DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is     current as of May 2...
DISCLAIMER Participants have an implied responsibility to use the newly acquired information      to enhance patient outco...
Disclosure of Conflicts of Interest   Mollie E. Moran, MSN, CNP, AOCNP®, has no real or    apparent conflicts of interest...
Learning Objectives                L                   Upon completion of this activity,                 participants shou...
Welcome and Introduction Mollie E. Moran, MSN, CNP, AOCNP®   The James Cancer Hospital at       The Ohio State University
Introduction to Faculty Panel   Mollie E. Moran, MSN, CNP, AOCNP®    – Oncology Nurse Practitioner    – The James Cancer ...
Activity Agenda                   A12:30 – 12:35 pm       I                       Introduction12:35 – 12:55 pm       T    ...
The Evolving Landscape   of CML Treatment    Michael R. Savona, MD, FACP  Sarah Cannon Research Institute /Sarah Cannon Ce...
Chronic Myeloid Leukemia (CML)Image courtesy of Michael R. Savona, MD, FACP.
CML            Incidence is 1.6–2.1 / 100,000 annually            Mortality is 0.2 / 100,000 annually in the US        ...
Philadelphia Chromosome Results              From Reciprocal Translocations                                               ...
Progression of CML                                                            BCR-ABL                       HSC           ...
Progression of CML (cont.)                                                    Independence                                ...
Targeted Molecular Therapy                     in the Management of CML            Imatinib               – Small molecul...
2010 ASH: 116 – CML Outcome in Sweden                   3,173 patients (1973–2008); median age 62 yrs                     ...
Mechanisms of Secondary                     Resistance to Imatinib             Secondary resistance                      ...
Role of Kinase Conformation                       in Imatinib Resistance             Point mutations in BCR-ABL kinase do...
Mutations in BCR-ABL Kinase Domain Confer             Varying Degrees of Resistance to Imatinib                           ...
Nilotinib            A more selective,             imatinib-derived ABL             inhibitor            Binds to the in...
Comparative IC50 Values for                         Targeted Molecules for CML                                         ABL...
Dasatinib           An oral, multi-kinase inhibitor           Binds to both inactive and active conformations of BCR-ABL...
Comparative IC50 Values for        Targeted Molecules for CML (cont.)                                         ABL   PDGFR ...
Targets of Tyrosine Kinase Inhibitors                 Imatinib                                            Nilotinib       ...
Saglio et al, 2010; Kantarjian et al, 2010.
ENESTnd: Cumulative Incidence                   of MMR3 (3-log reduction)                                                 ...
DASISION: Cumulative Incidence of MMR3                 100       Dasatinib 100 mg QD                           Imatinib 40...
Hasford Risk:      Age      Spleen size      Platelet count      Basophils      Eosinophils      MyeloblastsMarin et al, 2...
Assessment of BCR-ABL1 Transcript Levels at    3 Months Is the Only Requirement for Predicting Outcome               for C...
How to Choose?
Adverse Events                             A thorough discussion                              on the risks of non-       ...
Adverse Events    (cont.)   Again, nuances in the    AEs seen even    between these    relatively similar drugs     – The...
Nilotinib Vs. Imatinib in CML-CP                      Drug-Related AEs (≥ 10% in Any Group)                               ...
Bosutinib Vs. Imatinib: CML Front-Line                          Therapy-Related AEs ≥ 10%                                 ...
CML Prevalence and Choice of TherapyHow Does Growing Prevalence Effect Our Choice?~ 5,000                             ~ 12...
Rational Design of Future CML                           Therapy                                                  Translati...
How to Address the Leukemia Stem Cell  Ideal Targetable Stem Cell    Pathways…     Pathway known to regulate       self-re...
Hedgehog Inhibition: Novel Mechanism With        Applications Across a Broad Range of Cancers            Hedgehog inhibit...
PF04449913 – HH Inhibition in Myeloid Disease           Major Inclusion Criteria                                        ...
Well Tolerated     Event, n (%)                         Grade 1                       Grade 2   Grade 3   Grade 4     Dysg...
AML: Reduction in Blasts (7 of 20)Jamieson et al, 2011.
Key Takeaways CML is characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 t(9;22)(q34;q11...
Roundtable Workshop:Interactive Case on Choosing   CML Front-Line Therapy Mollie E. Moran, MSN, CNP, AOCNP®   The James Ca...
Case Study            A 48-year-old flight attendant presents for her annual             physical exam. She is in her usu...
Case Study (cont.) – Medical History    • Type II DM controlled with metformin    • HTN controlled with lisinopril and HCT...
Case Study (cont.)           BMB + for CML              – 8% blasts              – 2% basophils           Cytogenetics 4...
Diagnostic Evaluation: Peripheral Blood     Diagnostic Study                           Clinical Significance     CBC, diff...
Diagnostic Evaluation:                                  Bone Marrow      Diagnostic Study                 Clinical Signifi...
Typical Laboratory Parameters                          by Phase of CML                                         Phase of CM...
CML Phases                     Chronic            Accelerated                BlasticPast           3–5 years            12...
Survival in Early CP-CML                                       YearsAdapted form Kantarjian et al, 2012.
Sokal and Hasford Scores             Calculated at diagnosis to predict prognosis             Sokal Index               ...
How to Calculate the Sokal and Hasford ScoresHasford score                                   Sokal score0.6666 x age (0 wh...
Case Study (cont.)   Sokal                    Hasford    – 0.97                    – 785    – Intermediate Risk       – ...
Case Study (cont.) She is initiated on one of the following therapies for CML:  – Imatinib 400 mg po daily  – Imatinib 80...
Roundtable Discussion Topics Patient   and disease characteristics  – Influence on choice of front-line therapy Lab   va...
Response Definitions and                           Monitoring of CML                              Hematologic             ...
Roundtable Discussion Topics                 (cont.)   Adverse events    – Primary prevention strategies/cautions and    ...
Roundtable Discussions      (10 minutes)
Faculty Roundtable  Presentations    (20 minutes)
Results With Imatinib in        Early CML-CP: IRIS Trial at 8 Years            304 (55%) patients on imatinib on study   ...
Long-Term Outcome With Imatinib              in Early CML-CP (ITT)                                    1.0                 ...
Criteria for Failure and Suboptimal               Response to Imatinib           Time                          Response   ...
High-Dose Imatinib as Initial Therapy in CML              281 patients Rx’d with imatinib 400 mg (n = 73) or 800 mg (n = ...
TOPS: Rate of MMR Over Time                   by Imatinib Dose (ITT)     476 patients with early CML-CP randomized to ima...
Dasatinib Vs. Imatinib Study in        Treatment-Naïve CML (DASISION) Trial Design                                        ...
Dasatinib Vs. Imatinib in                          Newly Diagnosed CML-CP   519 patients randomized to dasatinib 100 mg Q...
Nilotinib Vs. Imatinib in                         Newly Diagnosed CML-CP    846 patients randomized to nilotinib 300 mg B...
Known Mechanisms of Imatinib ResistanceBranford et al, 2003; Weisberg et al, 2000; Donato et al, 2003.
BCR-ABL Point Mutations         Point mutations in ABL kinase alter TKI binding            – Most frequent mechanism of r...
CCyR Rates for Approved TKIs                Time of       TKI                CML Phase                Therapy             ...
EFS by Treatment in Early CML-CP      Probability EFS (%)                                   Time (months)Adapted from Cort...
Toxicity Profiles                                        GRADE 3/4 HEM (%)                                               N...
Myelosuppression            Generally occurs in the first few months            Mild-to-moderate in severity (grade 1–2)...
General Fluid Retention            Patient education key to allow patients to recognize             and report symptoms  ...
Pleural Effusion         Patients                       should be aware of symptoms                – Chest pain          ...
Metabolic Abnormalities             Nilotinib                – Mild-to-moderate in severity                – Lipase or am...
Management of QTc Prolongation            Prolongation of the QTc interval can occur with nilotinib             (black bo...
QTc Prolongation (cont.)             Obtain EKG at baseline; at 7 days after any              dose adjustment           ...
Managing Gl and Musculoskeletal Toxicities             Gl toxicities include nausea,                                Musc...
Muscle-Related AEs         Grade        3/4 are infrequent         Symptomatic      relief may be achieved with         ...
Cutaneous Reactions         Primary AE                      Drug Specific Considerations         Dermatologic             ...
Numerous Drug Interactions                                 IMATINIB                  DASATINIB                NILOTINIB   ...
General Patient Education             Do not crush or cut tablets             Missed doses should not be made up, instru...
Medication Adherence:Patient and Caregiver TeachingKathleen K. Curran, MSN, RN, CRNPUniversity of Pittsburgh Medical Center
“Drugs Don’t Work in Patients Who Don’t           Take Them.” – C. Everett Coop, MD             Low-adherence to prescrib...
Oral Therapy Adherence        About      25% of patients being treated for CML             did not take imatinib as presc...
As Many Reasons as Snowflakes There is not one intervention that will work for all people Patients        must be includ...
