one dose level in 5/26 patients (19%) due to fatigue; 3 patients from panobinostat 40mg cohort. In 16 patients taken off study, the most common cause was disease progression (9), infection (2), atrial fibrillation treated with panobinostat interacting medication (2), patient choice (2) and fatigue (1).  The median number of treatment cycles initiated was 4 (1-16). Preliminary efficacy in 18 AML patients, 3 achieved PR, 7 SD, 7 PD and 1 death unrelated to disease or therapy. In 8 MDS patients, 2 achieved CR, 3 PR, 2 SD, and 1 not evaluable (withdrawal due to patient choice). After a median follow-up of 276 days, the median OS is 239 days (22-472). Conclusion: In previously untreated MDS/AML, panobinostat and azacitidine is well tolerated and preliminary assessments demonstrate clinical activity. The MTD was determined to be 30mg of panobinostat in combination with a 5-day azacitidine schedule of 75mg/m2 daily. Further evaluation of this combination with panobinostat 30mg dose is ongoing in the dose-expansion phase of the study.
  • Transcript of "The 2012 Oncology Nurse Hematology Conference "

    1. 1. DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline forpatient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. DISCLOSURE OF UNLABELED USE This activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. IMER does not recommend the use of any agent outside of the labeled indications. The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of IMER. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
    2. 2. Disclosure of Conflicts of Interest Sandra E. Kurtin, MS, RN, ANP, AOCN®Reported a financial interest/relationship or affiliation inthe form of: Consultant, Celgene Corporation, MillenniumPharmaceuticals, Inc., Novartis PharmaceuticalsCorporation.
    3. 3. Activity OverviewSandra E. Kurtin, MS, RN, ANP, AOCN® Arizona Cancer Center
    4. 4. Learning Objectives Upon completion of this activity, participants should be better able to: Evaluate recent research highlights for patients with DLBCL, CLL, CML, TCL, FL, MCL, MDS, and MM Describe the diagnostic work-up and various stages of hematologic malignancies and their prognostic significance Explain how prognostic indicators are used to determine treatment options for patients with DLBCL, CLL, CML, TCL, FL, MCL, MDS, and MM Identify the current and ongoing treatment regimens available for patients with newly diagnosed, relapsed, and refractory DLBCL, CLL, CML, TCL, FL, MCL, MDS, and MM Describe the optimal administration and schedule of current and novel agents used in the treatment of DLBCL, CLL, CML, TCL, FL, MCL, MDS, and MM Apply effective oncology nursing toxicity assessment and monitoring strategies to help patients achieve positive clinical outcomes Develop individualized patient and family education strategies for patients receiving therapies for hematologic malignancies
    5. 5. Activity Agenda 8:00 – 8:30 AM Registration and Breakfast 8:30 – 8:35 AM Welcome and Activity Overview 8:35 – 8:55 AM Introduction to Lymphoma 8:55 – 9:25 AM Diffuse Large B-Cell Lymphoma 9:25 – 9:55 AM T-Cell Lymphoma 9:55 – 10:05 AM BREAK 10:05 – 10:35 AM Follicular Lymphoma 10:35 – 11:05 AM Mantle Cell Lymphoma 11:05 – 11:25 AM Supportive Care Case Study Breakout Session 1 11:25 – 11:35 AM Panel Discussion / Q&A 11:35 – 12:35 PM LUNCH 12:35 – 1:05 PM Chronic Lymphocytic Leukemia 1:05 – 1:35 PM Chronic Myeloid Leukemia 1:35 – 2:05 PM Multiple Myeloma 2:05 – 2:15 PM BREAK 2:15 – 2:45 PM Myelodysplastic Syndrome 2:45 – 3:05 PM Supportive Care Case Study Breakout Session 2 3:05 – 3:15 PM Panel Discussion / Q&A 3:15 – 3:25 PM Survivorship 3:25 – 3:30 PM Closing Remarks and Evaluations
    6. 6. Introduction to Lymphoma Sandra E. Kurtin, MS, RN, NP, AOCN® The University of Arizona Cancer Center
    7. 7. Incidence  NHL – A heterogeneous group of neoplasms with differing patterns of growth and response to treatment  Cases – ~ 70,130 estimated new cases for 2012 – There were ~ 66,360 new cases in 2011 – NHL ranks 7th among men and women as the most frequently newly diagnosed cancer in the US  Deaths – NHL accounted for ~ 19,320 deaths in 2011 (~ 3% of all cancer deaths) – NHL is the 9th leading cause of cancer deaths in men and the 7th leading cause of cancer deaths in womenNHL = non-Hodgkin lymphoma.Siegel et al, 2012; ACS, 2012, 2011.
    8. 8. Risk Factors Associated With NHL  Age  Immunodeficiency – AIDS, organ transplants, autoimmune disorders  Infectious agents – HTLV-1: Adult T-cell lymphoma – EBV: Burkitt’s lymphoma (Africa) – Helicobacter pylori (MALT lymphomas)  Environmental exposure – Drugs, chemicals, occupational exposureAIDS = acquired immune deficiency syndrome; HTLV-1 = human T-lymphotropic virus type I; EBV = Epstein-Barr virus.Lister, 2004.
    9. 9. Common Sites of Disease in Lymphoma  Lymphatic vessels, nodes, Waldeyer’s ring and organs  Primary organs – BM, thymus  Secondary organs – LNs – Spleen – MALT – Waldeyer’s ringBM = bone marrow; LNs = lymph nodes; MALT = mucosa-associated lymphoid tissue.Lister, 2004.
    10. 10. Lymphoma: A Blood-Related CancerYarbro et al, 2000; Canellos et al, 2006.
    11. 11. B-Cell Development  Malignancies occur at all stages  Specific disease depends upon when malignancy occursYarbro et al, 2000; Canellos et al, 2006.
    12. 12. Where Do B-Cell Lymphomas Originate?CLL = chronic lymphocytic leukemia; SLL = small lymphocytic lymphoma; MALT = mucosa-associated lymphoid tissue.Jaffe et al, 2008.
    13. 13. Normal LN OrganizationAdapted from Willard-Mack, 2006.
    14. 14. Ann Arbor Staging System  Stage I – Single LN group  Stage II – Multiple LNs on same side of diaphragm  Stage III – Multiple LNs on both sides of the diaphragm  Stage IV – Multiple extranodal sites or LNs and extranodal disease  Substaging – Extranodal extension (E) – Systemic symptoms (A/B) – Bulk > 10 cm (X)Lister, 2004; NCCN, 2012a.
    15. 15. NHL Subtypes N = 1,403REAL = Revised European American Lymphoma; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma;MCL = mantle cell lymphoma; PTCL = peripheral T-cell lymphoma; SLL = small lymphocytic lymphoma.Armitage et al, 1998; Lichtman, 2006.
    16. 16. Clinical Behavior of NHL Subtypes Indolent Aggressive Very Aggressive CLL/SLL MCL Precursor B-lymphoblastic Lymphoplasmacytic/WM Follicle center lymphoma, lymphoma/leukemia follicular, grade 3 MZL B-cell acute leukemia DLBCL Follicle center lymphoma, Therapy undertaken follicular, grade 1/2 Primary mediastinal large with curative intent B-cell lymphoma Most are incurable Cure rates vary Require immediate therapy Goal is control and minimize symptoms Variable treatment goals Cure rates varyWM = Waldenström’s macroglobulinemia.Ansell et al, 2005; Goroll et al, 2009.
