1. Individualizing Therapy to Optimize Patient Outcomes in MDS This program is supported by educational grants from

2. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS About These Slides  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Program Co-Chairs Alan F. List, MD Executive Vice President and Physician-in-Chief H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida Rami Komrokji, MD Assistant Professor of Oncologic Services University of South Florida Clinical Director Hematologic Malignancies H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida

4. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Disclosures Alan F. List, MD, has no significant financial relationships to disclose. Rami Komrokji, MD, has disclosed that he has received fees for non-CME services from Celgene and Novartis and contracted research support from Celgene, Genentech, and Novartis.

5. Topic 1: MDS Classification Criteria and Cytogenetic Abnormalities

6. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Myelodysplastic Syndromes  A group of malignant hematopoietic disorders sharing an ineffective production of one or more myeloid cell lines (accelerated apoptosis) with a variable % of leukemic blasts  Usually there is a discrepancy between a cellular marrow and peripheral cytopenias  Median age is 70 and 30% progress to AML Bennett J, et al. The myelodysplastic syndromes. In: Abeloff MD, et al, editors. Clinical oncology. New York NY: Churchill Livingstone; 2004. pp. 2849-2881.

7. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Epidemiology  Overall incidence: 3.4 per 100,000 Incidence Rate (per 100,000) Age at Diagnosis (Yrs) *P for trend <.05 Rollison DE, et al. Blood. 2008;112:45-52. 0 10 20 30 40 50 < 4040-4950-5960-6970-79≥ 80 0.1 0.7 2.0 7.5 20.9 36.4* Females MalesOverall

8. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Diagnosis of MDS  The commonest presentation is cytopenia  Diagnosis requires –Peripheral blood examination –Bone marrow aspirate and biopsy –Cytogenetic studies  The diagnosis requires demonstration of dysplastic features in 1 or more cell line Bennett J, et al. The myelodysplastic syndromes. In: Abeloff MD, et al, editors. Clinical oncology. New York, NY: Churchill Livingstone; 2004. pp. 2849-2881.

9. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Minimal Diagnostic Criteria for MDS  Prerequisite criteria –Constant cytopenia in 1 or more of the following cell lineages –Erythroid (hemoglobin < 11 g/dL) –Neutrophilic (ANC < 1500/μL) –Megakaryocytic (platelets < 100,000/μL) –Exclusion of all other hematopoietic or nonhematopoietic disorders as primary reason for cytopenia/dysplasia  MDS-related (decisive) criteria –Dysplasia in at least 10% of all cells in 1 of the following lineages in the bone marrow smear: erythroid, neutrophilic, or megakaryocytic or > 15% ringed sideroblasts (iron stain) –5% to 19% blast cells in bone marrow smears –Typical chromosomal abnormality (by conventional karyotyping or FISH Valent P, et al. Leuk Res. 2007;31:727-736.

10. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS 2 categories of “dysmyelopoietic syndromes”: RAEB and CMML 5 categories of myelodysplastic syndromes: RA, RARS, RAEB, RAEB-t, CMML This research was originally published in Steensma DP. Hematology AM Soc Hematol Educ Program. 2009;645-655. © the American Society of Hematology. Evolution of Classification of MDS Early history ??? 1976 FAB Cooperative Group Leukemia Classification 1982 FAB Group Myelodysplastic Syndromes Classification 2008 4th WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues 1999 (draft)/2001(final) 3rd WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues ~ 11 MDS categories Changes from 2001 WHO system Added: RN and RT (with RA, comprise RCUD), childhood MDS (including provisional RCC) Merged: RCMD with RCMD-RS, t-MDS/t-AML due to any cause Refined: MDS-U ~ 10 MDS categories Changes from 1982 FAB system: Added: RCMD, RCMD-R5, MDS with del(5q), MDS-U, t-MDS/t-AML due to alkylators, t-MDS/t-AML due to topoisomerase II inhibitors Divided: RAEB into RAEB-1 and -2 Moved: CMML (to MDS/MPD) Eliminated: RAEB-t Idiopathic-acquired sideroblastic anemia (1956) Smoldering acute leukemia (1963) Preleukemia anemia (1949/1953) Refractory anemia (1938) il morbo di Guglielmo (1920s) “Preleukemia”

11. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS MDS (FAB)MDS (WHO) RA with excess of blasts (RAEB); 5% to 19% blasts  RA with excess blasts-1 (RAEB-1); 5% to 9% blasts  RA with excess blasts -2; 10% to 19% blasts RA with excess of blasts in transformation (RAEB-t); 20% to 29% blasts  Acute myeloid leukemia (AML) CMML; monocytes in PB > 1000/mm 3 and BM blasts ≤ 30%  CMML:< 5% to 19% blasts; moved into MDS/MPD category WHO Reclassification of Higher-Risk FAB Subtypes Bennett JM, et al. Br J Haematol. 1982;51:189-199. Harris NL, et al. J Clin Oncol. 1999;17:3835-3849.

12. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS CategoryPatients, n (%)Transformation to AML, % Median Survival, Mos RA107 (8.5)7.569 RARS138 (11.0)1.469 RCMD306 (24.0)10.033 RCMD-RS183 (15.0)13.032 RAEB-I256 (21.0)21.018 RAEB-II235 (18.5)34.510 MDS 5q-28 (2.2)8.0116 Germing U, et al. Leuk Res. 2000;24:983-992. Prognosis by WHO Classification

13. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Greenberg P, et al. Blood. 1997;89:2079-2088. Favorable Intermediate Unfavorable Cytogenetic Abnormalities: IPSS Prognosis Patients, n (%) -Y17 (2) Iso del(5q)48 (6) Normal489 (60) Del(20q)16 (2) Misc single74 (9) +838 (5) Double29 (3) Misc double14 (2) Chrom 7 abn10 (1) Misc complex15 (2) Complex66 (8)

14. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS 5q- Syndrome: Clinical Characteristics  Del(5q) as sole cytogenetic abnormality  Female predominance (sex ratio: 7:3)  Median age at diagnosis: 68 yrs  Macrocytic anemia, mild leukopenia, normal or increased platelet count  Indolent course, favorable prognosis –AML transformation: 12% to 16% –Median survival: > 5 yrs Boultwood J, et al. Blood. 1994;84:3253-3260. Mathew P, et al 1993:81:1040-1045.

15. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS IPSS Modifying Factors Age and comorbidityLow/Int-1 Secondary MDSNatural history Cytopenia severityLow/Int-1 Transfusion dependenceLow/Int-1 BM pathologyNumber of dysplastic lineages, ALIP, PB CD34+%, fibrosis Other chromosome abnormalities  Favorable: -12/12p  Unfavorable: 3q36, +11/11q23, t(4q), t(5q) Other factors  LDH  Iron overload  B2 microglobulin

16. Topic 2: Current and Evolving Treatment Approaches in MDS

17. Treatment Options for Low- and Intermediate-Risk MDS

18. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Anemia Management Algorithm 2011: Low/Int-1 Risk MDS Epo > 500 mU/mL RCMD ≥ 2 U RBC/mo Del(5q) Lenalidomide Epo < 500 mU/mL < 2 U RBC/mo ESA Del5q + GCSF HMA Age > 60 ≤ 60 IST List AF. Hematology. 2007. EPO, serum erythropoietin; ESA, erythropoiesis-stimulating agents; GCSF, granulocyte colony-stimulating factor; HMA, human monocyte antigen; IST, immunosuppressive therapy; RBC, red blood cells; RCMD, refractory cytopenias with multilineage dysplasia.

19. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Erythropoietin in MDS  Response rates to erythropoietin much lower in MDS than in other malignancies –Mean response rate: 16% to 20% –Predictors for good response were serum EPO level < 500 U/L, nonrefractory anemia with ring sideroblasts subtype, and lack of previous need for transfusion  Response rates may improve when given in combination with G-CSF (> 40%) Ludwig H. Semin Oncol. 2002;29(3 suppl 8):45-54. Hellström-Lindberg E. Br J Haematol. 1995;89:67-71. Casadevall N, et al. Blood. 2004;104:321-327.

20. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Score > +1 Score -1 to +1 Score < -1 RA, RARS, RAEB Intermediate (23%, n = 31) Poor (7%, n = 29) Good (74%, n = 34) Response Probability Treatment Response CriteriaTreatment Response Score Predictive Model for Response to Treatment With rhuEPO + G-CSF CR Stable hemoglobin > 11.5 g/dL PR Increase in Hb with >1.5g/dL or total stop in RBC transfusions S-EPO U/l < 100 100-500 > 500 +2 +1 -3 Transf U RBC/ m < 2 units/m ≥ 2 units/m +2 -2 Hellström-Lindberg E, et al. Br J Hematol. 2003;120:1037-1046.