What Works?             Identify patients at high risk—missed              appointments, missed refills, evaluate barrier...
Interventions to Try Patients   will bring ALL of their medication to  clinic visits Calling the patient frequently to a...
Consider Health   literacy Health   beliefs Patient-practitioner   relationship Depression Support   system or lack o...
Compliance-Adherence-Persistence            Compliance implies paternalism and obedience            Adherence is the ext...
Three Decades of Research Many,  many, many interventions have been tried to assist people with medication adherence have...
Medication Adherence                  Discussions1)   Roundtable Discussion (5 minutes)     – Best practices for ensuring ...
Final Key Takeaways   There are a number of oral TKIs available for effectively    treating CML-CP   Patients require cl...
Final Key Takeaways (cont.)   Patients who were not 100% compliant did not achieve    CR in clinical trials   Assess eve...
Establishing Best Practices for CML Therapy: A Workshop Symposium for the Advanced Practice Oncology Nurse
Establishing Best Practices for CML Therapy: A Workshop Symposium for the Advanced Practice Oncology Nurse
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Establishing Best Practices for CML Therapy: A Workshop Symposium for the Advanced Practice Oncology Nurse

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In 2011, the treatment armamentarium dramatically expanded with the approval of the anti-CTLA4 antibody ipilimumab and the BRAF inhibitor vemurafenib. Oncology nurses who care for patients with melanoma are beginning to administer these new agents and have numerous questions regarding their efficacy, different response patterns, unique toxicity profiles, how they may be integrated into current treatment regimens, and how to educate patients on their benefits and risks.


Downloadable slide decks are a great tool for self study and teaching purposes. They are non-certified resources available to enhance your knowledge.

Review a downloadable slide deck by Mollie E. Moran, MSN, CNP, AOCNP®, covering the most clinically relevant new data reported from Establishing Best Practices for CML Therapy: A Workshop Symposium for the Advanced Practice Oncology Nurse.

Target Audience
This activity has been designed to meet the educational needs of oncology advanced practitioners involved in the care of patients with chronic myelogenous leukemia (CML) who are interested in an advanced course on this topic.

Slide Deck Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of May 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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  • The Translocation of t(9;22)(q34;q11) in CML. The Philadelphia (Ph) chromosome is a shortened chromosome 22 that results from the translocation of 3' (toward the telomere) ABL segments on chromosome 9 to 5' BCR segments on chromosome 22. Break- points (arrowheads) on the ABL gene are located 5' (toward the centromere) of exon a2 in most cases. Various breakpoint locations have been identified along the BCR gene on chromosome 22. Depending on which breakpoints are involved, different-sized segments from BCR are fused with the 3' sequences of the ABL gene. This results in fusion messenger RNA molecules (e1a2, b2a2, b3a2, and e19a2) of different lengths that are transcribed into chimeric protein products (p190, p210, and p230) with variable molecular weights and pre- sumably variable function. The abbreviation m-bcr denotes minor breakpoint cluster region, M-bcr major breakpoint cluster region, and μ-bcr a third breakpoint location in the BCR gene that is downstream from the M-bcr region between exons e19 and e20.
  • … And as the disease progresses, the growth capacity of the hematopoietic system in the marrow is amplified by acquisition of self-renewal capacity within the otherwise committed progenitor cells (such as GMPs) The development of chronic myelogenous leukaemia. Chronic myelogenous leukaemia (CML) is a biphasic disease initiated by expression of the BCR–ABL fusion gene product in self-renewing, haematopoietic stem cells (HSCs). HSCs can differentiate into common myeloid progenitors (CMPs), which then differentiate into granulocyte/macrophage progenitors (GMPs; progenitors of granulocytes (G) and macrophages (M)) and megakaryocyte/erythrocyte progenitors (MEPs; progenitors of red blood cells (RBCs) and megakaryocytes (MEGs), which produce platelets). HSCs can also differentiate into common lymphoid progenitors (CLPs), which are the progenitors of lymphocytes such as T cells and B cells. The initial chronic phase of CML (CML-CP) is characterized by a massive expansion of the granulocytic-cell series. Acquisition of additional genetic mutations beyond expression of BCR–ABL causes the progression of CML from chronic phase to blast phase (CML-BP), characterized by an accumulation of myeloid (in approximately two-thirds of patients) or lymphoid blast cells (in the other one-third of patients). Although the CML stem cell is multipotent, production of B cells from the neoplastic clone occurs only at low levels, and only rare T-cell precursors can be detected. This indicates that lymphopoiesis, particularly the development of T cells, is compromised by BCR–ABL expression.
  • In fact, this graphically encapsulates all of those ideas insofar as the linear growth rate and acquisition of genetic instability morphs at some point, asymptotically in which the aberrations are acquired exponentially fast, and, beyond what I have termed the “anaplastic threshold”, BCR-ABL - the genesis of this disease -actually becomes superfluous. Role of Oncogenic Addiction in Chronic Myeloid Leukaemia (CML). The natural history of CML most commonly includes an indolent progrNeastsuioren Rweivthiewdise| Casaencer susceptible to suppression by tyrosine kinase inhibitors. During this period, the disease is ‘addicted’ to the oncogenic events stimulated by breakpoint cluster region (BCR)–ABL (Abelson kinase). If the disease is left unchecked, it will progress to a more disorganized state marked by increased genetic instability. At some point during disease progression, the anaplastic threshold is reached and the disease is sufficiently disorganized and driven independently of input from the BCR–ABL tyrosine kinase. At this point, the disease is no longer addicted to BCR–ABL, and the therapeutic value of BCR–ABL- targeted tyrosine kinase inhibitors is vastly diminished.
  • That background on CML helps us understand the rational design of the different treatment modalities, and this is where the magic of IM as a targeted agent directed at BCR-Abelson kinase comes in. … and whereas we call this “targeted therapy” it actually hits many targets… …
  • Cumulative relative survival by calendar period of diagnosis Incidence remained stable over time with a consistent male predominance. Relative survival improved with calendar period with the greatest improvement in the last two calendar periods (figure). Five-year cumulative relative survival ratios (RSRs; 95% confidence intervals) were 0.21 (0.17-0.24), 0.23 (0.20-0.27), 0.37 (0.33-0.41), 0.54 (0.50-0.58) and 0.80 (0.75-0.83) in the five calendar periods, respectively. Ten-year RSRs were 0.06 (0.04-0.08) and 0.78 (0.73-0.83) in the first and last calendar periods, respectively. This improvement was confined to age groups up to 79 years of age but most pronounced in patients below 60 years. The 5-year RSRs for patients diagnosed 2001–2008 were 0.91 (0.85-0.94), 0.87 (0.78-0.92), 0.82 (0.72-0.90), 0.75 (0.61-0.86), and 0.25 (0.10-0.47) for the five age groups, respectively. Older age at diagnosis and male sex were associated with significantly higher excess mortality rates in models adjusted for potential confounding factors. In this large population-based study including > 3,000 CML patients survival increased significantly after 2001 (when imatinib mesylate was approved for clinical use in Sweden) for patients up to 79 years of age. Future studies are needed to assess if very old (>79 years) CML patients may benefit from an increased use of TKIs. Also newly introduced, targeted treatment options for CML need to be evaluated in future population-based studies.
  • Proposed mechanisms of action of ima- tinib-resistant mutations based upon the crystal structure of ABL complexed with imatinib. Ribbon representation of the kinase domain of ABL complexed to imatinib (Nagar et al., 2002), depicting resistant mutations. Imatinib is shown in gold. Positions 1–3 (red) are mutations that directly affect imatinib binding. All other positions are those that likely affect the ability of the kinase to achieve the conformation required to bind imatinib, including those in the P loop and those in the vicinity of the activation loop (green). The activation loop is colored purple. The positions of amino acids found mutated are depicted by spheres: 1, F317; 2, T315; 3, F359; 4, M244; 5, G250; 6, Q252; 7, Y253; 8, E255; 9, M351; 10, E355; 11, V379; 12, L387; 13, H396.
  • BCR-ABL kinase domain mutants exhibit varying degrees of biochemical and biological resistance to imatinib. Ba/F3 populations stably expressing mutant BCR-ABL isoforms were plated in the presence of varying concentrations of imatinib in triplicate, and viable cell counts were performed after 48 hr of exposure. Cell counts were normalized to the number of viable cells from control cultures grown in the absence of imatinib.
  • Abl-AMN107 (nilotinib) complex. Superposition of AMN107(nilotinib) (magenta) bound to AblM351T (orange), and imatinib (green) bound to Abl (yellow). H bonds within the AMN107-AblM351T complex are depicted as dashed red lines, whereas those in the imatinib complex are shown in black. The variability in the positions of side chains from the C-helix (top right corner) is due to crystal contacts that influ- ence the position of the N-terminal lobe of the kinase. The methyl-imidazole group of AMN107 packs in a hydrophobic pocket formed by these residues with the nitrogen exposed to solvent.