    17. 17. General Diagnostic Workup for Lymphoma  History and Physical – Physical exam • Particular attention to node-bearing areas, including Waldeyer’s ring, hepatomegaly, splenomegaly, abdominal masses, skin nodules • Presence of distal swelling or lymphedema – Performance status – B symptoms  Laboratory analysis  Tissue biopsy  Bone marrow biopsy and aspirate  Imaging studies for completion of stagingNCCN, 2012b.
    18. 18. Diagnostic Evaluation: Tissue Biopsy Diagnostic Study Clinical Significance Morphology – Review of cytology using low-power microscope to define basic architecture of the lymphatic tissue Immunohistochemistry – Excisional biopsy is the standard for initial diagnosis of NHL (fine needle aspirates are inadequate) – Used to isolate cellular proteins which correlate with phases of B-cell differentiation Flow cytometry – Immunophenotyping used to describe antigen expression on B-cells using peripheral blood and bone marrow – Used to correlate with the tissue biopsy for WHO classification of subtype Molecular profiling – Newer molecular profiling has identified key prognostic markers as well as potential targets for new therapiesWHO = World Health Organization.Kurtin, 2008; Morice et al, 2008; LeBien et al, 2008; NCCN, 2012b.
    19. 19. Diagnostic Evaluation: Peripheral Blood Diagnostic Study Clinical Significance CBC + differential + platelets – Evaluate presence of cytopenias, lymphocytosis, reticulocyte count morphological abnormalities, and bone marrow response to anemia LDH, haptoglobin, coombs, and – Evaluate for underlying hemolysis - particularly important reticulocyte count in CLL LDH – Necessary for risk stratification – Evaluate for aggressive disease, risk for TLS, and hemolysis Serum β2m – Prognostic relevance – Reflects WBC membrane turnover – Levels are affected by renal function Hepatic profile – Treatments have potential renal and hepatic toxicities or may be affected by renal or hepatic insufficiencies – Dose modification may be required for elevated bilirubin levels – Serum albumin reflects nutritional status and is used to estimate prognosisCBC = complete blood count; LDH = lactate dehydrogenase; β2m = beta-2-microglobulin; IPI = International Prognostic Index;TLS = tumor lysis syndrome; WBC = white blood cell.Federico et al, 2007; NCCN, 2012b; Kurtin, 2009; WebMD, 2010; MedlinePlus, 2012.
    20. 20. Diagnostic Evaluation: Bone Marrow Diagnostic Study Clinical Significance Aspirate – Evaluation of morphological abnormalities of hematopoietic Should include spicules and be precursors to allow WHO classification cellular enough to assess at least – Used for flow cytometry, FISH analysis, and cytogenetics 500 cells Biopsy Evaluate cellularity, topography, presence of lymphocytic infiltrates, Should be of adequate size for exclusion of other bone marrow disorders or infiltration by solid evaluation (1–2 cm) tumors Cytogenetics – Evaluate for possible non-random chromosomal abnormalities t(11;14) is the hallmark for MCL – Based on evaluation of 20 metaphases – Greater than 2 metaphases is considered non-random Molecular Testing Newer molecular profiling has identified key prognostic markers as well as potential targets for new therapiesFISH = fluorescent in situ hybridization.Kurtin, 2008; Jaffe et al, 2008; NCCN, 2012b.
    21. 21. Flow Cytometry: The Zip Code for Primary Cell Type of B-Cell NeoplasmsCML-LBC = chronic myeloid leukemia-lymphoid blast crisis; HL = Hodgkin lymphoma.LeBien et al, 2008.
    22. 22. Immunohistochemistry: Unraveling the Patchwork of B-Cell Malignancies Normal LN With Germinal Center and Surrounding MZL (C) Normal Germinal Center (F) MCL (D) ALL – Peripheral Growth Pattern Blood (A) and May Be Diffuse, BM (B) Nodular, or Blastoid FL (G) CLL in Peripheral Blood (E) DLBCL (H) Hodgkin Disease (J) HCL in Peripheral Blood (L) and BM (K) BL (I) MZL (M) PL (P) WM (N) MM (O)ALL = acute lymphoblastic leukemia; HCL = hairy cell leukemia; PL = plasmablastic lymphoma; MM = multiple myeloma.LeBien et al, 2008.
    23. 23. Diagnostic Evaluation: Imaging Diagnostic Study Clinical Significance MUGA scan or – Baseline evaluation for patients receiving anthracycline therapy echocardiogram CT chest, abdomen, and – Current standard of care for initial staging on NHL pelvis – Estimation of anatomic extent of disease and areas of abnormal LNs (> 1 cm) 18 FDG-PET – PET with FDG shows functional metabolic status reported as SUV – Useful in evaluation of LNs < 1 cm – Not useful in all subtypes of NHL – Scanning after a few cycles of therapy have been shown to predict treatment outcomes in MCL CXR – Baseline evaluation for any underlying disease and as a source of comparisonMUGA = multi-gated acquisition scan; CT = computed tomography; 18FDG-PET = 18-fluorodeoxyglucose-positron emission tomography;CXR = chest X-ray; LNs = lymph nodes; SUV = standardized uptake value.NCCN, 2012b; Kurtin, 2009; Dupuis et al, 2007; Podolofff et al, 2007.
    24. 24. The Role of PET  PET is most useful for aggressive lymphomas  More susceptible to false positives – Rituximab – Myeloid growth factors – If used for restaging, wait 8 wks after completion of chemotherapy/radiotherapy  PET/CT  notable radiation risk – NCCN: “optional”  Cost and conveniencePfreundschuh, 2010; Friedberg et al, 2003.
    25. 25. Recommendations for PET Scans in Lymphoma Therapy and Trials Histology Pre-Tx Mid-Tx Post-Tx F/U DLBCL Yesa Trial Only Yes No HL Yesa Trial Only Yes No FL Nob Trial Only Nob No MCL Nob Trial Only Nob No Other Aggressive NHL Nob Trial Only Nob,c No Other Indolent NHL Nob Trial Only Nob,c Noa Strongly recommended but not mandated.b Only if response is a primary study end point.c Only if PET+ pretreatment. HL = Hodgkin lymphoma; MCL = mantle cell lymphoma; Tx = treatment; F/U = follow-up. Seam et al, 2007.
    26. 26. Risk Stratification in NHL: IPI, FLIPI, MIPI, and Beyond  Risk stratification systems – IPI: Diffuse Large B-Cell Lymphoma – FLIPI: Follicular Lymphoma – MIPI: Mantle Cell Lymphoma  Cytogenetic and molecular factors – Hallmark translocations for common subtypes with associated molecular abnormalitiesNCCN, 2012b.
    27. 27. IPI Stratifies Risk by Clinical Factors in Aggressive NHL  Prognostic factors (APLES) 100 OS (all) – Age > 60 yrs – PS > 1 Patients 50 L (%) LI – LDH > 1 x normal HI – Extranodal sites > 1 H 0 – Stage III or stage IV 0 2 4 6 8 10  Risk category 100 OS (age ≤ 60)  Factors L Patients Low (L) 0 or 1 (%) 50 LI Low-Intermediate (LI) 2 HI High-Intermediate (HI) 3 H High (H) 4 or 5 0 0 2 4 6 8 10Extranodal sites of disease are excluded from the AAIPI.aPS = performance status; AAIPI = age-adjusted IPI.Sehn et al, 2007.
    28. 28. Revised IPI Criteria  Proposes 3 risk groups based on the number of IPI risk factors with recommendations for treatment strategies  Very good = no risk factors – 90% chance of long-term PFS – Large trials will be necessary to propose treatment approaches other than CHOP-R  Good = 1–2 risk factors – 80% chance of long-term PFS – Treatment strategies without excessive toxicity will be necessary due to favorable survival  Poor = 3–5 risk factors A = PFS in 365 patients treated with CHOP-R – 50% chance of long-term PFS – Clinical trials are recommended to evaluate disease characteristics and novel treatment approachesCHOP-R = cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab; PFS = progression-free survival.Sehn et al, 2007.
