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RTP TV: An 8-Part Live CME Webcast Series

RTP TV: An 8-Part Live CME Webcast Series. Part VIII – Chronic Myeloid Leukemia Tuesday, August 2, 2011 7:30 PM – 8:30 PM ET. Neil Love, MD Research To Practice Miami, Florida. Susan M O’Brien, MD Professor of Medicine Department of Leukemia

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RTP TV: An 8-Part Live CME Webcast Series

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  1. RTP TV: An 8-Part Live CME Webcast Series Part VIII – Chronic Myeloid Leukemia Tuesday, August 2, 20117:30 PM – 8:30 PM ET

  2. Neil Love, MDResearch To PracticeMiami, Florida Susan M O’Brien, MD Professor of Medicine Department of Leukemia The University of Texas MD Anderson Cancer Center Houston, Texas Neil P Shah, MD, PhD Co-Leader, Hematologic Malignancies Program UCSF Helen Diller Comprehensive Cancer CenterAssistant Professor of MedicineDivision of Hematology/Oncology University of California, San Francisco San Francisco, California

  3. Disclosures for Moderator Neil Love, MD Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Allos Therapeutics, Amgen Inc, Astellas Pharma Global Development Inc, AstraZeneca Pharmaceuticals LP, Aureon Laboratories Inc, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Daiichi Sankyo Inc, Dendreon Corporation, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, ImClone Systems, a wholly owned subsidiary of Eli Lilly and Company, Lilly USA LLC, Millennium: The Takeda Oncology Company, Mundipharma International Limited, Myriad Genetics Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi and Seattle Genetics

  4. Disclosures for Susan M O'Brien, MD

  5. Disclosures for Neil P Shah, MD, PhD

  6. Agenda — Chronic Myeloid Leukemia Initial Treatment of CP CML Case 1: 18 yo college freshman — Dr Shah Case 2: 59 yo retired military surgeon — Dr Shah Staging CML and monitoring patients receiving TKIs ENESTnd, DASISION and Intergroup S0325 Management of Side Effects; Adherence to TKIs Case 3: 58 yo woman with toxicity to imatinib who received nilotinib then dasatinib — Dr O’Brien Disease Progression, Mutations and Novel Agents Case 4: 43 yo woman with recurrent CP CML — Dr Shah Accelerated-Phase CML Case 5: 40 yo man with accelerated-phase CML — Dr O’Brien

  7. Dr Shah (Case 1) • 2008: 18 yo male college freshman dx with atypical cystic fibrosis • 9/2010: Leukocytosis on routine CBC • WBC = 45,000 with immature granulocytes, rare blasts • Hemoglobin = 14.6 g/dL, platelet count = 594,000 • BM bx: Ph+ CML-CP with qPCR for BCR-ABL grossly positive

  8. 46,t(9;22)(q34;q11.2)

  9. 1. Which treatment would you likely recommend for this patient?

  10. Dr Shah (Case 2) • Summer 2010: 59 yo retired male surgeon with WBC = 187,000, 5% blasts, 12% basophils, hematocrit 36%, platelet count = 934,000 • CML-CP with Ph chromosome in all 20 metaphases evaluated • FISH+ in 96% of nuclei • BCR-ABL qPCR: grossly positive • ECG: QTc = 424 msec

  11. 2. Which treatment would you likely recommend for this patient?

  12. Snapshot Survey of CML in Clinical Practice • 25 practicing oncologists - July 26-29, 2011 • 234 cases • Median 9 cases per oncologist • 224 (96%)receiving a TKI • 30 (15%)have difficulty adhering to treatment

  13. Percent of patients with CML receiving… Imatinib (n = 152) 68% Nilotinib (n = 35) 16% Dasatinib (n = 30) 13% Other (n = 7) 3% 0% 10% 20% 30% 40% 50% 60% 70% 80% CML survey July 2011

  14. In general, what is your preferred initial TKI for CP CML? Imatinib 15% Nilotinib 30% Dasatinib 20% Nilotinib ordasatinib 30% Other 5% 0% 5% 10% 15% 20% 25% 30% 35% CML survey July 2011

  15. 3. For patients who achieve a CCyR to a TKI, how often do you generally order qPCR?

