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Blood cancer 19oct

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One of my best friends (when I was a teenager) died of leukemia. Several advances have been made in the ensuing decades (see attached document). Watch this space for additional notes.

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Blood cancer 19oct

  1. 1. BLOOD CANCERS 2016 update and relevant immunology basics Zeena Nackerdien
  2. 2. BLOOD CANCERS  From mature B cells ─ Uncommon  Six types of HL, including one involving Reed- Steenberg cells  Subtypes include ─ Nodular sclerosis ─ Mixed cellularity CHL  From B cell/T cell progenitors, mature T/B cells, or NK cells ─ ~4% of all cancers in the USA  >61 Types  Non-Reedberg- Steenberg-cell disease = NHL  DLBCL is most common subtype  Often occurs in white blood cells, but can also occur in other types of cells ─ > common in clildren & teens  4 Types ─ AML ─ CML ─ ALL ─ CLL  Cancer of plasma cells in the bone marrow ─ Uncommon, but risk increases with age  Molecular cytogenetic classification of MM has been proposed by a working group ─ Trisomies and IgH translocations are the most common cytogenetic abnormalities Flat with shadow HL HLNHL Lk ALL, Acute lymphocytic leukemia; CHL, Classical Hodgkin’s lymphoma; AML, Acute myelogenous leukemia; CLL, Chronic lymphocytic leukemia; CML, Chronic myelogenous leukemia DLBCL, Diffuse large B-cell lymphoma; HL, Hodgkin’s lymphoma; NHL,, Non-Hodgkin’s lymphoma; Lk, Leukemia; MM, multiple myeloma 1. http://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-non-hodgkin-lymphoma?source=search_result&search=non-hodgkin%27s+lymphoma&selectedTitle=1~150 2. http://www.cancer.org/cancer/non-hodgkinlymphoma/detailedguide/non-hodgkin-lymphoma-key-statistics; 3. Fonseca R, Bergsagel PL, Drach J, et al. Leukemia, 2009;23(12):2210-21 4. Rajan AM, Rajkumar SV. Blood Cancer J. 2015;5:e365. MM
  3. 3. HODGKIN LYMPHOMA STATISTICS % of all new US cancer cases in 2016: 0.5 % of all US cancer deaths in 2016: 0.2 Relative 5-year survival rate (2006-2012): 86.2% 1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets 2016 . http://seer.cancer.gov/statfacts/html/hodg.html.
  4. 4. NON-HODGKIN LYMPHOMA STATISTICS % of all new US cancer cases in 2016: 4.3 % of all US cancer deaths in 2016: 3.4 Relative 5-year survival rate (2006-2012): 70.7 1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheetshttp://seer.cancer.gov/statfacts/html/nhl.html. .
  5. 5. LEUKEMIA STATISTICS % of all new US cancer cases in 2016: 3.6 % of all US cancer deaths in 2016: 4.1 Relative 5-year survival rate (2006-2012): 59.7 1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program: http://seer.cancer.gov/statfacts/html/leuks.html.
  6. 6. MYELOMA STATISTICS % of all new US cancer cases in 2016: 1.8 % of all US cancer deaths in 2016: 2.1 Relative 5-year survival rate (2006-2012): 48.5% 1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets. http://seer.cancer.gov/statfacts/html/mulmy.html. .