    29. 29. Follicular Lymphoma IPI Survival as defined by FLIPI  FLIPI Risk Factors 1.0 Low Risk (0–1) (1 patient each) Survival Probability (%) 0.8 – Age > 60 yrs Intermediate Risk (2) – LDH > ULN 0.6 – Hgb < 12 g/dL High Risk (≥ 3) 0.4 – Ann Arbor stage III/IV – > 4 involved node 0.2 regions N = 1,795 0.0 12 24 36 48 60 72 84 96 Time (mos)ULN = upper limt of normal; Hgb = hemoglobin.Solal-Céligny, 2006.
    30. 30. Gene Profiling and Survival Rates in Different DLBCL Genetic Groups Activated B-cell–like diffuse Germinal center B-cell–like Primary mediastinal large B-cell lymphoma (ABC) (GCB) B-cell lymphoma (PMBL) G e n e s Lymphoma Biopsies 1.0 0.8 5-Yr Survival Probability (%) 0.6 PMBL 64% GCB 59% 0.4 0.2 ABC 30% 0 0 2 4 6 8 10 OS (Yrs)Dave et al, 2006; Rosenwald et al, 2003; Lenz et al, 2008.
    31. 31. Mantle Cell Lymphoma IPI  Established in 2008 to identify OS According to MIPI prognostic factors relevant to MCL  Multivariate analysis of 455 patients 1.0 0.9 from 3 randomized clinical trials Probability of OS (%) 0.8  4 independent prognostic factors for 0.7 survival (age, PS, LDH, leukocyte 0.6 0.5 counts) 0.4 – LR: 0–3 points 0.3 – IR: 4–5 points 0.2 – HR: 6–11 points 0.1 p = .108 0  Ann Arbor stage, BM involvement, 0 12 24 36 48 60 72 84 96 number of extranodal sites used in Time (mos since registration) the IPI were not prognostically relevant in MCL LR: Median not reached  More recent studies have added the IR: Median 51 proliferation index (Ki67 > 30) HR: Median 29 PS = performance score; LR = low risk; IR = intermediate risk; HR = high risk.Hoster et al, 2008; Smith, 2008; Schaffel et al, 2010.
    32. 32. Molecular Indices in Lymphocytic Malignancies Lymphoma Morphology Immunophenotyping Common Molecular Testing Subtype Favorable = f Cytogenetic Unfavorable = u Abnormalities Diffuse large Diffuse pattern with CD20+, CD45+, CD3- T(14;18), t(3;v), Testing for bcl-2, bcl-1, B-cell (DLBCL) distortion of the normal t(8;14) c-myc architecture of the All offer a survival lymph node or advantage to the lymphoma extranodal site cells. u Follicular Nodal lymphoma with a CD10+,CD20+, sIg+, T(14;18)(q32;q21) IgH re-arrangement with lymphoma (FL) follicular growth pattern CD23 , CD22 , CD25 +/- + +/- 85% bcl-2 expression which leads to cellular resistance to apoptosis u Small Usually appear normal, CD5+, CD20dim+, sIgdim+, Trisomy 12 Patients with variable region lymphocytic may be large, smudge CD23+, CD22-, CD25-(+) t(11q;v) u Ig mutations have a more lymphoma/ cells may be present, CD38+ - u del(11q) u favorable prognosis u chronic pro-lymphocytes are del(17p) u lymphocytic common del(13q) f leukemiaKurtin, 2009.
    33. 33. Molecular Indices in Lymphocytic Malignancies (cont.) Lymphoma Morphology Immunophenotyping Common Molecular Testing Subtype Favorable = f Cytogenetic Unfavorable = u Abnormalities Mantle cell Cells populating CD5+, CD20+, sIg+, t(11;14) IgH re-arrangement lymphoma the mantle zone CD22+, CD45+ (q13;q32) with bcl-1 (increased (MCL) of the follicle CD10-, CD23-, CD25- de-regulates cell proliferation), and Cyclin D1+ Cyclin D1 bcl-6 expression expression (resistance to interfering with apoptosis) u cell cycle regulation Peripheral Peripheral T- CD4+, CD7-, CD8- Clonal re- T-cell cells and no arrangements of the lymphoma features of other receptor genes seen (PTLC) subtypes in non-cancerous T-cell disease are commonKurtin, 2009.
    34. 34. Response Criteria for NHL (not including PET) Response Physical LNs LN Masses BM Category Examination CR Normal Normal Normal Normal Normal or CRu Normal Normal > 75% decrease indeterminate Positive or Normal or irrelevant if Normal or ≥ 50% Normal or ≥ 50% PR decrease in other decrease decrease liver/spleen parameters are not normal Enlarging Relapse/ New or liver/spleen or New or increased Reappearance Progression increased new sitesPET = positron-emission tomography; CR = complete response; CRu = complete response unconfirmed; PR = partial response.NCCN, 2012b.
    35. 35. Revised Response Criteria for NHL (including PET) Response Definition Nodal Masses Spleen, Liver BM Infiltrate cleared on a) FDG-avid or PET+ prior to therapy; mass of repeat biopsy; if Disappearance of any size permitted if PET- Not palpable, indeterminate by CR all evidence of nodules morphology, disease b) Variably FDG-avid or PET-; regression to disappeared normal size on CT immunohistochemistry should be negative ≥ 50% decrease 50% decrease in SPD of up to 6 largest in SPD of dominant masses; no increase in size of other nodules (for Regression of nodes Irrelevant if positive single nodule in measurable prior to therapy; cell PR disease and no b)FDG-avid or PET+ prior to therapy; 1 or more greatest type should be PET+ at previously involved site transverse new sites specified diameter); no c)Variably FDG-avid or PET-; regression on CT increase in size of liver or spleen a) FDG-avid or PET+ prior to therapy; PET+ at prior sites of disease and no new sites on CT Failure to attain or PET SD CR/PR or PD b) Variably FDG-avid or PET-; no change in size of previous lesions on CT Appearance of new lesion > 1.5 cm in any axis, Any new lesion or ≥ 50% increase in SPD of > 1 node or ≥ 50% Relapsed > 50% increase increase by ≥ 50% increase in longest diameter of a previously from nadir in the New or recurrent Disease of previously identified node > 1 cm in sort axis SPD of any involvement or PD involved sites from Lesions PET+ if FDG-avid lymphoma or PET+ previous lesions nadir prior to therapySD = stable disease; PD = progressive disease; FDG = fludeoxyglucose; SPD = sum of the product of the diameter.NCCN, 2012b.
    36. 36. General Treatment Strategies  Dependent on – Type of disease – Indolent or aggressive – Age of patient – General health/comorbidities – Initial/relapsed/refractory/transformed NHLNCCN, 2012b.
    37. 37. Key Takeaways Non-Hodgkin lymphomas are a heterogeneous group of neoplasms with differing patterns of growth and response to treatment Several prognostic indices have been developed that have predictive and prognostic significance Diagnosis requires bone marrow evaluation, peripheral blood tests, tissue biopsy, and/or imaging Revised treatment response criteria take into account PET scan results, physical exam, and bone marrow findings
    38. 38. Diffuse Large B-Cell Lymphoma Kevin E. Brigle, PhD, NP Massey Cancer Center atVirginia Commonwealth University Hospital System
    39. 39. Diffuse Large B-Cell Lymphoma  Most common form of adult NHL: 30% – Peak incidence in 6th decade  Curable in 40% or more of cases but median survival weeks to months if not treated  Complex and heterogeneous disease with variable clinical outcomes – WHO classification includes 15 subtypes – Molecular classification includes 3 subtypes  Large cells with loss of follicular architecture of the node – 30%–40% present with a rapidly enlarging, symptomatic mass with B symptoms – May present as extranodal disease (stomach, CNS, testis, skin)Michallet et al, 2009.