  16. What is your level of comfort with ordering and interpreting follow-up CML assays? No problem 56% A bit confusing 44% Confusing 0% 0% 10% 20% 30% 40% 50% 60% CML survey July 2011

  17. Monitoring for Patients with CML Receiving TKI Therapy Akard LP and Wang YL. Clin Lymphoma Myeloma Leuk. 2011 [Epub ahead of print]

  18. ELN Monitoring for Patients with CML Receiving TKI Therapy Akard LP and Wang YL. Clin Lymphoma Myeloma Leuk. 2011 [Epub ahead of print]

  19. Disease Burden and Tests Cytogenetics FISH 1-2 log reduction RT-PCR Log Reduction in CML Burden MMR = 3 log ~ 5 log reduction MMR defined as >3 log reduction in BCR-ABL/control gene ratio Radich JP. Blood 2009;114(16):3376-81.

  20. Anchor Values in the International Scale Diagnosis, pretreatment, or hematologic relapse 1012 1011 1010 109 108 107 106 100 10 1 0.1 0.01 0.001 0.0001 CHR CCyR BCR-ABL/Control Gene Ratio(according to the International Scale) MMR Number of Leukemic Cells MMR Undetectable transcript(complete molecular response) Baccarani M et al. Blood 2006;108(6):1809-20.

  21. A Survey of Current Practices in the Management of CML Mauro MJ et al. Proc ASCO 2011;Abstract 6513. US-based survey of 507 board certified medical oncologists/hematologists who treated at least 5 non-clinical trial patients with CML in the past 2 years Imatinib 60% Initial Therapy Dasatinib or Nilotinib 40% 0% 10% 20% 30% 40% 50% 60% 70% Primary Goals of Treatment MMR or CMR 72% 0% 20% 40% 60% 80%

  22. Comparison of Nilotinib and Imatinib in Patients (Pts) With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd 24-Month Follow-Up Larson RA et al. Proc ASCO 2011;Abstract 6511. Dasatinib or Imatinib (IM) in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Two-Year Follow-up from DASISION Kantarjian H et al. Proc ASCO 2011;Abstract 6510.

  23. Phase III Studies of Dasatinib or Nilotinib versus Imatinib in Newly Diagnosed CML-CP 1Kantarjian H et al. Proc ASCO 2011;Abstract 6510. 2Larson RA et al. Proc ASCO 2011;Abstract 6511.

  24. Larson RA et al. Proc ASCO 2011;Abstract 6511. Cumulative Incidence of MMR* * ITT population used for all efficacy analyses

  25. Larson RA et al. Proc ASCO 2011;Abstract 6511. Progression to Accelerated Phase/Blast Crisis on Treatment* p = .0003 p = .0089 p = .0059 17 18 p = .0196 16 14 12 12 Number of Patients 10 8 5 6 3 4 2 2 2 0.7% 1.1% 4.2% 0.7% 1.8% 6.0% 0 Including Clonal Evolution Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD * Defined as progression to AP/BC or death due to CML while on treatment Data cut-off: 20 Aug 2010

  26. DASISION: Cumulative Incidence of MMR Dasatinib 100 mg QD Imatinib 400 mg QD By 24 months64% By 12 months46% p < 0.0001 % 46% 28% Months With permission fromKantarjian H et al. Proc ASCO 2011;Abstract 6510.

  27. DASISION: Transformation to AP/BP CML (ITT Population) Dasatinib 100 mg QD Imatinib 400 mg QD 100 6 4 2 0 5.8 5.0 % 3.5 2.3 6/259 13/260 9/259 15/260 On study Including follow-up beyond discontinuationa Including follow-up beyond discontinuationa aYearly evaluations after discontinuation are currently stipulated by the protocol; additional information on patient status may be provided by the investigators at other times. With permission fromKantarjian H et al. Proc ASCO 2011;Abstract 6510.

  28. A Randomized Phase II Trial of Dasatinib 100 Mg vs Imatinib 400 Mg in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): The S0325 Intergroup Trial Radich JP et al. Proc ASH 2011;Abstract LBA6.