  7. 7. What do we know about Hodgkin Lymphoma management? How to Approach , Workup, Stage & individualize Treatment of Hodgkin Lymphoma
  8. 8. HODGKIN LYMPHOMA: APPROACH The WHO defines 5 disease sub- types ie, nodular sclerosing, mixed cellularity (see the image below), lymphocyte depleted, lymphocyte rich, and nodular lymphocyte- predominant. Up to 30% of cases of classical Hodgkin lymphoma may be positive for EBV proteins. Differential diagnosis includes excluding any other disease presenting with lymphadenopathy and constitutional symptoms, other solid tumors and non-Hodgkin lymphoma How do doctors diagnose the disease? What is the workup? http://emedicine.medscape.com/article/201886-overview
  9. 9. HODGKIN LYMPHOMA: WORKUP Clinical and laboratory histories as well as accurate staging are workup fundamentals. Imaging (CT and PET scanning), sampling (biopsy and histologic findings), and an assessment of prognostic factors are required for staging. Hematologic (complete blood cell [CBC] count) and blood chemistry studies may be non-specific, but remain valuable in mapping the extent of the disease. What is the workup? What are the disease stages??http://emedicine.medscape.com/article/201886-overview
  10. 10. HODGKIN LYMPHOMA: STAGING The Ann-Arbor classification system, mainly citing lymph node involvement, is used to stage the disease. • Stage I - A single lymph node area or single extranodal site • Stage II - Two or more lymph node areas on the same side of the diaphragm • Stage III - Lymph node areas on both sides of the diaphragm • Stage IV - Disseminated or multiple involvement of the extranodal organs What are the disease stages? How do doctors treat the disease?http://emedicine.medscape.com/article/201886-overview
  11. 11. HODGKIN LYMPHOMA: TREATMENT Therapies Examples Radiation Therapy Involved-site RT Induction ABVD regimen Salvage Chemotherapy Stanford V regimen Autologous/ Allogenic Stem Cell Transplantation Patient/someone marrow stem cells How do doctors treat the disease? …Overview/Prognosis Although the disease is considered curable., treatment is associated with long-term toxicities and the potential for the development of resistance. The following relative 5-year survival rates are associated with the respective localized, regional and metastatic states of the disease ie, 91.5%, 93.1%, and 77.3%. Menu Download Treatment Protocols ABVD regimen includes The ABVD regimen includes doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine); Stanford V regimen includes doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone given in a 28-day cycle http://emedicine.medscape.com/article/201886-treatment; 2. http://emedicinhttp://emedicine.medscape.com/article/201886-overview
  12. 12. What do we know about Non-Hodgkin Lymphoma management? How to Approach , Workup, Stage & individualize Treatment of Non-Hodgkin Lymphoma
  13. 13. NON-HODGKIN LYMPHOMA (NHL): APPROACH NHLs are clonal expansions of B cells (85% of all NHLs) or T cells and/or NK cells (15% derived from T/NK cells) arising from an accumulation of lesions affecting proto-oncogenes or tumor suppressor genes, resulting in cell immortalization. The t(14;18)(q32;q21) translocation is the most common chromosomal abnormality associated with NHL. Differential diagnosis includes excluding any other disease presenting with benign lymph node infiltration or reactive follicular hyperplasia secondary to infection How do doctors diagnose the disease? What is the workup? http://emedicine.medscape.com/article/203399-overview Download Key NHL subtypes
  14. 14. NON-HODGKIN LYMPHOMA (NHL): WORKUP • Complete blood cell (CBC) count • Serum chemistry studies, including lactate dehydrogenase (LDH) • Serum beta2- microglobulin level • HIV serology • Chest radiography • Computed tomography (CT) scan of the neck, chest, abdomen, and pelvis • Positron emission tomography (PET) scan • Excisional lymph node biopsy • Bone marrow aspirate and biopsy • Hepatitis B testing in patients in whom rituximab therapy is planned because reactivation has been reported • Other studies as needed What is the workup? What are the disease stages?http://emedicine.medscape.com/article/203399-overview
  15. 15. NON-HODGKIN LYMPHOMA (NHL): STAGING What are the disease stages? How do doctors treat the disease? *A,B,X , and E sub-categories of stages: A: No fever, no exaggerated sweating and no weight loss are present; B: Fever, excessive sweating and weight loss are present; X: Bulky disease (large masses of lymphocytes) is present; E Category: The lymphoma has spread to areas or organs outside of the lymph nodes, or to tissues beyond, but near, the major lymphatic areas. https://www.lls.org/lymphoma/non-hodgkin-lymphoma/diagnosis/nhl-staging More than half of all patients with intermediate or aggressive disease and more than 80 percent of all patients with indolent disease are diagnosed with stage III or IV NHL. Stage*/Description I – 1 lymph node group II –≥ lymph node groups on same side of diaphragm III – Lymph node groups on both sides of diaphragm IV – ≥ organs other than lymph nodes & possible involvement of lymph nodes