    40. 40. Gene Profiling and Survival Rates in Different DLBCL Genetic Groups Activated B-cell–like diffuse Germinal center B-cell–like Primary mediastinal large B-cell lymphoma (ABC) (GCB) B-cell lymphoma (PMBL) G e n e s Lymphoma Biopsies 1.0 0.8 5-Yr Survival Probability (%) 0.6 PMBL 64% GCB 59% 0.4 0.2 ABC 30% 0 0 2 4 6 8 10 OS (Yrs)Dave et al, 2006; Rosenwald et al, 2003; Lenz et al, 2008.
    41. 41. Molecular Markers and Survival Molecular Marker bcl-2 bcl-6 Activated CD 10 GCET1 FoxP Cell of Origin expression expression NF-kappa B expression expression expression - + - + + - Germinal Center B-Cell like (GCB) + - + - - + Activated B-Cell like (ABC) 74% 40% 3-yearLenz et al, 2010.
    42. 42. Evaluating the New Patient With DLBCL All Patients Selected Patients • Coagulation studies • History and physical • Erythrocyte sed rate • B symptoms • General • HBV, HCV, HIV Performance status Serum β2m workup • Labs: CBC, differential, • LDH, CMP • Uric acid, phosphate • Pregnancy testing in women of child-bearing potential • Lymph node biopsy • Hematopathology review Identification • Immunophenotyping • Ki-67 index of subtypes • Molecular studies • Cytogenetic studies • CT scan: neck, trunk, pelvis • PET scan Staging • MRI • Bone marrow biopsy • Ultrasound • Lumbar puncture, if paranasal sinus, testicular, Site-specific epidural, bone marrow involvement with large cell assessment, lymphoma, HIV lymphoma or ≥ 2 extranodal sites occult • Thoracentesis involvement • MUGA scan/echocardiogramCBC = complete blood count; CMP = complete metabolic panel; CT = computed tomography; LDH = lactate dehydrogenase;MRI = magnetic resonance imaging; MUGA = multigated acquisition scan; PET = positron emission tomography.NCCN, 2012b.
    43. 43. The Fusion PET/CT Scan for Staging  Provides information on both structure and activity  Recommended both pre- and post-treatment – PET negative complete response at end of treatment associated with longer PFS – Role of interim PET less clearNCCN, 2012b.
    44. 44. Interim PET Analysis in DLBCL  Study of 112 patients with DLBCL treated with rituximab- anthracycline-based chemotherapy had an interim PET after 2 cycles of therapy  Positive/Negative PET scans were significantly predictive of both PFS and OS (p < .001 and p = .003, respectively) – 3-yr PFS 84% with negative PET vs. 47% with positive PET – 3-yr OS 88% with negative PET vs. 62% with positive PET  May lead to an early change in treatment strategy – Decrease therapy (side effects) for good responders – Intensify treatment for poor respondersSafar et al, 2012.
    45. 45. Initial Treatment Regimens First-Line Therapy NCCN Category R-CHOP 1 Dose-Dense R-CHOP 14 2B Dose-Adjusted R-EPOCH 2B For Patients With Poor Left Ventricular Function R-CEPP 2A R-CDOP 2A R-CNOP 2A Dose-Adjusted R-EPOCH 2A R-CEOP 2A First-Line Consolidation HDT with autologous stem cell transplant in high-risk 2B patientsRCHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; EPOCH = etoposide, prednisone, vincristine, cyclophosphamide,doxorubicin; RCEPP = rituximab, cyclophosphamide, etoposide, prednisone, procarbazine;RCDOP = rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, prednisone; RCNOP = rituximab, cyclophosphamide,mitoxantrone, vincristine, prednisone; DA-EPOCH = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin;RCEOP = rituximab, cyclophosphamide, etoposide, vincristine, prednisone; HDT = high-dose therapy.NCCN, 2012b.
    46. 46. First-Line Consolidation With HDT and ASCT  No clear consensus but recommended if patient has high risk of recurrence – < 60 yrs of age – High LDH level at diagnosis – Multiple extranodal sites of disease – Ann Arbor stage III or stage IV disease – IPI 4–5ASCT = autologous stem cell transplant.NCCN, 2012b.
    47. 47. Treatment by Stage for DLBCL Disease Stage Regimens Localized disease (stage I, II) (considerations based on nonbulky vs. • R-CHOP x 3 cycles + RT bulky > 10 cm and whether adverse risk • R-CHOP x 6 cycles ± RT factors present in nonbulky disease) • R-CHOP x 6 cycles Advanced disease (stage III, IV) • Clinical trialsR-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; RT = radiation therapy.NCCN, 2012b.
    48. 48. Second-Line Therapy for DLBCL Patient Considerations Regimens • DHAP ± rituximab • ESHAP ± rituximab Patients who are candidates for HDT • GDP ± rituximab with ASCT • GemOx ± rituximab • ICE ± rituximab • MINE ± rituximab • Clinical trial • Rituximab • CEPP ± rituximab Patients who are not candidates for • Lenalidomide ± rituximab HDT with ASCT • CEOP ± rituximab • DA-EPOCH ± rituximab • GDP ± rituximab • GemOx ± rituximabCEPP = cyclophosphamide, etoposide, prednisone, procarbazine; DHAP = dexamethasone, cisplatin, cytarabine;DA-EPOCH = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; ESHAP = etoposide, methylprednisone, cytarabine,cisplatin, GDP = gemcitabine, dexamethasone, cisplatin; GemOx = gemcitabine, oxaliplatin; ICE = ifosfomide, carboplatin, etoposide;MINE = mesna, ifosfamide, mitoxantrone, etoposide; CEOP = cyclophosphamide, etoposide, vincristine, prednisone.NCCN, 2012b.
    49. 49. HDT With ASCT in Relapsed/Refractory DLBCL  HDT with ASCT is the treatment of choice for relapsed or refractory DLBCL  Patients require salvage therapy prior to ASCT – No single preferred salvage regimen – Transplant recommended only for chemo-sensitive disease – May be combined with radiotherapy for better local control  Patients relapsing after ASCT should be treated on a clinical trial or with best supportive care  Allogeneic transplantation has shown limited benefit in multiple relapsed disease – High non-relapse mortality – Minimal graft vs. lymphoma effectNCCN, 2012b; Dreger, 2011; van Kampen et al, 2011; Rigacci et al, 2012.
    50. 50. Prevention of CNS Relapse  CNS involvement uncommon at diagnosis – Most events occur during therapy or shortly after completion of treatment – Risk estimated 2%–7% and median survival is < 6 months  Risk factors include paranasal sinus, testicular, epidural, or bone marrow involvement, HIV lymphoma, or ≥ 2 extranodal sites but predictive models are poor  Benefit of CNS prophylaxis is controversial as studies have been equivocal – Intrathecal chemotherapy with 4–6 doses methotrexate or cytarabine • NCCN recommended but little supporting data, inconsistent tissue concentrations, poor brain penetration – High dose (> 3 g/m2 methotrexate) • Higher toxicity but better CNS penetration and distribution – Should be given early in the course of treatment for systemic diseaseNCCN, 2012b.
