1. Copyright © 2010, Research To Practice, All rights reserved. Part I: Myelodysplastic Syndromes/ Acute Myeloid Leukemia Monday, September 20, 2010 7:30 PM - 8:30 PM ET Monday Night with Research To Practice: An 8-Part Live CME Webcast Series

3. Mikkael A Sekeres, MD, MS Associate Professor of Medicine Director, Leukemia Program Taussig Cancer Institute Department of Hematologic Oncology and Blood Disorders Cleveland, Ohio Hagop M Kantarjian, MD Chairman and Professor, Leukemia Department The University of Texas MD Anderson Cancer Center Houston, Texas Neil Love, MD Moderator Research To Practice Miami, Florida

4. 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: Abraxis BioScience, Allos Therapeutics, Amgen 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, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, Genzyme Corporation, Lilly USA LLC, Millennium Pharmaceuticals Inc, Monogram BioSciences Inc, Myriad Genetics, Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi-Aventis and Spectrum Pharmaceuticals Inc.

5. Disclosures for Mikkael A Sekeres, MD, MS N/A = Not Applicable Advisory CommitteeCelgene Corporation, Seattle Genetics Paid ResearchN/A Speakers BureauCelgene Corporation

6. Disclosures for Hagop M Kantarjian, MD Advisory CommitteeN/A Paid Research Bristol-Myers Squibb Company, Genzyme Corporation, Novartis Pharmaceuticals Corporation Speakers BureauN/A N/A = Not Applicable

7. Myelodysplastic Syndromes (MDS) Case 1: 71-year-old man with MDS and pancytopenia 2 years after initial growth factor treatment - Dr Sekeres Case 2: 79-year-old man with 5q minus MDS - Dr Kantarjian Acute Myeloid Leukemia (AML) Case 1: An otherwise healthy 82-year-old man presenting with AML - Dr Sekeres Case 2: 64-year-old man with FLT3+ AML - Dr Kantarjian

8. Case History: Dr Sekeres 71-yo man with fatigue and isolated anemia Bone marrow biopsy: hypercellular marrow; 20% dysplastic erythroid precursors, < 5% blasts Normal cytogenetics Serum erythropoietin level 80mU/mL (normal 4-24 mU/mL) IPSS 0

9. Nothing – I would choose watchful waiting An erythropoiesis stimulating agent, such as erythropoietin or darbepoetin Lenalidomide Azacitidine Decitabine 1) What therapy would you recommend for this patient?

10. Case History: Dr Sekeres (continued) Patient treated with darbepoetin Hemoglobin improved to 11-12 g/dL After 2-3 years, developed pancytopenia Bone marrow biopsy: 8% myeloblasts Cytogenetics: Del 20q IPSS 1.0

11. 2) What therapy would you now recommend for this patient? Nothing – I would choose watchful waiting Continue the erythropoiesis stimulating agent Lenalidomide Azacitidine Decitabine

12. Case History: Dr Sekeres (continued) Patient treated with SC azacitidine days 1-6 q 4-weeks CBC showed objective hematologic improvement (HI) after cycle 4 Repeat bone marrow evaluation after four cycles: < 5% blasts After cycle 7, CBC normalized, and azacitidine administration frequency changed to q 5-weeks After 2 years, blood counts dropped Bone marrow aspirate and biopsy: 40% blasts Cytogenetics: Del 20q plus Trisomy 8

13. Slide courtesy of David Steensma 5-9% Blasts 10-19% Blasts >20% Blasts = AML! Lower Risk

14. Copyright © 2010, Research To Practice, All rights reserved. Characteristics of US Patients With Myelodysplastic Syndromes: Results of Six Cross-sectional Physician Surveys Sekeres MA et al. J Natl Cancer Inst 2008;100(21):1542-51.