  • Nonetheless, this Phase II data for Nilotinib and dasatinib was very encouraging, and led to the inevitable phase III studies published this year testing both agesnts in the front line against the standard of care IM.
  • Lower left image: Eight-year cumulative incidence of complete molecular response (CMR) for patients receiving imatinib therapy according to the BCR-ABL1 transcript level at 3 months. The transcript level at 3 months identifies those patients with higher probability of achieving CMR on imatinib therapy. The 57 patients who had a 3-month transcript ratio ≤ 0.61% (blue line) had an 8-year cumulative incidence (CI) of CMR of 84.7%, and the 222 patients with a ratio of more than 0.61% (gold line) had a CI of CMR of only 1.5% (P < .001). Similar thresholds with high predictive power could be identified for 6 and 12 months (Table 2). Patients in the low-risk group defined at 3, 6, and 12 months also had significantly higher CI of CMR (Table 2). Lower right image: Evolution of the transcript level according to the 3-, 6-, and 12-month risk group. Transcript levels are expressed on a log10 scale. (A) Evolution of the transcript level over time. Patients are classified as high risk (gold circles) and low risk (blue circles) according to their transcript level at 3 months (higher or lower than 9.84%). The horizontal black lines represent the transcript level that defines the 3-month (9.84%), 6-month (1.67%), and 12-month (0.53%) risk groups. The majority of patients (all but six) who are classified as high risk at 3 months are also classified as high risk at 6 months, and all are classified as high risk at 12 months. The transcript level declines over time in the low-risk patients, although it remains comparatively high in the high-risk population. Many of the high-risk patients eventually abandon imatinib therapy because of unsatisfactory response, loss of response, or progression.
  • RR for OS, PFS, and EFS at 8 Years and Cumulative Incidences of CCyR, MMR, and CMR According to the Transcript Level at 3, 6, and 12 Months Table shows the cutoff in transcript levels that distinguishes low-risk and high-risk groups with maximal sensitivity and specificity for each outcome, the 8-year probability of outcome in each of the two groups created by applying the cutoffs identified for each outcome, and the 8-year probabilities for the various outcomes according to the risk group defined by OS.
  • ENESTnd Update: Continued Superiority of Nilotinib Versus Imatinib In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP)
  • An Ongoing Phase 3 Study of Bosutinib (SKI-606) Versus Imatinib In Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia (BELA)
  • Mechanisms of new agents attacking BCR-ABL
  • a | Sonic hedgehog (SHH) secreted by a localized source (shown in green) creates a gradient of concentration that provides positional information to the cells in the gradient, dependent on the concentration and duration of the signal, and specifies distinct cell fates accordingly (represented by different shades of blue). The amount of SHH signal received by a cell affects the ratio of glioma-associated oncogene (GLI) activator form–GLI repressor form (GLIact–GLIrep) protein content, with increased amount of GLIact in cells closer to the SHH secreting source and increased GLIrep in cells receiving low or no SHH. The ratio of GLIact:GLIrep proteins is instrumental in the interpretation of the SHH gradient. b | In the absence of SHH protein, patched (PTCH1) inhibits smoothened (SMO) activity allowing the protein kinase A (PKA)-mediated phosphorylation and truncation of GLI2 and GLI3. GLI2rep and GLI3rep are transported to the nucleus where they negatively regulate gene transcription. In the presence of SHH, interaction of SHH with PTCH1 relieves the inhibition of SMO. Activated SMO protects the GLI proteins from PKA-mediated modification and activates them. GLI1act–GLI3act are translocated to the nucleus where they activate target gene transcription.
  • Phase 1 Dose-Escalation Study of PF-04449913, An Oral Hedgehog (Hh) Inhibitor, in Patients with Select Hematologic Malignancies ASH 2011 abstract 424.
  • A patient case will focus on a newly diagnosed patient with CML. The case will include initial diagnosis assessments and continue through the treatment armamentarium. Attendees will participate in one of several roundtable discussion topics on options for the patient as he initiates frontline therapy. Each table will include 10 participants. Each table will be given a different frontline treatment approach to discuss to incorporate 4 different case scenarios using standard dose imatinib, escalated dose imatinib, dasatinib, or nilotinib . The moderator will assist with peer-to-peer collaboration on optimal strategies based on applying current effective clinical experiences. 5 minutes will be used for the chair to present the case 15 minutes will be used for the groups to discuss their designated case In the remaining 20 minutes, the Chair will present the four cases to the entire group and present what the consensus/discussion points were for each table regarding treatment approaches and managing the patient ’s symptoms and side effects as the case evolved.
  • The diagnostic and clinical evaluation of the patient suspected of having CML is critical to making an accurate diagnosis and selecting the most appropriate therapy for the patient. A complete history including co-morbid conditions and concomitant medications is necessary to identify the onset of the disease and to anticipate potential difficulties with the disease itself or with toxicities of active therapies. Common physical findings include splenomegaly or hepatomegaly as a result of extrameduallry clonal expansion. Analysis of the peripheral blood, bone marrow, and selected radiological testing is required to verify the phase and extent of disease.
  • The diagnostic and clinical evaluation of the patient suspected of having CML is critical to making an accurate diagnosis and selecting the most appropriate therapy for the patient. A complete history including co-morbid conditions and concomitant medications is necessary to identify the onset of the disease and to anticipate potential difficulties with the disease itself or with toxicities of active therapies. Common physical findings include splenomegaly or hepatomegaly as a result of extrameduallry clonal expansion. Analysis of the peripheral blood, bone marrow, and selected radiological testing is required to verify the phase and extent of disease.
  • [slide 8] Typical Laboratory Parameters by Phase of CML Diagnostic tests are critical for confirming the presence of CML and staging the disease to determine potential treatment options. In a peripheral complete blood count (CBC) with differential, the WBC count is typically  20 x 10 9 /L and may increase as the disease progresses. Increased numbers of granulocytes at all stages of maturation account for many of the elevated WBC counts. The increase in peripheral blast counts is characteristic as the disease enters the accelerated phase and blast crisis, at which time the disease resembles acute leukemia. 1 Although elevated platelets are frequently seen in the chronic phase, thrombocytopenia may signal the onset of advanced disease. Progressive anemia and basophilia are also characteristic of the advanced stages of CML, although lymphocyte and monocyte counts may remain relatively normal. In bone marrow aspirates and biopsy samples, the marrow is hypercellular with excessive myeloid hyperplasia and a shift to more immature myeloid forms and blasts; the myeloid-to-erythroid ratio is elevated to 10:1 to 30:1 (normal = 2:1 to 5:1). Eosinophils, basophils, and megakaryocytes are increased in number and may appear dysplastic. Cytogenetic analysis shows the presence of the Ph chromosome in 95% of patients; however, with advanced disease, additional karyotypic abnormalities may develop. The detection of bcr-abl RNA transcripts by the sensitive polymerase chain reaction is also used. 2-4 References 1. Cortes JE, Talpaz M, Kantarjian H. Chronic myelogenous leukemia: a review. Am J Med . 1996;100:555-570. 2. Hill JM, Meehan KR. Chronic myelogenous leukemia. Curable with early diagnosis and treatment. Postgrad Med . 1999;106:149-152, 157-159. 3. Faderl S, Kantarjian HM, Talpaz M. Chronic myelogenous leukemia: update on biology and treatment. Oncology (Huntingt). 1999;13:169-180. 4. Sawyers CL. Chronic myeloid leukemia. N Engl J Med . 1999;340:1330-1340.
  • How to calculate the Sokal and Hasford scores.
  • The table gives both the definitions and the suggested monitoring frequencies for CML. It is based on the NCCN 2011 guidelines. It should be noted that each successive level of monitoring represents a “deeper” level of remission in CML.
  • At this point, the audience will be given 15 minutes in their roundtable groups to discuss a different frontline treatment approach using standard dose imatinib, escalated dose imatinib, dasatinib, or nilotinib .
  • At this point, the Chair, Mollie Moran, will have 20 minutes to summarize/present all 4 roundtable group discussions to the entire audience. The handouts from the roundtables will be collected and handed to Mollie Moran.
  • Reactivation of BCR-ABL kinase activity within the leukemic cell can occur despite the presence of imatinib by either gene amplification or point mutation. 1 Three distinct mechanisms have been most commonly reported to contribute to imatinib resistance: 1. BCR-ABL Kinase Mutations The most commonly reported resistance mechanism 1 These mutations maintain BCR-ABL in the active conformation where imatinib cannot bind 1 Interrupt critical contact points preventing imatinib from binding 1 Mutations may be either acquired or, less frequently, primary (preexisting imatinib therapy) 2 2. Overexpression or Amplification of the BCR-ABL Transcripts Amplification of the levels of the BCR-ABL transgene, increased levels of BCR-ABL mRNA, and protein may contribute to imatinib resistance 3 3. Other Oncogenic Pathways SRC overexpression and activation of the LYN and HCK kinases 4 1. Branford S, Rudzki Z, Walsh S, et al. Blood . 2003;102:276-283. 2. Hochhaus A, La Ros ée P. Leukemia . 2004:1-17. 3. Weisberg E, Griffin JD. Blood . 2000;95:3498-3505. 4. Donato NJ, Wu JY, Stapley J, et al. Blood . 2003;101:690-698.