    51. 51. DLBCL Key Takeaways DLBCL is a heterogeneous disease with unique molecular subtypes that respond differently to treatment – Gene profiling may lead to tailored treatment plans R-CHOP chemotherapy continues to be the standard of care – For patients with cardiac dysfunction, non-anthracycline containing regimens are recommended CNS relapse is rare but occurs early in the course of the disease and carries a poor prognosis – Chemo-prophylaxis remains controversial PET scans are recommended pre- and post-treatment – Use early in therapy to guide treatment requires further study HDT with ASCT is the standard for relapsed disease
    52. 52. Tumor Lysis Syndrome (TLS)  Oncologic emergency that occurs as a result of rapid tumor cell breakdown and the consequent release of intracellular contents – Commonly occurs following cytotoxic therapy – Occurs spontaneously in rapidly growing cells  Mainly involves calcium, phosphorous, potassium, and uric acid – Levels increase too rapidly for the body’s homeostatic mechanisms to deal with – Renal excretion is the primary means of clearing these ions and optimal management involves preservation of renal function  May lead to acute kidney failure, cardiac arrhythmias and sudden death, seizures, and neuromuscular irritability  Primary management involves identifying patients at risk and starting treatment prior to initiating chemotherapyNCCN, 2012b; Elitek® prescribing information, 2011.
    53. 53. Features of TLS Salient Features of TLS • High potassium (> 6.0 nmol/L), phosphorus (> 4.5 mg/dL), Lab Hallmarks and uric acid (> 8.0 mg/dL) • Low calcium (< 7.0 mg/dL corrected) Clinical • Nausea and vomiting, shortness of breath, irregular heartbeat, Symptoms clouding of urine, lethargy, joint discomfort • Burkitt’s and lymphoblastic lymphoma, occasionally DLCBL and CLL • Elevated WBC and bulky tumors • Bone marrow involvement and organ infiltration by cancer cells • Renal disease or renal involvement by tumor High-Risk • Dehydration Features • Exposure to nephrotoxins (IV contrast, NSAIDs) • Spontaneous TLS • Pre-existing elevated uric acid • Ineffectiveness of allopurinolNCCN, 2012b.
    54. 54. TLS PathophysiologyHoward et al, 2011.
    55. 55. TLS: Prevention and Treatment  Identify patients at risk – Obtain baseline labs and identify disease- and patient-related risk factors  Initiate allopurinol – Oral xanthine-oxidase inhibitor that blocks production of UA (takes several days to impact UA levels) – Begin 2–3 days prior to chemotherapy and continue for 10–14 days  Utilize rasburicase – Recombinant urate oxidase (enzyme not found in humans) that catalyzes UA to a soluble compound with a peak effect in 4 hours – Given 0.2 mg/kg IV over 30 mins and may be repeated once daily – Black box warnings: Anaphylaxis and hemolysis in patients with G6PD deficiency – Indicated for patients with high-risk features, especially compromised renal function and those presenting with spontaneous TLSUA = uric acid.NCCN, 2012b.
    56. 56. TLS: Prevention and Treatment (cont.)  Aggressive intravenous fluid and monitoring of urine output  Frequent monitoring of electrolytes, UA, and creatinine q4–8hrs  Telemetry for hyperkalemia  Decrease the rate of tumor lysis with the use of low intensity initial therapy prior to starting initial therapy – Common in Burkitt’s lymphoma regimensNCCN, 2012b.
    57. 57. Anthracycline-Induced Cardiomyopathy  Clinical heart failure: 1%–5%  Asymptomatic decrease in left ventricular function: 5%–20%  Impacts long-term survival and quality of life  Reduces range of suitable anticancer therapies  Cause unclear but likely multifactorial – Free radical-mediated myocyte damage – Circulating pro-inflammatory cytokinesGranger, 2006.
    58. 58. Anthracycline-Induced Cardiomyopathy Risk Factors Risk Factor Comment • Cumulative dose • Higher incidence as cumulative dose increases • Rate of administration • Bolus dosing more toxic than CIV • Concurrent or prior mediastinal • Especially radiation to left side of chest radiation • Concomitant administration of other • Cyclophosphamide, ifosfamide, cardiotoxic drugs methotrexate, cytarabine • Age at time of exposure • < 18 yrs or > 65 yrs have greater risk at lower cumulative doses • Female • Unclear • Pre-existing cardiovascular disease • CAD, hypertension, left ventricular dysfunction • Longer duration of survival • Chronic cardiotoxicity may occur > 30 yrs after completion of treatmentDolci et al, 2008; Shakir et al, 2009.
    59. 59. Types of Anthracycline-Induced Cardiomyopathy Type Onset Main Features • Uncommon and transient; Immediately after • May involve transient ECG abnormalities (ST and T Acute single dose or wave changes, QT interval prolongation and course of therapy arrhythmias) and rarely, CHF and pericarditis/myocarditis syndromes • Most frequent type and related to cumulative anthracycline dose Within 1 yr of Early-onset • Often starts with asymptomatic decline in myocardial therapy; typically chronic function and then manifests as CHF with ventricular rapid onset and progressive dilation, pulmonary and venous congestion, poor progression perfusion, and pleural effusions • Frequently unresponsive to therapy • Often starts with asymptomatic decline or with Late-onset symptoms of clinical heart failure 1 yr to decades chronic • Ultimately, manifests as symptomatic CHF as a result of after therapy progressive slowly progressive decline following earlier myocyte injuryMaradia et al, 2009; Shakir et al, 2009.
    60. 60. Anthracycline-Induced Cardiomyopathy Cumulative Doxorubicin Dose (mg/m2) Incidence (%) 300 1–2 400 3–5 450 5–8 500 6–20  The risk of developing CHF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 400 mg/m2Adriamycin® prescribing information, 2006.
    61. 61. Common Cumulative Doses of Doxorubicin Regimen Cumulative Doxorubicin (mg/m2) R-CHOP x 6 50 mg/m2 per cycle 300 R-EPOCH x 6 40 mg/m2 per cycle (10 mg/m2/day CIV Days 1–4) Note: Doxorubicin dose may progressively 240–397 increase with DA-EPOCH R-HyperCVAD x 4 50 mg/m2 CIV Day 4 each cycle 200 < 5% risk based on anthracycline exposure for first-line treatment
    62. 62. Monitoring High-Risk Patients  There are no specific guidelines for monitoring for chemotherapy- induced cardiomyopathy  Serial monitoring: Baseline, throughout treatment, and post treatment  Monitor for signs and symptoms by – Physical exam – ECHO, radionuclide angiography (MUGA), EKG – CXR – Troponin levels  Following therapy, provide a survivor care plan for the patient and their other providers related to their cancer treatment and its potential long-term side effectsDolci et al, 2088; Cardinale et al, 2006.
    63. 63. Preventing Cardiomyopathy in High Risk Patients  Maintain adequate blood pressure control (all patients)  Be aware of total cumulative anthracycline dose (all patients)  Use continuous infusion dosing  Add cardioprotectants (dexrazoxane)  Use anthracycline analogs – Pixantrone (R-CPOP) 2011 ASH Annual Meeting Abstract 4966 – Liposomal anthracycline (R-COMP14)  Use of non anthracycline-containing regimens – Gemcitabine (R-GCVP) 2011 ASH Annual Meeting Abstract 1634Cardinale et al, 2006; Fields et al, 2011; Herbrecht et al, 2011.
    64. 64. Anthracycline-Induced Cardiomyopathy Treatment  ACE inhibitors – Enalapril  Beta blockers – Carvedilol  Appropriate supportive care – Diuretics – Weight monitoring – Fluid restriction  Assistive devices  Heart transplant if permanent damageACE = angiotensin-converting enzyme.Dolci et al, 2008; Shakir et al, 2009.