15. Age (Median)Newly diagnosed71 years Established72-75 years Sex (Mean) Male (Newly diagnosed) (Established) 55% 51-57% Duration of MDS (Median) 13-16 months MDS StatusPrimary88 – 93% Secondary7 – 12% SecondaryChemotherapy55 – 80% CauseRadiation6 – 21% Chemical exposure2 – 9% US MDS Characteristics Sekeres et al. J National Cancer Inst 2008;100:1542

16. Copyright © 2010, Research To Practice, All rights reserved. Perceptions of Disease State, Treatment Expectations, and Prognosis Among Patients with Myelodysplastic Syndromes Sekeres MA et al. Proc ASH 2009;Abstract 1771.

17. Disease Understanding Among Patients with MDS 6%-7% recognized this as "cancer" or leukemia More than half did not understand the treatment goal or recall prognosis being discussed Mixed perceptions of curability Sekeres MA et al. Proc ASH 2009;Abstract 1771

18. Copyright © 2010, Research To Practice, All rights reserved. Efficacy of Azacitidine Compared with That of Conventional Care Regimens in the Treatment of Higher-Risk Myelodysplastic Syndromes: A Randomised, Open-Label, Phase III Study Fenaux P et al. Lancet Oncol 2009;10(3):223-32.

19. Azacitidine Improves Survival in High-Risk MDS N=179 Fenaux. Lancet Oncology 10:223, 2009 Screening/Central Pathology Review Investigator CCR Tx Selection Randomization AZA 75 mg/m 2 /d x 7 d q28 d CCR Best Supportive Care (BSC) only Low Dose Ara-C (LDAC, 20 md/m2/d x 14 d q28-42 d) Std Chemo (7 + 3)

20. Number at risk AZA179152130855230101 CCR1791329569321450 Survival with Azacitidine vs CCR p = 0.0001 HR = 0.58 Deaths: AZA = 82, CCR = 113 0510152025303540 Time (months) from Randomization 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Proportion Surviving CCR AZA Fenaux. Lancet Oncology 10:223, 2009

21. Copyright © 2010, Research To Practice, All rights reserved. Low Dose Decitabine versus Best Supportive Care in Elderly Patients with Intermediate or High Risk MDS Not Eligible for Intensive Chemotherapy: Final Results of the Randomized Phase III Study (06011) of the EORTC Leukemia and German MDS Study Groups WijerMans P et al. Proc ASH 2008;Abstract 226.

22. 233 pts; median age 70 yrs; IPSS int-2 55%, high 38%; poor CG 46%; prior Rx 20% Decitabine 15 mg/m 2 over 4 hrs Q8 hrs x 3 days (135mg/m 2 /course) Q 6 wks; maximum 8 courses; median 4 courses; ≤ 2 cycles 40% Decitabine vs Supportive Care in MDS (EORTC) ParameterDecitabineSupportp-value % CR+PR+HI13 + 6 + 150 + 0 + 2<0.001 Median survival (mos)10.18.50.38 Median PFS (mos)6.63.00.004 Median to AML or death8.86.10.24 Wijermans. Blood 112:abst 226, 2008

23. Copyright © 2010, Research To Practice, All rights reserved. A Study Comparing Dosing- Regimens and Efficacy of Subcutaneous to Intravenous Azacitidine (AZA) for the Treatment of Myelodysplastic Syndromes (MDS) Sekeres MA et al. Proc ASH 2009;Abstract 3797.

24. Most US AZA Dosing Does Not Follow FDA Schedule Sekeres et al. Blood 2009;114:3797a

25. Similar RR for IV vs SC Dosing in 331 Pts Sekeres et al. Blood 2009;114:3797a

27. Case History: Dr Kantarjian 79-yo man with fatigue Hb 8.5 g/dL, WBC 2,300/µL, platelets 220,000/µL Bone Marrow Aspirate and Biopsy: Dysplastic changes with 3% blasts Cytogenetics: Del 5q Patient started on lenalidomide 10mg PO QD After 4 weeks… Hb 10.0 g/dL, WBC 1,000/µL, platelets 70,000/µL