  • The majority of patients treated with TKI therapy in CP-CML achieve a complete cytogenetic response (CCyR). Achievement of a complete cytogenetic response (CCyR) is associated with a favorable long-term outcome (90%). Loss of response or late events are rare in patients who achieve a CCyR. Some patients are able to come off therapy and roughly 40% will remain in molecular remission. Some patients become negative for RQ-PCR – but most continue to have detectable levels of RQ-PCR. Patients who do not achieve a CHR by 3 months, any cytogenetic response by 6 months, a major cytogenetic response by 12 months or a CCyR within 18 months of the start of therapy are declared failures. CCyR rates for imatinib resistant or AP, BP disease remain suboptimal and highlight the need to continue clinical trials to elucidate Radich, J. Chronic Myeloid Leukemia 2010: Where are We Now and Where Can We Go? Hematology. 2010;122-128.
  • Turning our attention to safety profiles, this table includes my compilation of the most clinically relevant or frequently discussed adverse events associated with each agent. It is not intended to be inclusive of all adverse events. Myelosuppression remains an issue with all agents, although it appears that thrombocytopenia may be seen more frequently with dasatinib, and neutropenia less frequent with nilotinib. Fluid retention exist with all TKIs, but is more frequently observed with imatinib. The frequently highlighted issue of pleural effusion was again noted with dasatinib, but it is important to recognize that these are usually grade 1-2 and easily managed. Overall, GI toxicity seems more common with imatinib, and rash more frequent with nilotinib. Asymptomatic elevations in amylase appear to be class effect. Finally, the much discussed issue of QTc prolongation is infrequent and most likely a class effect.
  • Imatinib mesylate is generally well tolerated. To minimize and/or manage gastrointestinal upset, nausea, vomiting, diarrhea Take dose with a meal and large glass of water. Take at least 2 hours before bedtime, especially in patients with a history of esophagitis or hiatal hernia. Take 800-mg dose as 400 mg bid. Use antiemetic and antidiarrheal medications for severe effects. In clinical studies the majority of patients experienced an adverse event at some point in time. However, most were of mild to moderate grade and were easily manageable. Edema and fluid retention are more common in patients older than 65 years and those with a history of cardiac disease. Doses can be reduced to 300 mg and re-escalated with careful patient monitoring. Severe fluid retention may present as pulmonary edema, pleural or pericardial effusion, or ascites and requires dose interruption until resolved. Weigh patients regularly in order to detect rapid weight gain associated with this potentially life-threatening adverse event. Bone pain may result from the rapid clearance of Ph+ leukemic cells from the BM. Generally occurs early during therapy and is usually self-limiting. Nonsteroidal anti-inflammatory drugs to control pain should be used with caution in patients with a history of gastrointestinal bleeding. Deininger MW, O ’Brien SG, Ford JM, Druker BJ. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol . 2003;21:1637-1647. Gleevec ® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2003.
  • Establishing Best Practices for CML Therapy: A Workshop Symposium for the Advanced Practice Oncology Nurse

    1. 1. DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is current as of May 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME 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. Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
    2. 2. DISCLAIMER Participants 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 for patient 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 ofagents 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 foreach product for discussion of approved indications, contraindications, and warnings.
    3. 3. Disclosure of Conflicts of Interest Mollie E. Moran, MSN, CNP, AOCNP®, has no real or apparent conflicts of interest to report. Michael R. Savona, MD, FACP, reported a financial interest/relationship or affiliation in the form of: Speakers Bureau, Celgene Corporation, Eisai, Inc. Kathleen K. Curran, MSN, RN, CRNP, has no real or apparent conflicts of interest to report.
    4. 4. Learning Objectives L Upon completion of this activity, participants should be better able to: Evaluate the efficacy and safety profiles of first and second generation TKIs for the treatment of patients with CML Apply primary and secondary prevention strategies for TKI- associated side effects that patients with CML experience Implement effective treatment management and supportive care strategies to optimize patient adherence for CML patients receiving oral therapy Plan health-literate, culturally-sensitive patient education regarding CML pathogenesis, diagnostics, treatment options, and potential side effects Cite accruing CML clinical trials, and determine patient enrollment eligibility
    5. 5. Welcome and Introduction Mollie E. Moran, MSN, CNP, AOCNP® The James Cancer Hospital at The Ohio State University
    6. 6. Introduction to Faculty Panel Mollie E. Moran, MSN, CNP, AOCNP® – Oncology Nurse Practitioner – The James Cancer Hospital at The Ohio State University Michael R. Savona, MD, FACP – Director of Leukemia Research, Senior Investigator Hematologic Malignancies Research and Drug Development – Sarah Cannon Research Institute / Sarah Cannon Center for Blood Cancers Kathleen K. Curran, MSN, RN, CRNP – Nurse Practitioner – University of Pittsburgh Medical Center
    7. 7. Activity Agenda A12:30 – 12:35 pm I Introduction12:35 – 12:55 pm T The Evolving Landscape of CML Treatment12:55 – 1:35 pm Roundtable Workshop: Interactive Case on C Choosing CML Front-Line Therapy1:35 – 1:55 pm Medication Adherence: Patient and C Caregiver Teaching1:55 – 2:00 pm Audience Questions and Answers
    8. 8. The Evolving Landscape of CML Treatment Michael R. Savona, MD, FACP Sarah Cannon Research Institute /Sarah Cannon Center for Blood Cancers
    9. 9. Chronic Myeloid Leukemia (CML)Image courtesy of Michael R. Savona, MD, FACP.
    10. 10. CML  Incidence is 1.6–2.1 / 100,000 annually  Mortality is 0.2 / 100,000 annually in the US  Median age at diagnosis: 66  Female / Male ratio is ~ 1:1.7  Disease at presentation – Chronic phase 85%–90% – Accelerated phase and blast crisis 10%–15%Radich, 2012; Cortes et al, 2011; Jabbour et al, 2012.
    11. 11. Philadelphia Chromosome Results From Reciprocal Translocations Chromosome 9 Chromosome 22  Occur between chromosomes 9 and 22 to create the BCR- ABL gene transcript 5 BCR 3 – BCR-ABL fusion protein – Constitutively activates ABL 5 ABL 3 tyrosine kinase – Increases cellular proliferation, modifies differentiation, and inhibits apoptosis – Ph+ is also found in 20% of ALL BCR-ABL (Ph chromosome)Ph+ = Philadelphia chromosome-positive; ALL = acute lymphoblastic leukemia; BCR = breakpoint cluster region.NCCN, 2012; Martinelli et al, 2005.Figure modified from Faderl et al, 1999.
    12. 12. Progression of CML BCR-ABL HSC CML-BP CML-BP (myeloid) CMP CLP (lymphoid) Additional GMP MEP Additional mutations mutations MEG CML-CP CML-CP G M RBC Chronic Phase RBC T cell B cell • Myeloid hyperplasia Platelets Blast Phase • 10%–15% blasts • > 30% blasts • Natural history of Accelerated Phase • ~ 2/3 of BC patients have disease progression, G • > 15%, < 30% blasts myeloid blast crisis • Basophilia • ~ 1/3 have lymphoid blast 3–5 years • New cytogenetic crisis abnormalities in 50%–80% • Very poor prognosis of patientsHSC = haematopoietic stem cells; CMP = common myeloid progenitors; GMP = granulocyte/macrophage progenitors; G = granulocytes; M= macrophages; MEP = megakaryocyte/erythrocyte progenitors; RBC = red blood cells; MEG = megakaryocytes; CLP = commonlymphoid progenitors.Ren, 2005; Cortes et al, 2006.
    13. 13. Progression of CML (cont.) Independence from addiction to BCR-ABL Anaplastic threshold Oncogenic addiction to BCR-ABL TimeImage adapted from Savona et al, 2008.
    14. 14. Targeted Molecular Therapy in the Management of CML  Imatinib – Small molecule inhibitor of BCR-ABL tyrosine kinase activity – Binds only to the inactive conformation of BCR-ABL – Inhibits the activity of multiple kinases • ABL N H H • ARG N N N N • Kit N O • PDGFRA, PDGFRB NPDGFR = platelet-derived growth factor receptor; ARG = ABL-related gene.Wong et al, 2004.Image adapted from O’Hare et al, 2005.
    15. 15. 2010 ASH: 116 – CML Outcome in Sweden 3,173 patients (1973–2008); median age 62 yrs Years Since DiagnosisImage adapted from Bjorkholm et al, 2010.
    16. 16. Mechanisms of Secondary Resistance to Imatinib  Secondary resistance P P  Kinase domain mutations in BCR-ABL – Occurs in ~ 50% of patients  Overproduction of native BCR- P P ABL – Associated with ~ 10% of patients  BCR-ABL–independent P P P P mechanisms (largely uncharacterized) – Src activation – Non–BCR-ABL chromosomal translocations (ie, nup98/ddx10 fusion gene)Shah, 2005.