    65. 65. Anthracycline-Induced Cardiomyopathy Patient Education  Discuss short- and long-term risks based on individual patient risk assessment and treatment  Discuss the plan for monitoring before, during, and after treatment  Educate patients about the signs and symptoms of heart failure and convey the importance of prompt reporting  Encourage strict compliance with current cardiac medications to avoid serious, negative, long-term sequelae  Provide a survivor care plan for the patient and their other providers related to their cancer treatment and its potential long-term side effectsShakir et al, 2009; Granger, 2006.
    66. 66. TLS Case Study  62-yr-old Caucasian man with a PMH of hypertension and hypercholesterolemia both well controlled with HCTZ, amlodipine, and simvastatin. He also takes ASA 81 mg.  Diagnosis: Ann Arbor Stage IVB DLBCL with bulky abdominal LAN, spleen and bone marrow involvement – IPI stage high intermediate (age > 60, stage IV, ↑LDH) – Drenching night sweats, 20 pound unintentional weight loss – Persistent nausea  Baseline studies – Echocardiogram 62% LVEF – Normal EKGPMH = past medical history; LAN = lymphadenopathy; LDH = lactate dehydrogenase; LVEF = left ventricular ejection fraction.Shakir et al, 2009; Granger, 2006.
    67. 67. TLS Case Study (cont.)  Baseline laboratory analysis – WBC: 6.0 × 109/L (normal); Hgb: 11.2 g/dL (low); Platelets: 135 × 109/L (low) – Potassium: 5.9 nmol/L (high), Phosphorous: 3.8 mg/dL (normal), UA: 10.8 mg/dL (high), Corrected Calcium: 7.2 mg/dL (low) – LDH: 920 U/L (250 U/L ULN - high) – BUN/creatinine: 30/1.3 mg/dL (high), Creatinine Clearance: 70 ml/min (low) – LFTs: normal  Clinical Decisions: – What therapy would he receive to treat his disease? – How would you interpret his laboratory data? – What are his risk factors for TLS? – What specific steps should be taken to prevent or treat TLS in this patient?Shakir et al, 2009; Granger, 2006.
    68. 68. Cardiotoxicity Case Study  67-yr-old Caucasian woman with PMH of HTN and osteoporosis. Meds include HCTZ, monthly ibandronate, and Calcium-Vitamin D.  Diagnosis: Ann Arbor Stage IIIA DLBCL with cervical, axillary, and inguinal LAN – IPI stage high intermediate (age > 60, ↑ LDH, stage III) – Asymptomatic  Baseline studies – Echocardiogram 54% LVEF – Normal EKGShakir et al, 2009; Granger, 2006.
    69. 69. Cardiotoxicity Case Study (cont.)  Baseline laboratory analysis – WBC: 5.2 × 109/L (normal); Hgb: 11.5 g/dL (low); Platelets: 205 × 109/L (normal) – Potassium: 3.5 nmol/L (low), Phosphorous: 2.7 mg/dL (normal), UA: 5.1 mg/dL (normal), Corrected Calcium: 8.1 mg/dL (low) – LDH: 305 U/dL (250 U/L ULN - high) – BUN/creatinine: 17/1.0 mg/dL (normal), Creatinine Clearance: 80 ml/min (low) – LFTs: normal except ALT 75 U/L (high)  Clinical Decisions: – What therapy would she receive to treat her disease? – How would you interpret her laboratory data? – What are her risk factors for anthracycline-induced cardiomyopathy? – What specific steps would you take to monitor for or prevent anthracycline- induced cardiotoxicity?Shakir et al, 2009; Granger, 2006.
    70. 70. T-Cell Non-Hodgkin LymphomaBarbara Barnes Rogers, MN, CRNP, ANP-BC, AOCN® Fox Chase Cancer Center
    71. 71. NHL Subtypes N = 1,403REAL = Revised European American Lymphoma; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma;MCL = mantle cell lymphoma; PTCL = peripheral T-cell lymphoma; SLL = small lymphocytic lymphoma.Armitage et al, 1998; Lichtman, 2006.
    72. 72. 2008 WHO Classification of T-Cell Neoplasms Cutaneous Extranodal Nodal Leukemic T-cell Prolymphocytic Mycosis Fungoides Extranodal NK/TCL, Peripheral TCL-NOS Leukemia Nasal Type T-Cell Large Granular Sézary Syndrome Angioimmunoblastic Lymphocytic Leukemia Enteropathy- TCL Primary Cutaneous Aggressive NK-cell Associated TCL Leukemia CD30+ Lymphoproliferative Anaplastic Large Cell Adult T-Cell Disorders: Hepatosplenic TCL Lymphoma (ALK +) Leukemia/Lymphoma •Primary Cutaneous ALCL Chronic •Lymphomatoid Papulosis* Lymphoproliferative •Borderline Lesions Subcutaneous Anaplastic Large Cell disorders of NK cells Panniculitis-Like TCL Lymphoma (ALK -) Primary cutaneous EBV+ T-cell peripheral T-cell Lymphoproliferative disorders of Childhood lymphomas, rare subtypes: Systemic EBV+ T-cell •Primary Cutaneous γδ TCL Lymphoproliferative •Primary Cutaneous CD8+ Disease of Childhood aggressive epidermotropic TCL •Primary Cutaneous CD4+ Hydroa Vacciniforme-like small/medium TCL LymphomaJaffe et al, 2008.
    73. 73. Peripheral T-Cell Lymphoma SubtypesALCL = anaplastic large-cell lymphoma; ALK = anaplastic lymphoma kinase; PTCL = peripheral T-cell lymphoma.International T-Cell Lymphoma Project, 2008; O’Leary et al, 2009; de Leval et al, 2008.
    74. 74. Presenting Symptoms of PTCL  Generalized lymphadenopathy  Mild anemia or thrombocytopenia  B symptoms (fevers, weight loss, and night sweats)  Extranodal disease – Spleen – Liver – Bone Marrow – Skin  RashRodriguez-Abreau, 2008.
    75. 75. Clinical Presentations of PTCL and B-Cell Lymphoma Clinical Characteristics PTCL (%) BCL (%) Disseminated disease 78 58 B symptoms 57 40 Bone marrow positive 31 17 Skin lesions 21 4Gisselbrecht et al, 1998.
    76. 76. Workup of Patients With Suspected TCL  Physical exam  Radiographic test  Biopsy – CT scan of – Lymph node chest/abdomen/pelvis – Bone marrow – PET/CT scan – Head CT or MRI  Laboratory tests (if appropriate) – Complete blood count with differential, platelets  Calculation of IPI or PIT – Comprehensive metabolic panel  Discussions of fertility issues • Hepatic transaminase levels (AST, ALT) • Alkaline phosphatase • LDH • Uric AcidALT = alanine aminotransferase; AST = aspartate aminotransferase; LDH = lactate dehydrogenase;IPI = International Prognostic Index; PIT = Prognostic Indicator PTCL-NOS.Yarbro et al, 2000.
    77. 77. IPI/PIT: Prognostic Indices for PTCL-NOS Prognostic Factors OS: PIT N = 322 IPI PIT Age Age PS PS LDH LDH Stage BM involvement No. of extranodal sitesGallamini et al, 2004; Ansell et al, 1997.
    78. 78. Overall Survival in PTCL The International PTCL and NK/T-Cell Lymphoma Study PTCL Subtypes ALK+ ALK– PTCL- NK/T-Cell AITL ATLL ALCL ALCL NOS Lymphoma 5-Yr OS Rate (%) 70 49 32 32 32 14ATLL = adult T-cell leukemia/lymphoma; OS = overall survival.International T-Cell Lymphoma Project, 2008.