28. Case History: Dr Kantarjian (continued) Lenalidomide administration held, and restarted at 5mg PO QD, after recovery of blood counts Good hemoglobin response to lenalidomide 14 months later… Hb 9.0 g/dL, WBC 1,500/µL, Platelets 30,000/µL Bone Marrow Aspirate and Biopsy: 12% blasts Cytogenetics: Complex Karyotype with Del 5q, Del 17p, Monosomy 7

29. Case History: Dr Kantarjian (continued) Patient started on azacitidine with good response After 12 months… worsening anemia and thrombocytopenia Bone Marrow Aspirate and Biopsy: 40% blasts Cytogenetics: Complex Karyotype ECOG PS 0 No cardiac or pulmonary problems

30. Copyright © 2010, Research To Practice, All rights reserved. Long-Term Clinical Benefit of Lenalidomide Treatment in Patients with Myelodysplastic Syndrome and Chromosome Deletion 5q List AF et al. Proc ASH 2006;Abstract 251. Phase 2 Study of Lenalidomide in Transfusion- Dependent, Low-Risk, and Intermediate-1-Risk Myelodysplastic Syndromes with Karyotypes Other Than Deletion 5q Raza A et al. Blood 2008;111(1):86-93.

31. Lenalidomide in MDS Parameterdel 5q 1 no del 5q 2 No. treated148214 % Tx independence6726 % HI — E—33 Median wks to resp.54.8 Media Hb  (g/dl) 5.43.2 Median resp. dur. (wks) 11641 % CG CR44 (25% of total)9 % G3-4 myelosuppression 50-5920-25 1 List AF et al. Proc ASH 2006;Abstract 251. 2 Raza A et al. Blood 2008;111(1):86-93.

32. Copyright © 2010, Research To Practice, All rights reserved. Efficacy and Safety of Lenalidomide in Intermediate-2 or High-Risk Myelodysplastic Syndromes with 5q Deletion: Results of a Phase 2 Study Ades L et al. Blood 2009;113:3947-52.

33. Efficacy of Lenalidomide in Higher Risk MDS by Baseline Characteristics CytogeneticsnCR Isolated del 5q967% Single Additional Abnormality 119% > 1 Additional Abnormality270% Platelet CountnCR > 100,000/mm 3 2035% < 100,000/mm 3 270% Bone Marrow BlastnCR < 20%2921% > 20%185% Ades L et al. Blood 2009;113:3947-52.

35. Case History: Dr Sekeres 82-yo man with recent history of fatigue and dyspnea on exertion Hb 6.0 g/dL, WBC 2,700/µL, platelets 74,000/µL Transfused with 4 units of PRBC Bone marrow aspirate and biopsy: AML with 42% blasts and a background of dysplasia Cytogenetics: Complex karyotype with chromosome 5 and 7 abnormalities

36. 3) Which of the following is NOT a valid treatment option for this octogenarian? 7 plus 3 induction chemotherapy Low-dose cytarabine A hypomethylating agent (azacitidine or decitabine) Gemtuzumab ozogamicin Watchful waiting

37. Copyright © 2010, Research To Practice, All rights reserved. Sekeres MA et al. Haematologica 2008;93(12):1769-72. Treatment of Older Adults with Acute Myeloid Leukemia: State of the Art and Current Perspectives

38. Challenges with Older Patient with AML Biological characteristics of AML High prevalence of poor-risk cytogenetics Less likely to have good risk cytogenetics More frequent secondary AML Less responsiveness to chemotherapy Intolerance to intensive remission induction therapies Comorbid conditions Differential drug metabolism resulting in supra- therapeutic drug levels Reluctance of physician to treat with intensive induction therapy Sekeres MA et al. Haematologica 2008; 93(12):1769-72

39. Current Options for Older Patient with AML Standard remission induction therapy Decision involves complex challenges even in a suitable patient Wait for cytogenetics to rule out adverse cytogenetics Novel cytotoxic agents Clofarabine, Cloretazine Hypomethylating agents Azacitidine, Decitabine 33% of patients in AZA-001 study had 20% blasts or greater Importance of prolonged administration Low-dose cytarabine Sekeres MA et al. Haematologica 2008;93(12):1769-72.