    17. 17. Role of Kinase Conformation in Imatinib Resistance  Point mutations in BCR-ABL kinase domain restricts its ability to adopt an inactive conformation Mutations that directly affect imatinib binding Imatinib Mutations that affect the conformation required to bind imatinibShah et al, 2002.
    18. 18. Mutations in BCR-ABL Kinase Domain Confer Varying Degrees of Resistance to Imatinib 1.4 Proportion of Viable Cells (%) E355G 1.2 M351T 1 F317L Y253F 0.8 Q252H 0.6 G250E T315I 0.4 E255K 0.2 WT P210 0 0.01 0.1 1 10 Imatinib (µM)  In select cases, dose escalation of imatinib may overcome mutation-based resistance, but this has not been seen with mutation T315IShah et al, 2002.
    19. 19. Nilotinib  A more selective, imatinib-derived ABL inhibitor  Binds to the inactive conformation of BCR-ABL  Also inhibits PDGFR and Kit kinases  ~ 20-fold more potent compared with imatinib  Inhibits kinase activity of Nilotinib most BCR-ABL mutants Imatinib – Not including T315IWalz et al, 2005; O’Hare et al, 2005.Image modified from Weisberg et al, 2005.
    20. 20. Comparative IC50 Values for Targeted Molecules for CML ABL PDGFR Kit Src-Family Kinases Cellular IC50 (nM)* Imatinib 630 30 100 NA Nilotinib 25 57 60 NA*Inhibition of cellular proliferation.Walz et al, 2005.
    21. 21. Dasatinib  An oral, multi-kinase inhibitor  Binds to both inactive and active conformations of BCR-ABL  325-fold more potent at inhibiting BCR-ABL kinase activity than imatinib  Active against all BCR-ABL mutants (to imatinib) tested – 1 exception is mutation T315IShah et al, 2004; O’Hare et al, 2005.Image adapted from O’Hare et al, 2005.
    22. 22. Comparative IC50 Values for Targeted Molecules for CML (cont.) ABL PDGFR Kit Src-Family Kinases Cellular IC50 (nM)* Imatinib 630 30 100 NA Nilotinib 25 57 60 NA Dasatinib <1 28† 5 0.5*Inhibition of cellular proliferation.†PDGFRB.Walz et al, 2005; Lombardo et al, 2004.
    23. 23. Targets of Tyrosine Kinase Inhibitors Imatinib Nilotinib Dasatinib Abl* ARG* PDGFRA* Abl* ARG* PDGFRA* Abl* ARG* PDGFRA* PDGFRB* PDGFRB* Src* Yes* PDGFRB* Src Yes Src Yes Fyn CSF1R Fyn CSF1R Fyn* CSF1R Fgr Kit* Fgr Kit* Fgr Kit* Blk Blk Blk Lck VEGFR2 Lck VEGFR2 Lck* VEGFR2 Hck Lyn VEGFR3 Hck Lyn VEGFR3 Hck* Lyn* VEGFR3 VEGFR1 VEGFR1 VEGFR1 Flk2 Flk2 Flk2 Src family Src family Src family kinases kinases kinasesCSF1R = colony stimulating factor 1 receptor; VEGFR = vascular endothelial growth factor receptor; PDGFR = platelet-derived growthfactor; ARG = ABL-related gene.*Sensitive to drug.Adapted from Walz et al, 2005; Lombardo et al, 2004; Wong at al, 2004.
    24. 24. Saglio et al, 2010; Kantarjian et al, 2010.
    25. 25. ENESTnd: Cumulative Incidence of MMR3 (3-log reduction) n 100 Nilotinib 300 mg BID 282 Nilotinib 400 mg BID 281 90 By 3 Years Imatinib 400 mg QD 283 80 73%, p < .0001 By 1 Year 70 % With MMR 55%, p < .0001 70%, p < .0001 60 Δ 17%–20% 50 51%, p < .0001 53% 40 Δ 24%–28% 30 20 27% 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Since RandomizationMMR = major molecular response.Saglio et al, 2011.
    26. 26. DASISION: Cumulative Incidence of MMR3 100 Dasatinib 100 mg QD Imatinib 400 mg QD 80 By 24 months 65% % of Patients By 12 months 60 47% Δ 18% 47% 40 Δ 19% 28% 20 0 0 3 6 9 12 15 18 21 24 27 Months*Response achieved by 24 months; calculated from randomized subjects with typical BCR-ABL transcripts.Kantarjian et al, 2011.
    27. 27. Hasford Risk: Age Spleen size Platelet count Basophils Eosinophils MyeloblastsMarin et al, 2011; Hasford et al, 1998.
    28. 28. Assessment of BCR-ABL1 Transcript Levels at 3 Months Is the Only Requirement for Predicting Outcome for CML Patients Treated With TKIs Outcome RR for Transcript Level (Log) 8-Year Probability of the Outcome No. of Cutoff Patients at Percent RR p Value (%) Risk (%) p Value BCR-ABL1 transcript level at 3 months OS 0.161 < .001 < .001 Low Risk ≤ 9.84 211 93.3 High Risk > 9.84 68 56.9 PFS 0.162 < .001 < .001 Low Risk ≤ 9.54 208 92.8 High Risk > 9.54 71 57.0 EFS 0.102 < .001 < .001 Low Risk ≤ 9.84 211 65.1 High Risk > 9.84 66 6.9 CCyR 5.17 < .001 < .001 Low Risk ≤ 8.58 169 99.4 High Risk > 8.58 79 21.7 MMR 12.98 < .001 < .001 Low Risk ≤ 2.81 141 82.5 High Risk > 2.81 137 21.1 CMR 10.95 < .001 < .001 Low Risk ≤ 0.61 57 84.7 High Risk > 0.61 222 1.5CCyR = complete cytogenetic response; CMR = complete molecular response; EFS = event-free survival; OS = overall survival;PFS = progression-free survival; RR = relative risk.Marin et al, 2011.
    29. 29. How to Choose?
    30. 30. Adverse Events  A thorough discussion on the risks of non- hematologic side effects is necessary  The vastly different side-effect profile between dasatinib and nilotinib/imatinib means near total compliance/toleranceKantarjian et al, 2010.
    31. 31. Adverse Events (cont.) Again, nuances in the AEs seen even between these relatively similar drugs – These match clinical practice*ALT = alanine aminotransferase;AST = aspartate aminotransferase.†Nilotinib was administered at a dose of either 300 mg or400 mg BID, and imatinib at a dose of 400 mg QD.‡Listed are all nonhematologic AEs that occurred in at least10% of patients in any group.Saglio et al, 2010.
    32. 32. Nilotinib Vs. Imatinib in CML-CP Drug-Related AEs (≥ 10% in Any Group) Nilotinib Nilotinib Imatinib % Patients 300 mg BID 400 mg BID 400 mg QD (n = 279) (n = 277) (n = 280) All Grade All Grade All Grade Grades 3/4 Grades 3/4 Grades 3/4 Nausea 14 <1 21 1 34 0 Muscle spasms 8 0 7 <1 27 <1 Diarrhea 8 <1 7 0 26 1 Vomiting 5 0 9 1 18 0 Peripheral edema 5 0 6 0 15 0 Facial edema <1 0 2 0 11 <1 Eyelid edema <1 0 2 <1 16 <1 Periorbital edema <1 0 1 0 14 0 Rash 32 <1 37 3 13 2 Headache 14 1 22 1 9 <1 Pruritus 16 <1 13 <1 6 0 Alopecia 9 0 13 0 5 0 Myalgia 10 <1 10 0 11 0 Fatigue 11 0 9 <1 10 <1Hughes et al, 2010.
    33. 33. Bosutinib Vs. Imatinib: CML Front-Line Therapy-Related AEs ≥ 10% Bosutinib Imatinib (n = 248) (n = 251) AE, % Any 3/4 Any 3/4 p Value Any AE 96 64 95 47 NS Diarrhea 68 10 21 1 < .001 Vomiting 32 3 13 0 < .001 Nausea 31 1 35 0 NS Rash 20 1 15 1 NS Pyrexia 16 1 9 1 .022 Abd pain upper 12 0 5 0 .007 Abd pain 12 1 5 0 .005 Fatigue 11 1 12 1 NS Headache 10 1 8 0 NS URI 10 0 6 0 NS Bone pain 4 0 10 1 .004 Muscle cramps 2 0 20 0 < .001 Periorbital edema <1 0 14 0 < .001Abd = abdominal; URI = upper respiratory tract infection.Gambacorti-Passerini et al, 2010.
    34. 34. CML Prevalence and Choice of TherapyHow Does Growing Prevalence Effect Our Choice?~ 5,000 ~ 120,0002001 2010 2020 2030
    35. 35. Rational Design of Future CML Therapy Translation HHT Post-translational Hsp modification Inh Transcription of Sfb BCR-ABLT315I HDAC I AKI FTI MKI mTOR SPI BCR-ABLT315I Crcm PEITC Inhibition of BCR-ABLT315I FTY720 Protein Degradation and Synthesis Direct Inhibition of JAK2-I BCR-ABLT315IHHT = Homoharringtonine; Hsp = heat shock proteins; Sfb = sorafenib; mTOR = mammalian target of rapamycin;HDAC = Histone deacetylases.Adapted from Cooper et al, 2009.
