1. Part VIII – Chronic Myeloid Leukemia Tuesday, August 2, 2011 7:30 PM – 8:30 PM ET RTP TV: An 8-Part Live CME Webcast Series

2. 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 Center Assistant Professor of Medicine Division of Hematology/Oncology University of California, San Francisco San Francisco, California Neil Love, MD Research To Practice Miami, Florida

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 No financial interests or affiliations to disclose

5. Disclosures for Neil P Shah, MD, PhD Advisory Committee ARIAD Pharmaceuticals Inc, Bristol-Myers Squibb Company

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

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

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

11. 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

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

14. 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

15. 13% 16% 68% 3% 0%10%20%30%40%50%60%70%80% Other (n = 7) Dasatinib (n = 30) Nilotinib (n = 35) Imatinib (n = 152) CML survey July 2011 Percent of patients with CML receiving…

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

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

18. 44% 56% 0% 10%20%30%40%50%60% Confusing A bit confusing No problem CML survey July 2011 What is your level of comfort with ordering and interpreting follow-up CML assays?

19. Monitoring for Patients with CML Receiving TKI Therapy IndicationMethodFrequency DiagnosisqPCR; bone marrow cytogenetics During TKI therapyqPCREvery 3 mo Bone marrow cytogenetics At 6, 12, and 18 mo, until CCyR is achieved After CCyR achievedqPCREvery 3 to 6 mo Bone marrow cytogeneticsAs clinically indicated FISH not recommended ≥1-log increase in BCR-ABL transcripts Evaluate compliance; repeat qPCR if MMR; bone marrow cytogenetics if no MMR; consider mutation testing Akard LP and Wang YL. Clin Lymphoma Myeloma Leuk. 2011 [Epub ahead of print]

20. ELN Monitoring for Patients with CML Receiving TKI Therapy IndicationMethodFrequency Diagnosis Hematologic; bone marrow cytogenetics During TKI therapyHematologic Every 15 d until CHR, then at least every 3 mo or as required Bone marrow cytogenetics At 3 and 6 mo, and every 6 mo thereafter until CCyR is confirmed qPCR Every 3 mo until MMR is confirmed, then at least every 6 mo thereafter After CCyR achieved Bone marrow cytogenetics Every 12 mo if regular molecular monitoring cannot be assured; for treatment failure and unexplained anemia, leukopenia, or thrombocytopenia qPCR Every 3 mo until MMR, then at least every 6 mo thereafter Suboptimal response or failure Mutation analysis Change in therapyMutation analysis Akard LP and Wang YL. Clin Lymphoma Myeloma Leuk. 2011 [Epub ahead of print]

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

23. Anchor Values in the International Scale Baccarani M et al. Blood 2006;108(6):1809-20. Diagnosis, pretreatment, or hematologic relapse CHR CCyR MMR BCR-ABL/Control Gene Ratio (according to the International Scale) Undetectable transcript (complete molecular response) 100 10 1 0.1 0.01 0.001 0.0001 MMR Number of Leukemic Cells 10 12 10 1110 10 9 10 8 10 7 10 6

24. 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 Initial Therapy Primary Goals of Treatment Imatinib Dasatinib or Nilotinib MMR or CMR 40% 60% 0%10%20%30%40%50%60%70% 72% 0%20%40%60%80%

27. 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.

28. Phase III Studies of Dasatinib or Nilotinib versus Imatinib in Newly Diagnosed CML-CP DASISION 1 ENESTnd 2 Outcomes: First 24 mos Dasatinib 100 mg daily (n = 258) Imatinib 400 mg daily (n = 258) Nilotinib 300 mg twice daily (n = 282) Nilotinib 400 mg twice daily (n = 281) Imatinib 400 mg daily (n = 283) CCyR86%82%——— MMR64%46%71%67%44% Transformation2.3%5.0%0.7%1.1%4.2% Discontinued therapy 23%25%16%18%21% 1 Kantarjian H et al. Proc ASCO 2011;Abstract 6510. 2 Larson RA et al. Proc ASCO 2011;Abstract 6511.