  16. 16. NON-HODGKIN LYMPHOMA (NHL): TREATMENT Therapies Examples Growth factor Granulocyte-colony stimulating factor Infusional eg, CHOP Radiation Therapy Involved-field RT Autologous/ Allogenic Stem Cell Transplantation Patient/someone marrow stem cells How do doctors treat the disease? …Overview/Prognosis NHL treatment varies depending on tumor stage,phenotype (B- cell, T-cell or natural killer NK] cell/null-cell), histology (ie, low-, intermediate-, or high-grade), symptoms, performance status, patient age, and comorbidities The following relative 5-year survival rates are associated with the respective localized, regional and metastatic states of the disease ie, 82.6%, 74.4%, and 63.1%. Menu Download Treatment Protocols In Special Populations CHOP: Prednisone, methotrexate, leucovorin, doxorubicin, cyclophosphamide, and etoposide—cyclophosphamide, etoposide, Adriamycin, cytarabine, bleomycin, Oncovin, methotrexate, leucovorin, and prednisone (ProMACE-CytaBOM); Methotrexate, bleomycin, doxorubicin (Adriamycin), cyclophosphamide, Oncovin, and dexamethasone (m-BACOD); Methotrexate-leucovorin, Adriamycin, cyclophosphamide, Oncovin, prednisone, and bleomycin (MACOP-B); RT, radiation therapy http://emedicine.medscape.com/article/203399-overview http://seer.cancer.gov/statfacts/html/nhl.html
  17. 17. What do we know about Multiple Myeloma management? How to Approach , Workup, Stage & individualize Treatment of Multiple Myeloma
  18. 18. MULTIPLE MYELOMA(MM): APPROACH MM is usually defined byneoplastic proliferation of plasma cells involving more than 10% of the bone marrow are clonal expansions of B cells. Patients with ≥ 60% clonal plasma cell involvement of the marrow, serum free light chain ratio of 100 or higher (provided involved free light chain level ≥ 100 mg/L), and/or greater than one focal lesion on MRI are defined as MM even in the absence of end-organ damage. Differential diagnosis includes excluding any other condition eg, metastatic bone disease/monoclonal gammopathies of undetermined significance How do doctors diagnose the disease? What is the workup? http://emedicine.medscape.com/article/204369-overview http://meetinglibrary.asco.org/content/159009-176 Download MM diagnostic criteria/related plasma cell disorders
  19. 19. MULTIPLE MYELOMA (MM): WORKUP • Serum and urine assessment for monoclonal protein (densitometer tracing and nephelometric quantitation; immunofixation for confirmation) • Serum-free light chain assay (in all patients with newly diagnosed plasma cell dyscrasias) • Bone marrow aspiration and/or biopsy • Serum β2-microglobulin, albumin, and lactate dehydrogenase measurement • Standard metaphase cytogenetics • Fluorescent in situ hybridization • Skeletal survey • Magnetic resonance imaging What is the workup? What are the disease stages? http://emedicine.medscape.com/article/204369-overview
  20. 20. MULTIPLE MYELOMA(MM): STAGING What are the disease stages? How do doctors treat the disease? The Revised ISS combines elements of tumor burden & disease biology (± high-risk cytogenetic abnormalitiesa/LDH) to create a unified prognostic index. Stage/Description ISS Stage I – (Serum albumin > 3.5, serum β2-macroglobulin < 3.5 & no high-risk cytogenetics; Normal LDH II – Neither Stage I/III ISS Stage III– Serum β2-macroglobulin > 5.5 & high-risk* cytogenetics; Elevated LDH *High-risk: [t(4:14), t(14;16), or del(17p)] aAbnormalities such as t(4:14), t(14;16), t(14; 20), gain 1(q), del(1p)or del(17p) influence disease course, response to therapy, and MM prognosis ISS, International Staging System; LDH, lactate dehydrogenase http://emedicine.medscape.com/article/204369-overview Rajkumar SV. ASCO Educational Handbook. Updated Diagnostic Criteria and Staging System for Multiple Myeloma.2016. http://meetinglibrary.asco.org/content/159009-176.
  21. 21. MULTIPLE MYELOMA(MM): TREATMENT Treatment Examples Initial Chemotherapy eg, Bortezomib/ dexamethasone in non- candidates Adjunctive treatment Erythropoietin/ Corticosteroids/ Plasmapheresis/Surgery Related bone disease treatment Bisphosphonates, How do doctors treat the disease? …Overview/Prognosis The deepest response in the first round is sought with appropriate treatment; this should lead to better overall survival in transplant & non-transplant patients. The following relative 5-year survival rates are associated with the respective Stage I, II and III disease stages ie, 82%, 62%, and 40%. Menu Download Treatment Protocols http://emedicine.medscape.com/article/204369-overview; http://meetinglibrary.asco.org/sites/meetinglibrary.asco.org/ files/edbook/176/images/EDBK_159009-table3.png