    36. 36. How to Address the Leukemia Stem Cell Ideal Targetable Stem Cell Pathways… Pathway known to regulate self-renewal, Hedgehog differentiation, and proliferation in stem cells that are necessary for embryogenesis, hijacked Wnt in carcinogenesis, and unnecessary/superfluous in homeostasisTu, 2010; Images courtesy of national geography, Copyright (c) Kanehisa Laboratories - www.kegg.org.Used with permission. Notch
    37. 37. Hedgehog Inhibition: Novel Mechanism With Applications Across a Broad Range of Cancers  Hedgehog inhibition plays a key role in regulating cancer stem cell survival and disrupting Hedgehog signaling in the malignant niche that contributes to disease resistance Smoothened (SMO) Regulates Cancer Stem Cells PF-04449913 PTCH1 SHH SHH Gradient SMO GLI rep GLI2, GLI3 PKA GLI1-GLI3 P GLI3 (GLI2) P GLI act GLI3rep (GLI2) GLI1act-GLI3act SHH-producing cellAdapted from Crompton et al, 2007.act = activated form; GLI = glioma-associated oncogene; PTCH = patched; SMO = smoothened; rep = repressor form; SHH = sonic hedgehog.
    38. 38. PF04449913 – HH Inhibition in Myeloid Disease  Major Inclusion Criteria  Major Exclusion Criteria – ≥ 18 years – Active graft vs. host disease – Previously treated (including – Life-threatening or clinically transplant) or untreated select significant uncontrolled hematologic malignancies infection including: – Active central nervous system • Myelodysplastic syndrome involvement by leukemia (MDS) • Myelofibrosis (MF) • Chronic myelomonocytic leukemia (CMML) • CML, including T315I mutants • AML – ECOG PS: 0–2 – Adequate organ function (renal, hepatic, cardiac)ECOG PS = Eastern Cooperative Oncology Group performance status; HH = hedgehog.Jamieson et al, 2011.
    39. 39. Well Tolerated Event, n (%) Grade 1 Grade 2 Grade 3 Grade 4 Dysgeusia 4 (11%) 2 (6%) 0 0 Alopecia 3 (9%) 0 0 0 Muscle spasms 1 (3%) 1 (3%) 0 0 Nausea 2 (6%) 0 0 0 Vomiting 2 (6%) 0 0 0  1 case of grade 3 hypoxiaJamieson et al, 2011.Photo courtesy of of Michael R. Savona, MD, FACP, national geography.
    40. 40. AML: Reduction in Blasts (7 of 20)Jamieson et al, 2011.
    41. 41. Key Takeaways CML is characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 t(9;22)(q34;q11) that causes fusion of the BCR and ABL genes There are a number of oral TKIs available for effectively treating CML-CP
    42. 42. Roundtable Workshop:Interactive Case on Choosing CML Front-Line Therapy Mollie E. Moran, MSN, CNP, AOCNP® The James Cancer Hospital at The Ohio State University
    43. 43. Case Study  A 48-year-old flight attendant presents for her annual physical exam. She is in her usual state of health and is without complaints. She is found to have a palpable spleen at 5 cm below the LCM. – WBC 38,000 K/uL • Basophils 2% • Eosinophils 2% • Blasts 7% – Platelets 550,000 K/uL – LDH 250 U/L (range 100–190 U/L) – UA 7.8 mg/dL (range 4.47.6 mg/dL) – Remainder of labs normal – Physical exam normal except as noted aboveWBC = white blood count; LDH = lactate dehydrogenase; UA = uric acid.
    44. 44. Case Study (cont.) – Medical History • Type II DM controlled with metformin • HTN controlled with lisinopril and HCTZ – Family History • Negative for leukemia or lymphoma • 2 brothers and 1 sister, all AW CML is suspected
    45. 45. Case Study (cont.)  BMB + for CML – 8% blasts – 2% basophils  Cytogenetics 46 XX t(9:22;11) 20/20 cells  FISH 98% + BCR-ABL metaphases  BCR-ABL fusion transcript is positive by RT-PCR  Diagnosis of CML is confirmedRT-PCR = real-time PCR.
    46. 46. Diagnostic Evaluation: Peripheral Blood Diagnostic Study Clinical Significance CBC, differential, plts, Evaluate for the presence of leukocytosis, basophilia, reticulocyte count with thrombocytosis, monocytosis, peripheral blasts, morphological evaluation of the peripheral abnormalities, cytopenias smear Establish baseline for monitoring of treatment-induced cytopenias LDH, UA, PO4, Ca++, K+ Elevated LDH is a poor prognostic indicator – indicative of higher cell turnover or tumor burden and increased risk for tumor lysis Baseline hepatic, renal, and Mild and transient transaminitis is common with imatinib therapy electrolyte profiles Mild hyperbilirubinemia is reported with imatinib, dasatinib, and Lipase for nilotinib nilotinib Elevated lipase levels have been reported with nilotinib Renal toxicities are rare, but patients requiring diuretic therapies will need continued monitoring HLA typing For possible BMT BCR-ABL by PCR Establish baseline for continued evaluation of molecular response Consistent lab recommendedPO4 = phosphate; Ca++ = calcium; K+ = potassium; HLA = human leukocyte antigen; BMT = bone marrow transplant.Kurtin, 2010; Druker et al, 2008.
    47. 47. Diagnostic Evaluation: Bone Marrow Diagnostic Study Clinical Significance Aspirate Evaluation of morphological abnormalities of hematopoietic precursors (myeloid vs. lymphoid and stage of maturation) Used for flow cytometry, FISH, or PCR analysis and cytogenetics Biopsy Evaluate cellularity, topography, presence of fibrosis Cytogenetics Evaluate for possible non-random chromosomal abnormalities – based on evaluation of 20 metaphases > 2 metaphases is considered non-random Most useful in initial diagnostic evaluation for t(9;22) Useful for detection of emerging chromosomal abnormalities in patients with evidence of persistent leukemic clone by RQ-PCR FISH 5%–10% false positive rate Does not replace regular cytogenetics to detect additional cytogenetic abnormalitiesRQ-PCR = real-time quantitative-PCR.Druker et al, 2008.
    48. 48. Typical Laboratory Parameters by Phase of CML Phase of CML Parameter Chronic Accelerated Blast Crisis WBC ≥ 20 x 109/L — — Blasts 1%–15% ≥ 15% ≥ 30% Basophils ↑ ≥ 20% — Platelets ↑ or normal ↓ or ↑ ↓ Bone marrow Myeloid hyperplasia Cytogenetics Ph+ BCR-ABL + + +CMLalliance.net.
    49. 49. CML Phases Chronic Accelerated BlasticPast 3–5 years 12–18 months 3–9 monthsPresent 25+ years 4–5 years 6–12 months • Asymptomatic • Blasts ≥ 15% • Blasts ≥ 30% (if treated) • Bl + pros ≥ 30% • Basophils ≥ 20% • Extramedullary • None of criteria for accelerated or blast • Plts < 100,000/mcl disease with localized blast phase • Clonal evolution immature blasts 50NCCN, 2012.
    50. 50. Survival in Early CP-CML YearsAdapted form Kantarjian et al, 2012.
    51. 51. Sokal and Hasford Scores  Calculated at diagnosis to predict prognosis  Sokal Index – Percent of peripheral blasts – Platelet count – Spleen size – Age  Hasford includes the above and – Eosinophils – BasophilsHiwase et al, 2011.
    52. 52. How to Calculate the Sokal and Hasford ScoresHasford score Sokal score0.6666 x age (0 when < 50 years, 1 otherwise) Exp. (0.0116 (age – 4.34)) + 0.042 x spleen size + 0.0345 (spleen – 7.51) (cm below costal margin) + 0.188 (platelets/700)2 – 0.563) + 0.0584 x blasts (%) 0.0887 (percentage of blasts – 2.1) + 0.0413 x eosinophils (%) + 0.2039 x basophils < 0.8 good prognosis (0 when < 3%, 1 otherwise) 0.8–1.2 moderate prognosis + 1.0956 x platelet count > 1.2 poor prognosis (0 when < 1,500, 1 otherwise) X 100≤ 780 low risk group> 780 and ≤ 1,480 intermediate risk group> 1,480 high risk groupThomas et al, 2001.