  29. Dr O’Brien (Case 3) • 58 yo woman with CP CML • 6/1991 - Summer 2001: Treated with hydroxyurea, clinical trial of homoharringtonine  IFN, IFN + ARA-C • Summer 2001: Imatinib 400 mg/d • Significant weight gain, fluid retention • 4/2005: Nilotinib 600 mg BID on protocol • 2006: Off study due to elevated troponin • 7/2006: Dasatinib with pleural effusions, CHF • Continues on treatment with dose reductions

  30. ENESTnd: Adverse Events No patient had a QT interval corrected for heart rate of more than 500 msec. Saglio G et al. N Engl J Med 2010;362(24);2251-9.

  31. DASISION: Drug-Related Adverse Events Observed in ≥10% of Treated Patients Kantarjian H et al. N Engl J Med 2010;362(24);2260-70.

  32. Global Assessment of TKI Toxicity: 25 Oncologists, 217 Cases 59% No problems Toxicity In between Imatinib(n = 152) 24% 17% Nilotinib(n = 35) 71% 26% 3% Dasatinib(n = 30) 53% 30% 17%

  33. 4. Assume you have 10 patients in your practice receiving a TKI for CML. With how many of them do you have or have you had concerns about adherence?

  34. Good Questions:Effective queries to your patients to determine adherence In the past two weeks, about how many doses of your medicine have you missed?

  35. In the past two weeks, about how many doses of your medicine have you missed? Interesting comments heard in response... • The dog ate my medication • My child threw the pills out of window on the turnpike • It interferes with my golf game • I can’t take a pill that color • It inhibits my creativity

  36. N = 202 patients from 34 Belgian centers • 1/3 of patients nonadherent to imatinib • 14% of patients perfectly adherent with 100% of imatinib taken

  37. Six-Year Probability of Major Molecular Response According to Adherence Rate Marin D et al. J Clin Oncol 2010;28(14):2381-8.

  38. Dr Shah (Case 4) • 6/2008: 43 yo woman with CML-CP, WBC = 103,000 • Peripheral blood: grossly positive for BCR-ABL by FISH and qPCR; No BM assessment • Imatinib 400 mg/d: Rapidly achieved CHR • After 9 months: Recurrent night sweats, leukocytosis • Peripheral smear: Recurrent CML-CP • BCR-ABL kinase domain mutation test ordered • Dasatinib 100 mg/d • After 2 weeks: Symptoms continued, leukocytosis persisted • BCR-ABL/T315I mutation identified • Phase I study of ponatinib • After 2.25 years: CCyR and 2.4-log reduction in BCR-ABL transcript level

  39. Sensitivity of BCR/ABL Mutants to TKIs Sensitive Moderately resistant Resistant Highly resistant Originally published by the American Society of Clinical Oncology. Redaelli S et al. J Clin Oncol 2009;27(3):469-71.

  40. A Phase I Trial of Oral Ponatinib (AP24534) in Patients with Refractory Chronic Myelogenous Leukemia (CML) and Other Hematologic Malignancies: Emerging Safety and Clinical Response Findings Cortes J et al. Proc ASH 2010;Abstract 210.

  41. Efficacy of Ponatinib in Patients with CML-CP Cortes J et al. ProcASH 2010;Abstract 210.

  42. Dr O’Brien (Case 5) • 6/2002: 40 yo man with CML • Splenomegaly, WBC = 191,000, platelets > 1,000,000 • BM: 6% blasts, Ph chromosome in all 20 metaphases • Imatinib 600 mg/d • Periorbital edema, muscle cramps, mild diarrhea • 2/2003: CCyR • 1/2005 • Cytogenetics: 15 of 20 metaphases contained Ph chromosome and isochromosome 17 in 3 metaphases • Mutation analysis: E355A mutation • Imatinib  800 mg/d, unrelated donor search undertaken • 8/2005: Enrolled on protocol with nilotinib 400 mg BID • Edema, diarrhea resolved; no side effects with nilotinib • 10/2005: CCyR and qPCR = 0.12% • 1/2006 - Present: CMR with inability to detect BCR-ABL fusion transcript by qPCR

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