  22. 22. What do we know about AML management? How to Approach , Workup, Stage & individualize Treatment of Acute Myelogenous/ Myeloid Leukemia (AML)
  23. 23. AML: APPROACH AML is a life-threatening condition, occurring largely in older adults. Although a normal karyotype can be a hallmark of de novo myelodysplastic syndromes AML, tumors characteristically have 11q23 abnormalities involving the MLL gene. Secondary AML associated with other diseases are prone to relapse and exhibit resistance to chemotherapy. Differential diagnosis includes ruling out other diseases eg, ALL, biphenotypic leukemia, chronic myelogenous leukemia blast crisis, and aplastic anemia. How do doctors diagnose the disease? What is the workup? https://online.epocrates.com/diseases/27411/Acute-myelogenous-leukemia/Key-Highlights ALL, acute lymphocytic leukemia; MLL gene, encodes histone-lysine N-methyltransferase 2A Most common type of acute leukemia in adults
  24. 24. AML: WORKUP A definitive diagnosis requires the presence of ≥ 20% blast cells in the bone marrow. Immunochemistry and histological methods are critical to establish the myeloid origin of the leukemia. Tests may include: • Physical exam/medical history • CBC with differential • Peripheral blood smear • Coagulation panel • Lumbar puncture • HLA typing • Imaging • Molecular and immunophenotyping What is the workup? What are the disease stages? https://online.epocrates.com/diseases/27431/Acute-myelogenous-leukemia/Diagnostic-Approach CBC, Complete Blood Cell count; HLA, human leukocyte antigen
  25. 25. AML: STAGING What are the disease stages? How do doctors treat the disease? French, American, and British researchers (FAB) as well as the WHO have devised separate staging criteria. FAB WHO • AML with certain genetic abnormalities • AML with myelodysplasia-related changes • AML related to previous chemotherapy/radiation • AML, not otherwise specified • MO: Undifferentiated AML • M1: AML + minimal maturation • M2: AML + maturation • M3: APML • M4: AMML • M4eos: AMML + eosinophilia • M5: Acute monocytic leukemia • M6: Acute erythroid leukemia • M7: Acute megakaryoblastic leukemia APML, acute promyelocytic leukemia; AMML, acute myelomonocytic leukemia; WHO, World Health Organization; http://www.cancer.org/cancer/leukemia-acutemyeloidaml/detailedguide/leukemia-acute-myeloid-myelogenous-classified Summary In the case of FAB staging, subtypes M0 through M5 all start in immature forms of white blood cells. M6 AML starts in very immature forms of red blood cells, while M7 AML starts in immature forms of cells that make platelets. See complete WHO staging system description here.
  26. 26. AML: TREATMENT Treatment* will depend on patient age, fitness, disease type (presumptive or acute AML/acute promyelocytic leukemia (APML). 1st/2nd/3rd-line/adj. therapies may include: How do doctors treat the disease? Menu http://emedicine.medscape.com/article/204369-overview http://seer.cancer.gov/statfacts/html/amyl.html AML, < 60 y or ≥ 60 y Relapsed /refractory AML/APMLAPML • Induction CT • Intrathecal cytarabine • Postinduction consolidation CT • Stem cell transplant • Low-dose subcutaneous CT • Induction CT:tretinoin + an anthracycline • Supportive care • Consolidated /maintenanceCT • Cessation of drug + corticosteroid • Intrathecal cytarabine • Clinical trial eval. or salvage CT + stem cell transplant + supportive care (AML, <60 y) • Clinical trial eval. ± stem cell transplant/reinduction reg. (AML, ≥60 y) • Salvage therapy+ Stem cell transplant+Supportive care (APML) Adj., adjuvant; CT, chemotherapy; eval., evaluation; reg., regimen Overview/Prognosis (US statistics for 2006-2012) Rates for new AML cases have been rising on average 3.4% over the last decade. Relative 5-year survival rate for this cancer is 26.6%.
  27. 27. What do we know about CLL management? How to Approach , Workup, Stage & individualize Treatment of Chronic Lymphocytic Leukemia (CLL)
  28. 28. CLL: APPROACH This chronic lymphoproliferative disorder accounts for up to 30% of all leukemias in the USA. Although it has different manifestations, the disease is identical to the mature (peripheral) B cell neoplasm small lymphocytic lymphoma (SLL), one of the indolent non-Hodgkin lymphomas. A CLL precursor is called monoclonal B lymphocytosis. Differential diagnosis includes ruling out other diseases eg, FL, Hairy Cell Leukemia, Splenic Marginal Lymphoma. How do doctors diagnose the disease? What is the workup?http://emedicine.medscape.com/article/199313-differential http://www.uptodate.com/contents/clinical-presentation-pathologic-features-diagnosis-and-differential-diagnosis-of- chronic-lymphocytic-leukemia?source=search_result&search=chronic+lymphocytic+leukemia&selectedTitle=4~150 ALL, Acute Lymphocytic Leukemia;; CLL, chronic lymphocytic leukemia; FL, Follicular Lymphoma. Most common type of chronic leukemia in adults