    79. 79. Front-Line Treatment Regimens for Management of PTCL  Front-line chemotherapy typically consists of doxorubicin-containing regimens – CHOP – HyperCVAD alternating with high-dose methotrexate and cytarabine  No clear benefit from use of anthracycline-containing regimen  No universally agreed-upon standard treatment  Other combinations – CHOP plus alemtuzumab (ORR 75%–80%; OS 2 yrs 53%; PFS 2 yrs 48%) – CHOP plus denileukin diftitox (ORR 80%–100%, depending on subtype; PFS 2 yrs 41%) – CHOP plus rituximab (ORR 80%, CR 44%, 2-yr PFS 43%, OS 62%): No better than CHOP aloneCHOP = cyclophosphamide, doxorubicin, vincristine, prednisone;HyperCVAD = cyclophosphamide, vincristine, doxorubicin, dexamethasone.Lichtman, 2006; Foss, 2009.
    80. 80. ASCT in the Management of PTCL  Front-line consolidation with high-dose chemotherapy and stem cell rescue – For all patients except those who are low risk and those with ALK+ ALCL – Is controversial, based on retrospective and phase II data – Multiple phase II trials • Overall Survival = 39%–73% (3 yrs) • Event-free Survival = 30% (4 yrs) • Transplant-related Mortality = 4% – Patients with high IPI/PIT score might not benefit from ASCTIPI = International Prognostic Index; PIT = Prognostic Index for T-cell lymphoma.Reimer et al, 2009; Mercadal et al, 2008; Rodriguez et al, 2007.
    81. 81. ASCT as First-Line Therapy in PTCL: Survival OS in Transplanted and Non-Transplanted Patients Transplanted (n = 55) (n = 83) Non-transplanted (n = 28)Reimer et al, 2009.
    82. 82. Treatment Options for PTCL  Romidepsin  Pralatrexate – ORR 30%–38%, CR 16% – ORR 27%, CR 6% – DOR 8.3–12 mos – DOR 9.4 mos – Side effects: Anemia, leukopenia, – Side effects: Stomatitis, neutropenia, thrombocytopenia, thrombocytopenia, nausea, fatigue, infection, EKG changes, asthenia, anemia, neutropenia, dyspnea, decreased appetite, headache, hypokalemia, altered LFTs, cough, rigors, weight loss abdominal pain, leukopenia, febrile neutropenia, sepsis, hypotension  Brentuximab Vedotin – B12 and folate supplements – ORR 86%, CR 53% administered to minimize toxicity – DOR 12.6 mos (myelosuppression and stomatitis – Side effects: Peripheral neuropathy, nausea, fatigue, pyrexia, diarrhea, rash, constipation, neutropeniaORR = overall response rate; DOR = duration of response.O’leary & Salvage, 2008.
    83. 83. Treatment Options for PTCL (cont.)  Denileukin diftitox  Alemtuzumab – ORR 50%, Cr 30% for CD25+, – ORR 36%–50%, CR 21%–33% 18% for CD25- – Side effects: Anemia, neutropenia, – DOR 8 mos thrombocytopenia, fever, infection, – Side effects: Fever, fatigue, rigors, viremia (CMV, EBV), hypotension, nausea, headache, edema, cough, rash, urticaria, diarrhea, nausea, dyspnea, pruritus, rash, vomiting, myalgias, insomnia, hypotension, back pain, myalgia, anxiety, bronchospasm, dyspnea chest pain, tachycardia, hypoalbuminemia, asthenia, altered LFTs, capillary leak syndrome, infusion reactions, visual impairmentORR = overall response rate; DOR = duration of response.O’leary & Salvage, 2008.
    84. 84. Therapies Under Investigation for the Management of PTCL Class of Agent Agent HDAC inhibitors • Vorinostat Farnesyl transferase inhibitors • Tipifarnib Multikinase inhibitors • Dasatinib IMIDS • Lenalidomide Proteasome inhibitors • Bortezomib Investigational agents • Belinostat • Plitidepsin • ZanolimumabClinicaltrials.gov
    85. 85. Management of PTCL: How to Improve Beyond CHOP? CHOP will not cure most patients with PTCL Transplant might consolidate remissions – But we need better front-line therapies New combinations make sense with the blockade of different pathways Limited number of patients on clinical trials Slow to make progress
    86. 86. Cutaneous T-Cell Lymphoma
    87. 87. Patient With Stage IB Disease With Folliculotropic Plaques on the Trunk© 2009 by American Society of Hematology; Prince et al, 2009.
    88. 88. Patient With Stage IB Disease With Patches and Thin Plaques© 2009 by American Society of Hematology; Prince et al, 2009.
    89. 89. Mycosis Fungoides: Tumor StageHabif, 2010.
    90. 90. Mycosis Fungoides: TNM Staging System Primary Tumor (T) – T1: Limited patch/plaque (< 10% of skin surface involved) – T2: Generalized patch/plaque (> 10% of skin surface involved) – T3: Cutaneous tumors (one or more > 1cm in diameter) – T4: Generalized erythroderma (with or without patches, plaques or tumors) > 80% body surface area Regional Lymph Nodes (N) – N0: No clinically abnormal peripheral lymph nodes; biopsy not required – N1: Clinically abnormal peripheral lymph nodes; histopathology Dutch Gr1 or NCI LN 0–2 – N2: Clinically abnormal peripheral lymph nodes; histopathology Dutch Gr2 or NCI LN 3 – N3: Clinically abnormal peripheral lymph nodes; histopathology Dutch Gr3–4 or NCI LN 4 – NX: Clinically abnormal peripheral lymph nodes; no histologic confirmationNCCN, 2012b.
    91. 91. Mycosis Fungoides: TNM Staging System (cont.)  Visceral (M) – M0: No visceral organ involvement – M1: Visceral disease present (must have pathology confirmation)  Blood Involvement (B) – B0: Absence of significant blood involvement: < 5% of peripheral blood lymphocytes are atypical (Sézary) cells – B1: Low tumor burden: > 5% of peripheral blood lymphocytes are atypical (Sézary) cells but does not meet the criteria for B2 – B2: High tumor burden: > 1,000/mcL Sézary cellsNCCN, 2012b.
    92. 92. Mycosis Fungoides: TNM Staging System (cont.)  Stage IA: T1, N0, M0, B0-1  Stage IB: T2, N0, M0, B0-1  Stage IIA: T1-T2, N1-2, M0, B0-1  Stage IIB: T3, N0-N2, M0, B0-1  Stage IIIA: T4, N0-2, M0, B0  Stage IIIB: T4, N0-2, M0, B1  Stage IVA1: T1-T4, N0-2, M0, B2  Stage IVA2: T1-4, N3, M0, B0-2  Stage IVB: T1-4, N0-3, M1, B0-2NCCN, 2012b.
    93. 93. Sézary Syndrome  Leukemic form of mycosis fungoides  Aggressive lymphoma  Accounts for 2.5% of CTCL  Estimated 5-yr survival rate 11%  Consists of triad of – Erythroderma – Lymphadenopathy – Cerebriform lymphocytes (Sézary Cells) in peripheral blood, lymph nodes, and skinWillemze et al, 1997; Sibaud et al, 2003.
    94. 94. Sézary CellAnderson & Poulsen, 2003.
    95. 95. General Approach to Management of Cutaneous T-Cell NHL  Lack of evidence based approach  Appreciate unique features of skin disease – Chronic control of skin infections (staph, HSV) – Use anti-itch regimens and emollients/sealants – Agents that work in lymph nodes may not work in skin – Can recycle therapies – Therapy is stage-basedKim, 2011.