    53. 53. Case Study (cont.) Sokal  Hasford – 0.97 – 785 – Intermediate Risk – Intermediate Risk
    54. 54. Case Study (cont.) She is initiated on one of the following therapies for CML: – Imatinib 400 mg po daily – Imatinib 800 mg po daily – Dasatinib 100 mg po daily – Nilotinib 300 mg BID
    55. 55. Roundtable Discussion Topics Patient and disease characteristics – Influence on choice of front-line therapy Lab values and diagnostic interpretation Cytogenetic evaluation – FISH and RT-PCR Treatment selection rationale
    56. 56. Response Definitions and Monitoring of CML Hematologic Cytogenetic Molecular Definitions Complete: Complete: Ph+ 0% Complete: BCR-ABL Plts < 450 x 109/L Partial: Ph+ 1%–35% undetectable by WBC < 10 x 109/L Major: Ph+ 36%–65% RT-PCR differential without Minor: Ph+ 66%–95% Major: ≥ 3-log reduction immature granulocytes in BCR-ABL mRNA nonpalpable spleen Monitoring Check q2wks until Check at 6, 12, Check q3mos; CR achieved and achieved and mutational analysis in confirmed, then q3mos confirmed, then at case of failure, unless otherwise least q12mos suboptimal response, or required transcript level increaseCR = complete response; mRNA = messenger ribonucleic acid.NCCN, 2012.
    57. 57. Roundtable Discussion Topics (cont.) Adverse events – Primary prevention strategies/cautions and contradictions with TKI use – Monitoring protocols – Overall side-effect management Dose adjustment protocols Evaluation and monitoring of response Treatment failure/resistant disease Patient education
    58. 58. Roundtable Discussions (10 minutes)
    59. 59. Faculty Roundtable Presentations (20 minutes)
    60. 60. Results With Imatinib in Early CML-CP: IRIS Trial at 8 Years  304 (55%) patients on imatinib on study  Projected results at 8 years – CCyR: 83% • 82 (18%) lost CCyR, 15 (3%) progressed to AP/BP – EFS: 81% – TFS: 92% • If MMR at 12 mos: 100% – Survival: 85% (93% CML-related)  Annual rate of transformation: 1.5%, 2.8%, 1.8%, 0.9%, 0.5%, 0%, 0%, 0.4%CCyR = complete cytogenic response; AP = accelerated phase; BP = blast phase; EFS = event-free survival;TFS = transformation-free survival; IRIS = International Randomized Study of Interferon and STI571.Deininger et al, 2009.
    61. 61. Long-Term Outcome With Imatinib in Early CML-CP (ITT) 1.0 0.9 0.8 Probability (%) 0.7 0.6 0.5 Survival 63% PFS 0.4 CHR 0.3 EFS Loss of MCyR 0.2 0.1 0 6 12 18 24 30 36 42 48 54 60 Time From Start of Imatinib Therapy (months)ITT = intent-to-treat.de Lavallade et al, 2008.
    62. 62. Criteria for Failure and Suboptimal Response to Imatinib Time Response (months) Failure Suboptimal Optimal 3 No CHR No CG Response < 65% Ph+ No CHR 6 ≥ 35% Ph+ ≤ 35% Ph+ > 95% Ph+ 12 ≥ 35% Ph+ 1%–35% Ph+ 0% Ph+ 18 ≥ 5% Ph+ No MMR MMR Loss of CHR Loss of MMR Stable or Any Loss of CCyR Mutation Improving MMR Mutation CEBaccarani et al, 2009.
    63. 63. High-Dose Imatinib as Initial Therapy in CML  281 patients Rx’d with imatinib 400 mg (n = 73) or 800 mg (n = 208) Overall Response (%) 400 mg 800 mg p Value CCyR 87 91 .49 MMR 78 87 .06 CMR 39 49 .21 Time to CMR EFS 1 1.0 Total CMR 800 mg 206 100 p = 0.04 0.8 400 mg 71 28 0.8 0.6 0.6 0.4 0.4 Total No.event 400mg 73 15 p = 0.01 800mg 208 22 0.2 0.2 0 0.0 0 12 24 36 48 60 72 84 96 108 120 0 12 24 36 48 60 72 84 96 108 120CMR = complete molecular response.Pemmaraju et al, 2010.
    64. 64. TOPS: Rate of MMR Over Time by Imatinib Dose (ITT) 476 patients with early CML-CP randomized to imatinib 400 mg daily vs. 800 mg daily Percent (%) Outcome at 24 months 400 mg 800 mg CCyR 76 76 MMR 54 51 EFS 95 95 PFS 97 98  Significant impact of dose intensity/treatment interruptions on MMR rateTOPS = tyrosine kinase inhibitor optimization and selectivity; PFS = progression-free survival.Baccarani et al, 2009.
    65. 65. Dasatinib Vs. Imatinib Study in Treatment-Naïve CML (DASISION) Trial Design Dasatinib 100 mg QD (n = 259)  N = 519 Follow-Up  108 centers Randomized a 5 yrs  26 countries Imatinib 400 mg QD (n = 260)  Primary end point: Confirmed CCyR by 12 mos  Secondary/other end points: Rates of CCyR and MMR; times to confirmed CCyR, CCyR, and MMR; time in confirmed CCyR and CCyR; PFS; OSStratified by Hasford risk score.aDASISION = dasatinib vs. imatinib study in treatment-naive CML patients.Kantarjian et al, 2011.
    66. 66. Dasatinib Vs. Imatinib in Newly Diagnosed CML-CP 519 patients randomized to dasatinib 100 mg QD (n = 259) or imatinib 400 mg QD (n = 260) Median follow-up: 24 months Outcome Dasatinib 100 Imatinib 400 % CCyR 86 82 % MMR 64 46 % BCR-ABL ≤ 0.0032% 17 8 % Discontinued Therapy 23 25 New Mutations (No.) 10 10Kantarjian et al, 2011.
    67. 67. Nilotinib Vs. Imatinib in Newly Diagnosed CML-CP 846 patients randomized to nilotinib 300 mg BID (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg QD (n = 283) Minimum follow-up: 24 months Outcome Nilotinib 300 Nilotinib 400 Imatinib 400 % CCyRa 87 85 77 % MMRa 71 67 44 % BCR-ABL ≤ 0.0032%a 26 21 10 % Discontinued Treatment 18 21 22 New Mutation (No.) 10 8 20a By 24 months.Larson et al, 2011; Kantarjian, Hochhaus, et al, 2011.
    68. 68. Known Mechanisms of Imatinib ResistanceBranford et al, 2003; Weisberg et al, 2000; Donato et al, 2003.
    69. 69. BCR-ABL Point Mutations  Point mutations in ABL kinase alter TKI binding – Most frequent mechanism of resistance – Maintains the “active” or “open” conformation of the BCR-ABL protein – Interrupts critical contact points preventing imatinib binding – Imatinib binds to the BCR-ABL protein in the “closed” or “inactive” conformation  P-loop mutations – Located along the adenosine triphosphate (ATP) binding site – Destabilize conformation necessary for imatinib binding – Shift kinase to favor “active” state  Activation loop mutations – Maintain the active conformation, preventing imatinib from bindingWeisberg et al, 2007.
    70. 70. CCyR Rates for Approved TKIs Time of TKI CML Phase Therapy CP (%) AP (%) BP (%) Newly Imatinib 75 20 10 Diagnosed Nilotinib 95 Dasatinib 95 Resistance or Nilotinib 45 20 30 Progression Dasatinib 50 30 30Radich, 2010.
    71. 71. EFS by Treatment in Early CML-CP Probability EFS (%) Time (months)Adapted from Cortes et al, 2009.
    72. 72. Toxicity Profiles GRADE 3/4 HEM (%) NON-HEM (%) Imatinib Anemia (5–7) Fluid Retention/Edema (39–42) Neutropenia (20) Nausea (20–21) Thrombocytopenia (9–10) Diarrhea (17–21) Rash (11–17) Elevated Amylase (18) Dasatinib Anemia (10) Fluid Retention/Edema (19) Neutropenia (21) Pleural Effusion (10, no grade 3/4) Thrombocytopenia (19) Nausea (8) Diarrhea (17) Rash (11) Elevated Amylase (not listed) Nilotinib Anemia (3) Fluid Retention/Edema (7–8) Neutropenia (10–12) Nausea (11–19) Thrombocytopenia (10–12) Diarrhea (6–8) Rash (31–36) Elevated Amylase (12–15) QTc > 500 msec • Nilotinib trial: 1 patient on imatinib, no patients on nilotinib • Dasatinib trial: 1 patient on imatinib, 1 patient on dasatinibGleevec® prescribing information, 2012; Sprycel® prescribing information, 2012; Tasigna® prescribing information, 2012.
    73. 73. Myelosuppression  Generally occurs in the first few months  Mild-to-moderate in severity (grade 1–2) and self-limiting  Monitoring of blood counts can detect serious events – Weekly during the first and/or second months – Monthly during second and third months – Every 3 months thereafter  Serious events can be managed by dose reduction or interruption – Per agent-specific prescribing information  Use of growth factors may be used to manage Neutropenia Dasatinib, Imatinib, Nilotinib Thrombocytopenia Dasatinib, NilotinibJabbour et al, 2011; NCCN, 2012; Tasigna® prescribing information, 2012.