  29. 29. AML: WORKUP • Microscopic examination • Clonality confirmed by flow cytometry • Serum immunoglobulin level quantitation • Serum-free light chain assays • Bone marrow aspiration and biopsy • Liver/spleen ultrasonography • Chromosomal Testing What is the workup? What are the disease stages? http://emedicine.medscape.com/article/199313-workup
  30. 30. CLL: STAGING What are the disease stages? How do doctors treat the disease? The Rai-Sawitsky (USA) and Binet (Europe) systems have been used to classify disease stages. http://emedicine.medscape.com/article/199313-workup#c9 Rai-Sawitsky Low risk (formerly stage 0) – Lymphocytosis in the blood and marrow only (25% of presenting population) Intermediate risk (formerly stages I and II) – Lymphocytosis with enlarged nodes in any site or splenomegaly or hepatomegaly (50% of presentation) High risk (formerly stages III and IV) – Lymphocytosis with disease-related anemia (hemoglobin <11 g/dL) or thrombocytopenia (platelets <100 x 10 9/L) (25% of all patients) Binet Stage A – Hemoglobin greater than or equal to 10 g/dL, platelets greater than or equal to 100 × 10 9/L, and fewer than 3 lymph node areas involved Stage B – Hemoglobin and platelet levels as in stage A and 3 or more lymph node areas involved Stage C – Hemoglobin less than 10 g/dL or platelets less than 100 × 10 9/L, or both
  31. 31. CLL: TREATMENT How do doctors treat the disease? …Overview/Prognosis The estimated number of new cases for 2016 is 18,960. Relative US 5-year survival rates (2006-2012) were 82.6%. Menu Download Chemotherapy Regimens Patients with low-risk, stable diease (Binet A) require only periodic follow-up. Rapid disease progression warrant chemotherapies ranging from nucleoside analogs to biologics. Symptoms include: • Weight loss of more than 10% over 6 months • Extreme fatigue • Fever related to leukemia for longer than 2 weeks In addition, allogeneic stem cell transplantation is the only known curative therapy. Pneumococcal and influenza vaccines are needed (patients are prone to common and unusual Infections). http://emedicine.medscape.com/article/199313-treatment#d1 http://seer.cancer.gov/statfacts/html/clyl.html
  32. 32. EMERGING THERAPIES Targeted agents and Immunotherapies
  33. 33. IMMUNE CHECKPOINT AXIS: NEW TREATMENTS CD-27 PD-1/ PD-L1 TIM-3 CTLA-4 4-1BB (CD137) LAG-3 OX40 CD40L • Ipilimumab • Tremelimumab Anti-PD1 • Nivolumab • Pembrolizumab • Pidilizumab • AMP-224 Anti-PD-L1 • Avelumab (MSB0010718C) • MEDI4736 • MEDL3280A • BMS-936559 • Urelumab (BMS-663513) • PF05082566 • Varlilumab (CDX-1127) Immune-checkpoint inhibitors target the inhibitory signals transduced through the PD-1– PD-L1 axis and CTLA-4 interactions Agonist • Dacetuzumab • Chi Lob 7/4 • CP-870893 Inhibitory receptors/Blocking antibodies Activating receptors/Agonistic/ Antagonistic antibodies MED16469 Antagonist • Lucatumumab CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed cell death protein 1; PD-L1, programmed cell death 1 ligand 1 Batlevi CL, Matsuki E, Brentjens RJ, Younes A. Nat Rev Clin Oncol. 2016;13(1):25-40. T cells recognize antigens presented on the MHC by the TCR. The fate of T cells upon antigen recognition is determined by the additional ligand–receptor interactions between the T cells and APCs (or tumor cells). The co-stimulatory signals activated via CD28, 4-1BB (CD137), OX40, and CD27 promote activation of T cells, whereas those sent via CTLA-4 and PD-1 decrease T-cell activation. Various treatment modalities are being developed to modulate these signals.
  34. 34. CLINICAL EFFICACY OF IMMUNE CHECKPOINT INHIBITORS ORR (%) B-NHL DLBCL FL T-NHL HL PR (%)CR (%) Response Duration*SD (%) 26 36 40 17 87 10 18 10 0 26 16 18 30 17 61 52 27 60 43 13 NA 22 weeks Not reached NA NA Nivolumab *Median Duration of Response ; B, B-cell; CR, Complete Response; DLBCL, Diffuse Large B-cell Lymphoma; FL, Follicular Lymphoma; HL, Hodgkin Lymphoma; NHL, Non-Hodgkin Lymphoma; PR, Partial Response; ORR, Overall Response Rate; OS, overall survival; PFS, Progression-free Survival; SD, Stable Disease; T, T-cell Batlevi CL, Matsuki E, Brentjens RJ, Younes A. Nat Rev Clin Oncol. 2016;13(1):25-40. PFS: 86% at 24 weeks OS: median not reached
  35. 35. CLINICAL EFFICACY OF IMMUNE CHECKPOINT INHIBITORS ORR (%) HL DLBCL FL T-NHL HL PR (%)CR (%) Response Duration*SD (%) 66 21 45 21 Not reached Pembrolizumab *Median Duration of Response ; B, B-cell; CR, Complete Response; HL, Hodgkin Lymphoma; PR, Partial Response; ORR, Overall Response Rate; SD, Stable Disease; T, T-cell Batlevi CL, Matsuki E, Brentjens RJ, Younes A. Nat Rev Clin Oncol. 2016;13(1):25-40.