    96. 96. Skin Directed Therapies  Topical steroids: Triamcinolone, clobetasol – ORR 75%–95%  Topical chemotherapy-mechlorethamine, carmustine – ORR mechlorethamine 75%–90%  Topical retinoids (bexarotene) – ORR 50%–75%  Phototherapy-UVB (narrow or broad band) or PUVA – ORR nb UVB 75%–100% – ORR PUVA 85%–100% – TSEBT (> 30Gy) 100%  Radiation-local or total skin electron beam therapynb = narrow-band; ORR = overall response rate; PUVA = psoralen and ultraviolet A; TSEBT = total skin electron-beam therapy.Zackheim, 2003; Navi et al, 2011.
    97. 97. Stage Based Therapy for CTCL  IA: Limited Patch/Plaque  IB/IIA: Generalized Patch/Plaque – Topical steroids - – Topical steroids-triamcinolone, triamcinolone, clobetasol clobetasol – Retinoid (bex) – Retinoid (bex) – Local XRT – Phototherapy – Phototherapy – Local XRT – TSEBT + ECP, IFN – Clinical Trial – Bex, denileukin diftitox, IFN, vorinostat, romidepsin (single agent or in combination) – Clinical Trial Bex = bexarotene - topical retinoid Topical chemotherapy - mechlorethamine, carmustine Phototherapy = UVB (narrow or broad band) or PUVA (psoralen + UVA) Radiation-local or total skin electron beam therapy TSEBT = total skin electron beam therapy ECP = extracorporeal phototherapy (photopheresis)
    98. 98. Stage Based Therapy for CTCL (cont.)  IIB Tumors – Topical steroids-triamcinolone, clobetasol – Retinoid (bex) – Phototherapy – Local XRT – Single-agent chemotherapya – Phototherapy – TSEBT + ECP, IFN – Bexarotene, denileukin diftitox, IFN, vorinostat, romidepsin (single agent or in combination) – Clinical Trial – Allo-HSCTMethotrexate, liposomal doxorubicin, gemcitabine, chlorambucil, pentostatins, pralatrexate.aNCCN, 2012b.
    99. 99. Stage Based Therapy for CTCL (cont.)  III Erythroderma – Topical steroids-triamcinolone, clobetasol – Retinoid (bex) – Phototherapy – Local XRT – ECP – Single-agent chemotherapy – Phototherapy = bexarotene or IFN – Alemtuzumab – TSEBT + ECP, IFN – Bex, denileukin diftitox, IFN, vorinostat, romidepsin (single agent or in combination) – Clinical Trial – Allo-HSCT  ECP = photopheresisNCCN, 2012b.
    100. 100. Stage Based Therapy for CTCL (cont.)  IV Extracutaneous Disease – ECP – Single-agent chemotherapy – Combination chemotherapy – Phototherapy = bexarotene or IFN – Alemtuzumab – TSEBT + ECP, IFN – Bexarotene, denileukin diftitox, IFN, vorinostat, romidepsin (single agent or in combination) – Clinical Trial – Allo-HSCTNCCN, 2012b.
    101. 101. Systemic Therapies for MF or SS CTCL  Category A in NCCN Guidelines  Category C in NCCN (Milder) Guidelines/Use for aggressive – Retinoids disease – IFN – Liposomal doxorubicin – HDAC inhibitors – Gemcitabine – Photopheresis – Denileukin diftitox – Denileukin diftitox – Romidepsin – Low-dose methotrexate – Pralatrexate  Category B in NCCN Guidelines – PTCL regimens (Single-agent cytotoxic therapies) – First-line: Liposomal doxorubicin, gemcitabine – Other single-agent cytotoxic therapiesNCCN, 2012b.
    102. 102. Systemic Therapies  Pralatrexate – Dose 15 mg/m2 wkly for 3 wks (4-wk cycle) – B12 IM q9wks – Folic acid 1 mg/day – ORR 58%; OS 13 mos; DOR 4.4 mos  Alemtuzumab – ORR 55%–86% – CR 32%IM = intramuscular; OS = overall survival; DOR = duration of response.Folotyn® prescribing information, 2011; Campath® prescribing information, 2012.
    103. 103. TCL Key Takeaways T-cell lymphomas are rare disorders Behavior is different from B-cell lymphomas-often less responsive to therapies CTCL should first be treated with therapies focused to the skin, unless aggressive New therapies need to be developed to optimize response and survival
    104. 104. Chemotherapy-Induced Peripheral Neuropathy (CIPN)  Common dose-limiting side effect of:  Occurs in 30% – 40% of patients  Symptoms of peripheral neuropathy: – Include sensory neuropathies with parasthesias and pain – Start in fingers and toes and spread in glove and stocking distribution – Can begin weeks to months after initial treatment – In most cases is only partially reversible and can be permanentPachman et al, 2011.
    105. 105. CIPN  Exact mechanism not clear  Can be disabling and negatively impact functional ability and quality of life  Should assess for common metabolic causes of neuropathy: – Diabetes – Vitamin B12 deficiency – Hypothyroidism – Paraproteinemias  No universally-accepted, well-validated measurement of assessment of CIPNPachman et al, 2011.
    106. 106. CIPN  No well-accepted proven therapy for CIPN  Agents with strongest preliminary data for preventing CIPN: – IV calcium and magnesium infusions – Glutathione  Therapies with strongest evidence for first-line treatment of CIPN: – Gabapentin – Topical pain relievers such as baclofen/amitriptyline/ketamine gel or 5% lidocaine patch – Seratonin and norepinephrine reuptake inhibitors such as venlafaxine and duloxetine – Opioid analgesics – Tramadol hydrochloride – Tricyclic antidepressants (nortriptyline hydrochloride or desipramine hydrochloride) – Cutaneous electrostimulationPachman et al, 2011; Vadalouca et al, 2006.
    107. 107. Neuropathy Case Study 68-yr-old man with anaplastic large cell NHL (ALK neg) that presented in his right calf Treatment – 6 cycles of CHOP – Slight increased FDG uptake on PET/CT at the completion of therapy and was treated with involved field XRT – He achieved a metabolic CR 6-mos follow-up – Complained of right upper arm discomfort and was diagnosed with recurrent ALCL – Radiation therapy to the site with a PR – Given pralatrexate with gemcitabine on a clinical trial with SD – Treated with MINE with anticipation of an autologous transplant
    108. 108. Neuropathy Case Study (cont.) He had PD while receiving MINE Brentuximab vedotin was initiated on a clinical trial Clinical findings – Numbness and tingling in his hands and feet – Sensitivity to cold and feeling “like his hands were always cold” Clinical decision – How would you assess for PN? – How do you manage PN at your institution? – What co-morbidities are frequently associated with neuropathy? – What is the best evidence-based management strategy for peripheral neuropathy?
    109. 109. BREAK
    110. 110. Follicular Lymphoma Amy L. Goodrich, MSN, RN, CRNP-BCThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    111. 111. Follicular Lymphoma (FL)  Median age: 60 yrs  Treatment is not curative in most cases  Focus is disease control and quality of life  Median survival: 9 yrs or 4.5 yrs after first relapse  Transformation common (affects ~ 30% of patients)Tan et al, 2008.
    112. 112. Follicular Lymphoma: Grades 1–3 Grade 1 Grade 2 Grade 3 Predominantly Mixture of small and Predominantly small cells large cells large cells Accounts for Accounts for Accounts for 40%–45% of FL 30% of FL 20% of FL Indolent Indolent Clinically aggressive Generally incurable Generally incurable May be curableTan et al, 2008.
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