40. Why Do Elderly Patients with AML Do Worse? Poor tolerance and  mortality with intensive chemoRx Poor PS and co-morbid conditions Different disease biology  MDR  incidence of adverse CG  other adverse molecular events

41. Copyright © 2010, Research To Practice, All rights reserved. Hypomethylating Agents for the Treatment of Elderly Patients with AML Fenaux P et al. J Clin Oncol 2010;28(4):562-9. Blum W et al. Proc Natl Acad Sci USA 2010;107(16):7473-8. Cashen AF et al. J Clin Oncol 2010;28(4):556-61.

42. Studies of Hypomethylating Agents in the Treatment of Elderly Patients with AML StudyN Median Age Median %Blasts Regimen (Median # cycles) Median Overall Survival 1 AZA-0011137023% AZA (8 cycles) CCR 24.5 mos 16.0 mos 2 Blum 2010 537452% Decitabine 20 mg/m 2 d 1-10 (4 cycles) 55 wks 3 Cashen 2010 557450% Decitabine 20 mg/m 2 d 1-5 (3 cycles) 7.7 mos 1 Fenaux P et al. J Clin Oncol 2010;28(4):562-9. 2 Blum W et al. Proc Natl Acad Sci USA 2010;107(16):7473-8. 3 Cashen AF et al. J Clin Oncol 2010;28(4):556-61.

43. Case History: Dr Kantarjian 64-yo man with fatigue and petechiae History of heavy smoking and COPD Hb 9.2 g/dL, WBC 9,200/µL, platelets 24,000/µL Bone marrow aspirate & biopsy: 72% blasts. Positive myeloid markers Cytogenetics: Complex karyotype with chromosome 5 and 7 deletions ECOG PS 2

44. 4) What would you recommend for this patient? Hydroxyurea and hospice care Low-dose cytarabine Daunorubicin 45 mg/m 2 IV daily x 3 with cytarabine Daunorubicin 90 mg/m 2 IV daily with cytarabine Idarubicin with standard-dose cytarabine Idarubicin with high-dose cytarabine Azacitidine or decitabine Referral to leukemia center for investigational therapies Clofarabine with or without low-dose cytarabine

45. Copyright © 2010, Research To Practice, All rights reserved. Questions Regarding Frontline Therapy of Acute Myeloid Leukemia Kantarjian H, O’Brien S. Cancer 2010;[Epub ahead of print].

46. < 60 years> 60 years Median Survival17.56.2 AML: Median Survival (mos) by Patient Age and Treatment Era Patient Age<19701970-19791980-19891990-19992000-2009 < 60 years2.711.814.018.022.8 > 60 years0.91.63.75.57.4 Kantarjian H, O’Brien S. Cancer 2010;[Epub ahead of print]. AML: Median Survival (mos) by Patient Age and Treatment Era — MDACC 1980 to Present

47. Questions Regarding Frontline Therapy of AML Kantarjian H, O’Brien S. Cancer 2010 July 9 [Epub ahead of print]. Prognosis for unselected patients with AML who receive standard frontline AML therapy? Significance of “residual leukemia” documented after 1 course of induction? –Should such bone marrow analyses be performed early (Day 10-14) and be followed with a second course of induction if “residual leukemia” is noted? Is daunorubicin at a dose of 45 to 60 mg/m2 daily for 3 days and cytarabine 100 to 200 mg/m2 daily for 7 days (“3 + 7 regimen”) still considered standard frontline AML therapy?

48. Molecular Studies in AML Marker%Prognosis FLT3 ITD/mutation30Worse MLL PTD7Worse  BAALC 6Worse  BCL2 and WT1 mRNA 10-20Worse  EVI1 expression 10Worse c-kit mutation in CBF15Worse NPM1 mutation50Better CEBPA mutation8Better