  36. 36. CLINICAL EFFICACY OF IMMUNE CHECKPOINT INHIBITORS ORR (%) B-NHL HL (post allo SCT) PR (%)CR (%) Response Duration*SD (%) 11.1 14.3 5.6 0 5.6 14.3 NA NA NA NA Ipilimumab *Median Duration of Response ; B, B-cell; CR, Complete Response; HL, Hodgkin Lymphoma; NHL, Non-Hodgkin Lymphoma; PR, Partial Response; ORR, Overall Response Rate; SD, Stable Disease; T, T-cell Batlevi CL, Matsuki E, Brentjens RJ, Younes A. Nat Rev Clin Oncol. 2016;13(1):25-40.
  37. 37. CHIMERIC ANTIGEN RECEPTORS (CAR) FEATURES CARs consist of an extracellular antigen-recognition domain and a signaling domain that provides ‘signal 1’ to activate T cells (1st-generation CARs). Co- signaling domain providing ‘signal 2’ is present in 2nd-generation CARs. Two co- stimulatory signaling domains are present in 3rd-generation CARs. First-generation Second-generation Third-generation Antigen- recognition domains Signaling DomainsSignal 1 Signal 1 Signal 1 Signal 2 Signal 2 Jackson HJ, Rafiq S, Brentjens RJ. Nat Rev Clin Oncol. 2016;13(6):370-83.
  38. 38. CAR-T CELL TARGETS FOR THE TREATMENT OF HEMATOLOGIC MALIGNANCIES Your Logo Target • CD22 • CD20 • ROR1 • Ig • CD30 • CD123 • CD33 • LeY • BCMA • CD138 Structure • CD3 and CD28 • CD3  or CD3  & 4-1BB • CD3  and 4-1BB • CD3  and CD28 • CD3  and CD28 • CD3  and CD28 • CD3  and CD28 • CD3  and 4-1BB • CD3  and CD28 • CD3  and 4-1BB Malignancy • FL, NHL, DLBCL, B-ALL • CD20+-malignancies • CLL, SLL • CLL, low-grade B-cell malignancies • HL, NHL • AML • AML • AML • MM • MM Does not include CD19 targets. AML, acute myeloid leukemia; B-ALL, B-cell acute lymphoblastic leukaemia; BCMA, B-cell maturation antigen; CLL, chronic lymphocytic leukaemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; HL, Hodgkin lymphoma; LeY, Lewis Y antigen; MM, multiple myeloma; NHL, non- Hodgkin lymphoma; ROR1, inactive tyrosine-protein kinase transmembrane receptor ROR1; SLL, small lymphocytic lymphoma Jackson HJ, Rafiq S, Brentjens RJ. Nat Rev Clin Oncol. 2016;13(6):370-83.
  39. 39. APPROACHES TO IMPROVING CAR-T TREATMENT CAR, chimeric antigen receptor; IL-12, inerleukin-12; NK, natural killer; NKG2, natural-killer-cell-recognition domain; Jackson HJ, Rafiq S, Brentjens RJ. Nat Rev Clin Oncol. 2016;13(6):370-83. e.g. infusion of tumour-targeted CAR- T cells together with B-cell-specific CAR-T cells CAR-T cell Armored CARs Dual- receptor chemokines/ CARs NK cell- receptor CARs Combination Therapies B-cell eradication Targeting tumor vasculature e.g. VEGFR-2- specific CAR-T cells e.g. IL-12- secreting CAR-T cells e.g. CAR T cells co- expressing tumour- specific CAR and chimeric cytokine receptor 4β e.g. NKG2-based CAR e.g. CAR-T cells and checkpoint blockade
  40. 40. SIDE EFFECTS: CYTOKINE RELEASE SYNDROME ETC. SYMPTOMS 1. Hypotension, vascular leak, coagulopathy, cytopenia 2. Respiratory/renal insufficiency 3. Myalgia, fevers 4.Neurological complications, including dyphasia, confusion, delirium, visual hallucinations, seizure-like activity DIAGNOSTICS 1. C-reactive protein 2. Ferritin TREATMENT/MANAGEMENT 1. Vasopressors 2. Ventilatory support 3. Corticosteroids 4. Anti-IL-6 receptor antibody (tocilizumab) therapy 5. Supportive care Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T-cells forward. Nat Rev Clin Oncol. 2016;13(6):370-83. Different “off-switches” eg, genes & drugs are being tested to mediate serious cytotoxicities
  41. 41. Antibody-drug conjugate targeting CD30 eg, Brentuximab vedotin Brentuximab vedotin and augmented ICE (ifosfamide, carboplatin, etoposide) prior to autotransplant PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ICE Panobinostat OTHER EMERGING HL TREATMENTS (RELAPSED/REFRACTORY/SALVAGE THERAPIES) HL, Hodgkin Lymphoma http://www.managinghodgkinlymphoma.com/melanoma/faq-library/117-what-new-emerging-treatments-for-relapsed-refractory-hl-are-most-likely-to-improve-patient-outcomes http://www.ascopost.com/issues/april-15-2014/better-options-emerging-for-salvage-therapy-in-hodgkin-lymphoma.aspx