21. Role of Lenalidomide in the Treatment of MDS

22. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Lenalidomide  Thalidomide analogue; has immunomodulatory, antiangiogenic, and antineoplastic properties  Approved for use in –Transfusion-dependent anemia due to low- or intermediate- 1-risk MDS associated with del(5q) with or without additional abnormalities –Multiple myeloma in combination with dexamethasone in patients who have receive at least 1 prior therapy  Inhibits growth of cells in del(5q) MDS, myeloma, secretion of proinflammatory cytokines (eg, TNF-α), and expression of COX-2

23. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Primary endpoint: transfusion independence Secondary endpoints: duration of TI, cytogenetic response, minor erythroid response, pathologic response, safety Lenalidomide in MDS With 5q Deletion MDS-003 Study Design RESPONSERESPONSE R E G I S T E R Lenalidomide 10 mg PO x 21 days Eligibility  IPSS diagnosed low/int-1 MDS  del(5q31)  ≥ 2 U RBC/8 wks  Platelets > 50,000/µL  ANC > 500/µL Yes Continue No Off study Wk Lenalidomide 10 mg/day PO 04812162024 List AF, et al. N Engl J Med. 2006;355:1456-1465.

24. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS MDS-003: Patient Characteristics Baseline CharacteristicValue Number enrolled, n148 Median age, yr (range)71 (37-95) Male, %34 Median duration of MDS, yr (range)2.5 (0.1-20.7) Median RBCs/8 wk (range)6 U (0-18)  ≥ 2 U/mo (%)105 (71) Prior erythropoietin therapy. N (%)108 (73) IPSS low-1/int-2 or high/unclassified, %37/44/5/14 Neutropenia/thrombocytopenia, n (%)*44 (30)/28 (19) *Neutropenia defined as < 1500 PMN neutrophils/mm 3 ; thrombocytopenia defined as < 1000,000 platelets/mm 3. List AF, et al. N Engl J Med. 2006;355:1456-1465.

25. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS MDS-003: Response to Lenalidomide Therapy Erythroid Response TI 99/148 (67%) 112/148 (76%) TI + Minor Cytogenetic Response List AF, et al. N Engl J Med. 2006;355:1456-1465. Response (%) 0 20 40 70 80 100 Response (%) 0 20 40 70 80 100 CCRCCR + PR 38/85 (45%) 62/85 (73%)  Median Hb increase was 5.4 g/dL  Time to response 4.6 wks  Duration of response > 2 yr

26. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Primary endpoint: TI, Hb response Secondary endpoints: cytogenetic response, safety MDS-002: Phase II Study of Lenalidomide in RBC-Dependent Non-Del (5q) MDS RESPONSERESPONSE R E G I S T E R Lenalidomide 10 mg PO x 21 days Eligibility  IPSS diagnosed low/int-1 MDS w/o del(5q) abnormality  ≥ 2 U RBC/8 wks  Platelets > 50,000/µL  ANC > 500/µL Yes Continue No Off study Wk Lenalidomide 10 mg/day PO 04812162024 Dose reduction 5 mg QD 5 mg QOD Raza A, et a. Blood. 2008;111:86-93.

27. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS MDS-002: Clinical and Hematologic Features CharacteristicPatients (N = 214) Median age, yr (range)72 (27-94) Male:female138:75 (38) Median MDS duration, yr (range)2.2 (0-12.9) Median RBC units/8 wk (range)4.0 (1-24) Pts receiving ≥ 2 RBC units/mo in mo before study entry, n (%)175 (82) IPSS score, n (%)  Low92 (43)  Int-176 (36)  Int-2 high8 (4)  Unclassified38 (18) Neutropenia < 1500/μL, n (%)57 (27) Thrombocytopenia < 100,000/μL, n (%)41 (20) Raza A, et al. Blood. 2008;111:86-93.

28. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Response (%) 0 20 40 70 80 100 Response (%) 0 20 40 70 80 100 MDS-002: Response to Lenalidomide Therapy CCRCCR + PR 4/47 (9%) 9/47 (19%) Erythroid Response Cytogenetic Response TITI + Minor 56/214 (26%) 93/214 (43%)  Median Hb increase was 3.2 g/dL  Time to response 4.8 wks  Median duration of response 41 wk Raza A, et al. Blood. 2008;111:86-93.

29. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS MDS-002/003: Treatment-Related Adverse Events Grade ≥ 3 Adverse Events, %Non-Del(5q)Del(5q) Thrombocytopenia2044 Neutropenia2555 Pruritus13 Rash46 Diarrhea13 Fatigue43 List AF, et al. N Engl J Med. 2006;355:1456-1465. Raza A, et al. Blood. 2008;111:86-93.

30. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS MDS-004: Phase III Placebo-Controlled Study of 2 Lenalidomide Doses in Del(5q) *Crossover at Week 16. Primary endpoint: transfusion independence ≥ 26 wks Secondary endpoints: duration of transfusion independence, progression to AML, adverse events Eligibility  IPSS low/int-1  Del(5q31)  Transfusion dependent  Lenalidomide naive Stratified by  IPSS  Complexity Continue for 52 wks Open-label treatment S T R A T I F Y A R S E S E P S O S N S E* R A N D O M I Z E Lenalidomide PO 10 mg/day for 21 days of each 28-day cycle Lenalidomide PO 5 mg/day for 28 days of each 28-day cycle Double blind Wk0481216 Response No response (Not included in efficacy analysis) Placebo Fenaux P, et al. ASH 2009. Abstract 944.

31. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS MDS-004: Transfusion Independence ITT PopulationConfirmed Low/Int-1 Placebo (n = 51) Len 5 mg (n = 46) Len 10 mg (n = 41) Placebo (n = 51) Len 5 mg (n = 46) Len 10 mg (n = 41) Transfusion independence (8+ wks), % 850*61*7.850.061.0 Transfusion independence (26+ wks), % 641*56*5.9 (1.2, 16.1) 41.3* (27.0, 56.8) 56.1* (39.7, 71.5) Median rise in hemoglobin, g/dL 2.35.1 † 6.3 † 2.35.16.3 *P < 0.001 vs placebo. † P < 0.05 vs placebo. Fenaux P, et al. ASH 2009. Abstract 944.

32. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS MDS 003/004: Early Lenalidomide Dose Intensity and RBC Transfusion Indep. List A, et al. ASCO 2011. Abstract 6522. CovariateRBC-TI ≥ 26 Weeks UnivariateMultivariate ORP ValueORP Value Total Cycle 1 dose received, x 10 mg1.108<.00011.080.0014 Age (> 65 vs ≤ 65 yrs)0.716.1734 Sex (male vs female0.717.1973 Time since diagnosis, yrs0.897.6947 Transfusion burden, units/8 wks0.821<.00010.861.0022 Platelets (≥ 150 vs < 150 x 10 9 /L2.481.00081.662.0955 ANC, x 10 9 /L1.034.4970 Hemoglobin, g/dL1.155.1687 Myeloblasts, ≥ 5% vs < 5%.753.3910 Cytopenias (2 or 3 vs 1).820.04110 Del5q (+ ≥ abn vs isolated)0.525.01970.532.0375

33. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Summary: Lenalidomide in Low/Int-1 MDS  MDS-004 confirmed results of MDS-003 [1,2] –Efficacy of 10 mg comparable between studies –Transfusion independence by IWG (61% vs 67%) –MDS-004 supports 10 mg as appropriate starting dose –Higher TI for 10 mg –Mean duration of TI: 106 wks –Greater proportion of cytogenetic responses vs 5 mg (41% vs 17%) –No significant differences in hematological toxicity –The rate of transformation to AML is comparable to the literature  MDS-001 and MDS-002 provided evidence that lenalidomide could be a choice for anemia treatment in lower-risk patients with adequate platelets and neutrophil count [3,4]  Lenalidomide mechanism of action is karyotype dependent, suppressing the clone in del(5q) and promoting erythropoiesis in non-del(5q) [5] 1. Fenaux P, et al. ASH 2009. Abstract 944. 2. List AF, et al. N Engl J Med. 2006;355:1456-1465. 3. List AF, et al. N Engl J Med. 2005;352:549-557. 4. Raza A, et al. Blood. 2008;111:86-93. 5. Sekeres MA, et al. J Clin Oncol. 2008;26:5943-5949.

34. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Azacitadine  Pyrimidine nucleoside analog of cytadine  Approved for use in MDS of the following subtypes: –Refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions –Refractory anemia with excess blasts –Refractory anemia with excess blasts in transformation –Chromic myelomonocytic leukemia  Causes hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow

35. Treatment Options for High-Risk MDS

36. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS SCT candidate No donor Allogeneic donor HMA Investigational SCT Favorable Unfavorable Treatment Algorithm 2011: Int-2/High-Risk MDS HMA, hypomethylating agent; IST, immunosuppressive therapy; SCT, stem cell transplantation.

37. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Approximate Life Expectancy (Yrs) for Ablative Allogeneic Transplantation Transplantation at Diagnosis Transplantation in 2 Yrs Transplantation at Progression Low6.516.867.21 Int-14.614.745.16 Int-24.933.212.84 High3.202.75 Cutler C, et al. Blood. 2004;104:579-585.  Median age: 42 years  Data precede all FDA-approved drugs for MDS

38. Hypomethylating Agents

39. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS A. 5-2-2: 75 mg/m 2 B. 5-2-5: 50 mg/m 2 C. 5: 75 mg/m 2 x6 IWG 2000 HI 12 Cycles AZA x 5d q4-6 wks Study Design (N = 151) Lyons RM, et al. J Clin Oncol. 2009;27:1850-1856. N = 50 N = 51 N = 50 Eligibility  All FAB  Cytopenia  ECOG PS: 0-3 Randomized Phase II Study of Alternative Azacitidine Dose Schedules

40. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS *IWG 2000 criteria Lyons RM, et al. J Clin Oncol. 2009;27:1850-1856. Alternate AzaC Dose Schedule Study: Frequency of Major HI in Evaluable Patients (N = 139) Lineage HI in Evaluable Pts,* n (%) 5-2-2 (n = 50) 5-2-5 (n = 51) 5d (n = 50) Erythroid Ma 19/43 (44) 20/44 (46) RBC-TI12/24 (50)12/22 (55)15/25 (64) Platelet Ma 12/28 (43)8/30 (27)11/22 (50) Any HI22/50 (44)23/51 (45)28/50 (56) Neutrophil Ma 4/23 (17) 9/24 (38) Heme AEs > Gr 333/50 (66)24/48 (50)17/50 (34) AE Tx delay34/50 (68)30/48 (63)17/50 (34)

41. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Azacitidine + BSC (75 mg/m 2 /day x 7 days SC q28 days) Stratified by  FAB: RAEB, RAEB-T  IPSS: int-2, high n = 179 Treatment continued until unacceptable toxicity or AML transformation or disease progression BSC, best supportive care; CCR, conventional care regimens; LDAC, low-dose Ara-C. CCR RANDOMIZERANDOMIZE Physician choice of 1 of 3 CCRs 1. BSC only 2. LDAC (20 mg/m 2 /day SC x 14 day q28-42 days) 3. 7 + 3 chemotherapy (induction + 1-2 consolidation cycles) Fenaux P, et al. Lancet Oncol. 2009;10:223-232. AZA-001: Trial Design

42. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS CCR Regimens (n = 179) Azacitidine (n = 179) CCR (n = 179) Age  Median yrs  ≥ 65, % 69 68 70 76 FAB (%)  RAEB  RAEB-T  CMMoL 58 34 3 58 35 3 IPSS (%)  Int-1  Int-2  High 3 43 46 7 39 48 WHO (%)  RAEB-1  RAEB-2  CMMoL-1  CMMoL-2  AML 8 55 1 6 31 10 53 0 3 32 *Numbers may not add up to 100%, some patient information unknown CCR Regimens (N = 179) BSC, Only (n = 105) LDAC (n = 49) 7 + 3 Chemo (n = 25) 70 77 71 86 65 52 65 29 4 51 39 2 40 52 0 9 44 4 43 8 12 72 12 57 0 3 26 6 49 0 41 4 44 0 8 44 AZA-001 Trial: Baseline Clinical Characteristics* Fenaux P, et al. Lancet Oncol. 2009;10:223-232.

43. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS 0 1.0 510152025303540 Time From Randomization (Mos) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Proportion Surviving CCR Azacitidine HR: 0.58 (95% CI: 0.43-0.77; log rank P =.0001) 24.5 mos 15 mos Fenaux P, et al. Lancet Oncol. 2009;10:223-232. AZA-001 Trial: Azacitidine Significantly Improves OS

44. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Fenaux P, et al. Lancet Oncol. 2009;10:223-232. AZA-001: Hematologic Improvement (2000 IWG) Patients (%) 0 10 30 40 50 60 Any HIHI-E Major 20 HI-P MajorHI-N Major 49.2 28.7 39.5 10.6 32.6 14.0 19.1 18.0 AzacitidineCCR