    74. 74. General Fluid Retention  Patient education key to allow patients to recognize and report symptoms Symptoms of Fluid Retention Management of Peripheral Edema or Rapid Weight Gain  Rapid weight gain  Diuretic therapy  Peripheral and peri-orbital  Limit salt intake edema  CXR for patients with  Heart- and lung-associated symptoms suggestive of symptoms pleural effusion (dyspnea or dry cough)  Dose reduction, interruption, or discontinuationCXR = chest X-ray.Jabbour et al, 2011; NCCN, 2012.
    75. 75. Pleural Effusion  Patients should be aware of symptoms – Chest pain – Dry cough – Dyspnea  Pleural effusions are manageable by – Dose interruption/reduction – Supportive measures (diuretics, steroids)  Severe pleural effusion may be require thoracentesis and oxygen therapyJabbour et al, 2011; NCCN, 2012; Sprycel® prescribing information, 2012.
    76. 76. Metabolic Abnormalities  Nilotinib – Mild-to-moderate in severity – Lipase or amylase elevation • Generally self-limiting – Use with caution in patients with a history of pancreatitis – Lipase and amylase levels should be checked as indicated  Hypokalemia, hypomagnesium – Mild-to-moderate in severity – Supplement if necessaryJabbour et al, 2011; Tasigna® prescribing information, 2012.
    77. 77. Management of QTc Prolongation  Prolongation of the QTc interval can occur with nilotinib (black box warning) or dasatinib  Prior to initiation of therapy, check serum potassium and magnesium levels as well as other medications  In case of severe events – Therapy should be withheld until resolution and serum potassium and magnesium levels are corrected – Check concomitant medications  Take caution in prescribing to patients at risk for or with known QTc prolongation – Hypokalemia, hypomagnesemia, or congenital long QT syndrome – Patients taking medicines known to prolong QT including antiarrhytmic drugs, azolesTasigna® prescribing information, 2012; Sprycel® prescribing information, 2012.
    78. 78. QTc Prolongation (cont.)  Obtain EKG at baseline; at 7 days after any dose adjustment  QTcF interval ≥ 480 msec, monitor electrolytes periodically and review concomitant medications  If QTcF returns to < 450 msec and to within 20 msec of baseline within 2 weeks, restart at previous dose  QTcF is between 450 msec and 480 msec after 2 weeks reduce the dose to 400 mg QDEKG = electrocardiogram; QTcF = QT interval corrected for heart rate using Fridericia’s formula.Tasigna® prescribing information, 2012.
    79. 79. Managing Gl and Musculoskeletal Toxicities  Gl toxicities include nausea,  Musculoskeletal toxicities vomiting, diarrhea include muscle cramps/bone – Take dose with a meal and pain/arthralgia large glass of water (imatinib) – Ca2+ supplements – Take at least 2 hours before – NSAIDs bedtime • Mild narcotics – Use antiemetic and – Quinine/tonic water antidiarrheal medications for severe effects  Hepatic toxicity – ± Proton pump inhibitors – With grade 2–3, dose • H2 inhibitors ± histamine interruptions, reductions, and potentially discontinuation – With grade 4, should consider alternative agentGI = gastrointestinal; NSAIDs = nonsteroidal anti-inflammatory drugs.Deininger et al, 2003.
    80. 80. Muscle-Related AEs  Grade 3/4 are infrequent  Symptomatic relief may be achieved with calcium and magnesium supplements  Quinine – Tonic waterJabbour et al, 2011.
    81. 81. Cutaneous Reactions Primary AE Drug Specific Considerations Dermatologic Imatinib 12.7% of patients reported with rash grade 1/2 Toxicity 40.9% incidence of depigmentation 3.6% hyperpigmentation Dasatinib 22% incidence of rash (grade 1/2) 0.5% (grade 3/4) Nilotinib 30% incidence of rash (grade 1/2) 2% (grade 3/4)Jabbour et al, 2011; Sprycel® prescribing information, 2012; Tasigna® prescribing information, 2012; Gleevec® prescribing information, 2012.
    82. 82. Numerous Drug Interactions IMATINIB DASATINIB NILOTINIB PPI ↑ Exposure (inhibit Pgp) ↓ Absorption (decreased solubility) ↑ Exposure (inhibit Pgp) H2-antagonists ↑ Exposure (inhibit Pgp) ↓ Absorption ↑ Exposure (inhibit (decreased solubility) CYP 3A4) ↓ Intracellular exposure (inhibit hOCT-1) ↑ Exposure (inhibit Pgp) Metoclopromide ↑ QTc ↑ QTc ↑ QTc Metformin ↓ Intracellular exposure (inhibit hOCT-1) Warfarin ↑ Increased ↑ Increased anticoagulation anticoagulation (↑ CYP 2C9 by TKI) (↑ CYP 2C9 by TKI) And many more….Haouala et al, 2011.
    83. 83. General Patient Education  Do not crush or cut tablets  Missed doses should not be made up, instruct patient not to double the doses  Should not be administered to pregnant women  Dasatinib: Antacid 2 hours pre- or post-dose, avoid medications that reduce stomach acid  Nilotinib: No food 2 hours prior and 1 hour after dose  No grapefruit juice  Notify staff of current, new, and OTC medications that are being consumedOTC = over-the-counter.Sprycel® prescribing information, 2012; Tasigna® prescribing information, 2012; Gleevec® prescribing information, 2012.
    84. 84. Medication Adherence:Patient and Caregiver TeachingKathleen K. Curran, MSN, RN, CRNPUniversity of Pittsburgh Medical Center
    85. 85. “Drugs Don’t Work in Patients Who Don’t Take Them.” – C. Everett Coop, MD  Low-adherence to prescribed treatments is very common – Typical adherence rate for medication to treat chronic disease is about 50%  Success rate for TKIs are high, but require long- term administration in responsive patients  Patients may feel that ‘drug holidays’ are to be expected when patients are advised to hold their dose to control neutropenia or side effects. They may feel that skipping doses is acceptable.Sackett, 1978; Guilhot, 2004.
    86. 86. Oral Therapy Adherence  About 25% of patients being treated for CML did not take imatinib as prescribed  Lack of compliance had adverse effect on cytogenetic and molecular responses – Patients who look < 90% of their imatinib (missing 3 doses in 1 month) had worse responses than those who were 100% compliant – None who took < 80% of imatinib had a complete responseBazeos et al, 2009.
    87. 87. As Many Reasons as Snowflakes There is not one intervention that will work for all people Patients must be included when adherence methods are being evaluated Patients who miss their appointments are at high risk for non-adherence to medication Patients with complex regimens are at high risk for missed doses
    88. 88. What Works?  Identify patients at high risk—missed appointments, missed refills, evaluate barriers  Evaluate your patients and discuss their feelings about the need for treatment  Make the regimen as simple as possible – Look at all the medications that have been prescribed and look for ways to simplify  Listen to the patient and family and align identified behaviors that may decrease forgetfulnessOsterberg et al, 2005.
    89. 89. Interventions to Try Patients will bring ALL of their medication to clinic visits Calling the patient frequently to assess side effects and adherence Medication reminder systems Recruit assistance from the pharmacist Have the patient identify what will help
    90. 90. Consider Health literacy Health beliefs Patient-practitioner relationship Depression Support system or lack of support Financial barriers and privacy concerns Denial of illness and its severity
    91. 91. Compliance-Adherence-Persistence  Compliance implies paternalism and obedience  Adherence is the extent to which a person’s behavior—taking medication, following a diet, making lifestyle changes—corresponds with agreed recommendations from a health-care provider  Persistence is the ability of a person to continue taking medication for the intended course of therapyWHO, 2003.
    92. 92. Three Decades of Research Many, many, many interventions have been tried to assist people with medication adherence have proven: – Nothing works for every person Find what works for some of your patients; find something else that works for other patients; then combine other strategies to work for the rest of them
    93. 93. Medication Adherence Discussions1) Roundtable Discussion (5 minutes) – Best practices for ensuring oral therapy adherence2) Microphone Session (10 minutes) – Volunteers to share their best practices with the audience Possible Discussion Topics – Medication precautions/drug interactions – Strategies to improve compliance and adherence – The “how to” on recording and reporting adverse reactions/keeping a diary – Healthy literacy and cultural sensitivities
    94. 94. Final Key Takeaways There are a number of oral TKIs available for effectively treating CML-CP Patients require close monitoring for response, resistance, and tolerance to optimize potential for a complete response to therapy Nurses play a key role by monitoring effective treatment management and implementing supportive care strategies to optimize patient adherence for CML patients receiving oral therapy Nurses can plan health-literate, culturally-sensitive patient education regarding CML pathogenesis, diagnostics, treatment options, and potential side effects to support patients receiving therapy for CML
    95. 95. Final Key Takeaways (cont.) Patients who were not 100% compliant did not achieve CR in clinical trials Assess every patient’s risk of medication non-adherence with every encounter For every patient, for every visit… have them bring in all medications. Assess for compliance and interactions. Excellent symptom management of side effects can assist patients to tolerate medication The nurse is at the perfect position to assist patients to achieve the best possible outcome

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