  42. 42. PI3K inhibitor eg, Idelalisib Btk inhibitors eg, Ibrutinib Syk inhibitors eg, fostamatinib BCL-2 inhibitors eg, Venetoclax Anti-CD20 monoclonal antibodies eg, obinutuzumab Antibody-drug conjugates EZH2 inhibitors OTHER EMERGING B-CELL NHL TREATMENTS NHL, Non-Hodgkin Lymphoma; EZH2, the catalytic subunit of the polycomb repressor 2 complex; PI3K, phosphatidyl-inositol-3-kinase; Syk, spleen tyrosine kinase Cheah CY, Fowler NH, Wang ML. Annals of Oncology. 2016 (e-pub).
  43. 43. Quizartinib: FLT3 inhibitor ASP-2215: FLT3 inhibitor with activity against TKD resistance mutation AG-221: IDH2 inhibitor AG-120: IDH1 inhibitor ABT-199: BCL-2 inhibitor OTHER EMERGING AML TREATMENTS ASCO Educational Handbook. Emerging Therapies for Acue Myeloid Leukemia. Progress at Last?: http://meetinglibrary.asco.org/content/161258-176 The most targeted protein is FLT3 because of its role as the most common recurrent genetic alteration in patients with de novo AML. FLT3 internal tandem duplications occur in 30% of AML cases, and portend a poor prognosis, especially in patients with a high allelic ratio.
  44. 44. Cyclin-dependent kinase inhibitors BCL-2 inhibitors Heat shock protein 90 inhibitors Histone deacetylase inhibitors Small modular immunopharmaceuticals EMERGING REFRACTORY CLL TREATMENTS http://www.medscape.com/viewarticle/756581_9 http://www.onclive.com/insights/cll-2015/emerging-treatments-for-chronic-lymphocytic-leukemia The selective BCL2 inhibitor venetoclax (ABT-199) has demonstrated significant results as both a single agent and in combination with rituximab (Rituxan). The primary side effect for venetoclax is tumor lysis syndrome, which must be carefully managed in the first 4 to 6 weeks of administration. Duvelisib is a phosphoinositide-3 (PI3)-kinase delta inhibitor that differs from the current FDA-approved PI3-kinase inhibitor idelalisib (Zydelig) in that duvelisib also inhibits the gamma isoform of PI3 kinase. This could potentially affect T-cells and myeloid cells. Ublituximab (TG-1101) is a novel monoclonal antibody that targets CD20 and may potentially have superior ADCC vs. other anti-CD20 antibodies.
  45. 45. Elotuzumab Carfilzumab Pomalidomide Panobinostat Ixazomib Anti-CD38 antibodies EMERGING MM TREATMENTS http://www.onclive.com/publications/oncology-live/2015/june-2015/new-paradigm-emerging-in-multiple-myeloma-therapy?p=1 Zagouri F, Terpos E, Kastritis E, Dimopoulos MA. Expert Opinion on Emerging Drugs. 2016;21(2):225-37. Amongst emerging antibodies, elotuzumab which targets SLAMF-7 and daratumumab which targets CD38, have been recently approved by FDA for patients with relapsed/refractory MM. Both agents are well tolerated. Multiple clinical trials incorporating these monoclonal antibodies in MM treatment are currently ongoing
  46. 46. IMMUNITY Basics
  47. 47. IMMUNITY BASICS • Two cooperative defense responses against pathogens – Non-specific/innate immunity – Specific/acquired/adaptive immunity • Hematopoietic stem cells give rise to myeloid & lymphoid lineages • Myeloid lineage includes: – Thrombocytes – Erythroid cells – Granulocytes (most abundant cells in normal peripheral blood) – Monocytes • Lymphoid lineage includes: – Lymphocytes . Lebman D. Lippincott Illustrated Reviews Flash Cards: Immunology (First Edition). Wolters Kluwer; 2016. Granulocytes are the most abundant cells in normal peripheral blood
  48. 48. WHITE BLOOD CELLS Neutrophil Eosinophil Basophil Neutrophil Monocyte Lymphocyte
  49. 49. WHITE BLOOD CELLS: NEUTROPHILS Approximately 50 to 80% of all white blood cells are neutrophils. These cells stain pink or purple-blue when using neutral dyes. The bone marrow has large reservoir that can be mobilized in response to an infection/inflammation. 1. Lebman D. Lippincott Illustrated Reviews Flash Cards: Immunology (First Edition). Wolters Kluwer; 2016 2 https://www.britannica.com/science/neutrophil.