29. Larson RA et al. Proc ASCO 2011;Abstract 6511. Cumulative Incidence of MMR* * ITT population used for all efficacy analyses Time from Randomization Percent with MMR Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) 12 months p-value 55% <0.0001 51% <0.0001 27% — 24 months p-value 71% <0.0001 67% <0.0001 44% —

30. Larson RA et al. Proc ASCO 2011;Abstract 6511. 22 3 5 12 17 0 2 4 6 8 10 12 14 16 18 Including Clonal Evolution Number of Patients Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD p =.0059 p =.0196 * Defined as progression to AP/BC or death due to CML while on treatment Progression to Accelerated Phase/Blast Crisis on Treatment* 0.7%1.1%4.2%0.7%1.8%6.0% p =.0003 p =.0089 Data cut-off: 20 Aug 2010

31. DASISION: Cumulative Incidence of MMR With permission from Kantarjian H et al. Proc ASCO 2011;Abstract 6510. By 12 months 46% 28% By 24 months 64% 46% p < 0.0001 Months % Dasatinib 100 mg QD Imatinib 400 mg QD

32. DASISION: Transformation to AP/BP CML (ITT Population) With permission from Kantarjian H et al. Proc ASCO 2011;Abstract 6510. a Yearly evaluations after discontinuation are currently stipulated by the protocol; additional information on patient status may be provided by the investigators at other times. Including follow-up beyond discontinuation a Dasatinib 100 mg QD Imatinib 400 mg QD On study % Including follow-up beyond discontinuation a 6/259 13/2609/259 15/260 100 6 4 2 0 2.3 5.0 3.5 5.8

33. 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.

35. 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

36. ENESTnd: Adverse Events Adverse Event, % All Grade (Grade 3/4), % Imatinib 400 mg QD Nilotinib 300 mg BID Nilotinib 400 mg BID Neutropenia 68 (20)43 (12)38 (10) Thrombocytopenia 56 (9)48 (10)49 (12) Anemia 47 (5)38 (3) Nausea 31 (0)11 (<1)19 (1) Rash 11 (1)31 (<1)36 (3) Peripheral edema 14 (0)5 (0) Muscle spasm 24 (1)7 (0)6 (1) Headache 8 (0)14 (1)21 (1) Saglio G et al. N Engl J Med 2010;362(24);2251-9. No patient had a QT interval corrected for heart rate of more than 500 msec.

37. DASISION: Drug-Related Adverse Events Observed in ≥10% of Treated Patients Adverse Event, % Dasatinib (n = 258)Imatinib (n = 258) All GradesGrade 3/4All GradesGrade 3/4 Anemia 9010847 Thrombocytopenia 70196210 Neutropenia 65215820 Headache 120100 Rash 110171 Pleural effusion 10000 Myalgia 60120 Kantarjian H et al. N Engl J Med 2010;362(24);2260-70.

38. 17% 53% 26% 3% 71% 24% 17% 59% 30% Global Assessment of TKI Toxicity: 25 Oncologists, 217 Cases Dasatinib (n = 30) Nilotinib (n = 35) Imatinib (n = 152) Toxicity No problems In between

39. 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?

40. 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?

41. 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

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

44. Marin D et al. J Clin Oncol 2010;28(14):2381-8. Six-Year Probability of Major Molecular Response According to Adherence Rate Adherence Rate (%)NMMR %p-value >906493.7 < 0.001 ≤902313.9

46. 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

47. Originally published by the American Society of Clinical Oncology. Redaelli S et al. J Clin Oncol 2009;27(3):469-71. BosutinibDasatinibImatinibNilotinib WT L248V G250E Q252H Y253F E255K E255V D276 G E279K V299L T315I F317L M351T F359V L384M H396P G398R F486S Resistant Moderately resistant Sensitive Highly resistant Sensitivity of BCR/ABL Mutants to TKIs

48. 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.

49. Efficacy of Ponatinib in Patients with CML-CP Clinical Response, n (%) All Pts (n = 32) Pts with T315I Mutation (n = 11) CHR30 (94)11 (100) MCyR20 (63)9 (82) CCyR12 (38)8 (73) PCyR8 (25)— Cortes J et al. Proc ASH 2010;Abstract 210.

50. 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