  50. 50. WHITE BLOOD CELLS: EOSINOPHILS Eosinophils make up less than 1% of white blood cells. These cells contain large granules and a nucleus, as seen by acid stains (eosin). Eosinophils play roles in mediating certain allergic reactions. IL-5 is linked to a specific allergic response and stimulates eosinophil growth. Abbreviations: IL-5, interleukin 5 1. Lebman D. Lippincott Illustrated Reviews Flash Cards: Immunology (First Edition). Wolters Kluwer; 2016 2. https://www.britannica.com/science/eosinophil
  51. 51. WHITE BLOOD CELLS: BASOPHILS Basophils make up ~0.4% of white blood cells. Histological characteristics can be determined with a basic stain. Mediates hypersensitive reactions of the immune system. 1. Lebman D. Lippincott Illustrated Reviews Flash Cards: Immunology (First Edition). Wolters Kluwer; 2016 2 https://en.wikipedia.org/wiki/White_blood_cell 3. https://www.britannica.com/science/basophil
  52. 52. WHITE BLOOD CELLS: MONOCYTES Monocytes are the largest blood cells (15-18 µm) and make up ~7% of white blood cells. Cells are types of phagocytes ie, surround and kill microbes, ingest foreign materials, remove dead cells, and boost immune responses. 1. Lebman D. Lippincott Illustrated Reviews Flash Cards: Immunology (First Edition). Wolters Kluwer; 2016 2. https://www.britannica.com/science/blood-biochemistry/Red-blood-cells-erythrocytes#toc257811
  53. 53. WHITE BLOOD CELLS: LYMPHOCYTES Lymphocytes make up ~20 to 40% of white blood cells. Two primary cell types, T and B cells, originate in the thymus and bone marrow, respectively. These cells comprise “immunologic memory,” ie, a rapid response to a 2nd encounter with the same antigen. 1. Lebman D. Lippincott Illustrated Reviews Flash Cards: Immunology (First Edition). Wolters Kluwer; 2016 2. https://www.britannica.com/science/lymphocyte
  54. 54. WHITE BLOOD CELLS: LYMPHOCYTES Human natural killer (NK) cells, the 3rd member of the lymphoid lineage, are large granular lymphocytes. These cells outnumber B cells by 3 to 1. The three cell types contribute to antiviral responses. Different types of T cells are referred to as helpers/killers. Uncontrollable growth of lymphocytes can result in blood cancers. The most common blood cancer is lymphoma. 1. Lebman D. Lippincott Illustrated Reviews Flash Cards: Immunology (First Edition). Wolters Kluwer; 2016 2. https://www.britannica.com/science/lymphocyte 3. Caligiuri MA. Human natural killer cells. Blood. 2008;112(3):461-9. T cell B cell NK cell
  55. 55. ANTIBODY STRUCTURE Interchain Disulfide bonds Antigen binding Biological Activity mediation Interchain Disulfide bonds Fab Fc 𝑉𝐻 𝑉𝐿 𝐶 𝐻 𝐶𝐿 Light-chain Hypervariable regions Heavy-chain Hypervariable regions 𝐶 𝐻2 𝐶 𝐻3 VL and VH: variable regions CL and CH: constant regions Complement-binding region Carbohydrate
  56. 56. MHC protein Processed viral antigen Interleukin - 1 HelperT cell T cell receptor that fits the particular antigen Virus Macrophage Antigen – presenting cell CytotoxicT cell Proliferati on MHC protein Viral antigen Infected cell destroyed by cytotoxicT cell Interleukin - 2 T CELL
  57. 57. B Cell Antibodie s Secretion Plasma cell B – cell receptor (BCR) B cell Mitosis and Differentia tion Lymphokines Helper T cell
  58. 58. Tumo ur cell NK Cell Apoptosis Necrosi s Fas (CD95 ) Fasl (CD95L ) NK cell Perforin ADCC FcR A g A b Granzy me B
  59. 59. Granzyme Perforin Granzyme release Perforin pore Target cell Endocytosis Granule exccytosis Receptor CTL Target Cell For CTL
  60. 60. CREDITS • Slides 47-59: slideteam.net

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