45. Future Directions

46. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Azacitidine Combination Studies CombinationPatient PopulationResponse Azacitidine + lenalidomide [1] High-risk MDS (n = 18) Overall RR: 67% CR: 44% Azacitidine + etanercept [2] MDS (low to high risk) (n = 18) CR: 72% (13/18) Azacitidine + vorinostat [3] MDS, elderly AML (n = 18) CR: 50% (9/18) Azacitidine + MGCD0103 [4] MDS, R/R AML (n = 52) CR/Cri: 35%; PR: n = 1 (18/52) Azacitidine + gemtuzumab [5] AML/high-risk MDS (n = 15) CR + CRp: 72% (11/15) Azacitidine + romiplostim [6] Low/int-1 MDS azacitidine or decitabine Platelet response 1. Sekeres M, et al. J Clin Oncol. 2010;28:2253-2258. 2. Holzinger 2007. 3. Silverman LR, et al. ASCO 2008. Abstract 7000. 4. Garcia Manero G, et al. ASCO 2007. Abstract 7062. 5. Nand S, et al. Leuk Lymphoma. 2008;49:2141-2147. 6. Kantarjian H, et al. ASH 2008. Abstract 224.

47. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS New Agents Targeting Thrombocytopenia 1. Kantarjian H, et al. J Clin Oncol. 2010;28:437-444. 2. Wroblewski S, et al. ASCO 2010. Abstract TPS184.  Romiplostim [1]  Eltrombopag [2]

48. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Other Novel Agents  Nucleoside analogues –Sapacitabine –Clofarabine  Kinase inhibitors –Arry-614 –ON1910  Glutathione analogue –Ezatiostat (TLK 199)  HDAC inhibitors –Vorinostat –Belinostat –PDX1010 –MCD0103  Immnunosuppressive therapy –Alemtuzumab

49. Topic 3: Key Issues in Supportive Care of Patients With MDS

50. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Cazzola M, et al. N Engl J Med. 2005;352:536-538 Transfusion Status and Outcomes University of Pavia Cohort (N = 374) Time (Mos) Cumulative Proportion of Patients Surviving (%) Transfusion-independent MDS patients Transfusion-dependent MDS patients Hazard ratio = 1.58; P =.005 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 140020406080100120

51. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Malcovati L, et. al. J Clin Oncol. 2005;23:7594-7603. Is Transfusion Dependency an Issue in MDS?  Transfusion-dependent patients had a significantly shorter OS than transfusion-independent patients (HR: 2.16; P <.001 overall) Cumulative Proportion Surviving 0 0.5 0.7 1.0 0.3 Survival Time (Mos) 080140 0.9 0.8 0.6 0.4 0.2 0.1 120100604020 *Excludes isolated 5q- Good IPSS Risk* Intermediate IPSS Risk Transfusion independent Transfusion dependent Cumulative Proportion Surviving 0 0.5 0.7 1.0 0.3 Survival Time (Mos) 080140 0.9 0.8 0.6 0.4 0.2 0.1 120100604020

52. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Survival Decreases With Increasing Serum Ferritin Levels Adapted with permission from Malcovati L et al. Haematologica. 2006;91:1588-1590 Malcovati L, Leuk Res. 2007;31 (suppl 3):S2-S6. Cumulative Proportion Surviving 0 0.5 0.7 60 1.0 0.3 Survival Time (Mos) 0100160180 sFerr = 2500 mcg/L N = 426 Patients With RA/RARS/del 5q (HR: 1.42; P <.001) sFerr = 2000 mcg/L sFerr = 1500 mcg/L sFerr = 1000 mcg/L 0.9 0.8 0.6 0.4 0.2 0.1 140120804020 Patients With RCMD/RCMD-RS (HR: 1.33; P =.07) Cumulative Proportion Surviving 0 0.5 0.7 60 1.0 0.3 Survival Time (Mos) 0100160180 0.9 0.8 0.6 0.4 0.2 0.1 140120804020 sFerr = 2500 mcg/L N = 426 sFerr = 2000 mcg/L sFerr = 1500 mcg/L sFerr = 1000 mcg/L

53. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Serum Ferritin Is Predictive of Survival and Risk of AML in MDS Development of transfusional iron overload is a significant independent prognostic factor for overall survival and evolution to AML Sanz G, et al. 2008 ASH. Abstract 640. Probability 0 0.4 1.0 0.6 5 0.8 0.2 Yrs From Diagnosis 0101520 Ferritin < 1000 mcg/L Ferritin ≥ 1000 mcg/L P <.0001 OSTime Without AML Probability 0 0.4 1.0 0.6 5 0.8 0.2 Yrs From Diagnosis 0101520 P <.0001

54. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS MDS Patients With Multiple Transfusions Have an Increased Risk of Cardiac Events  705 new cases of MDS from January-March 2003 in US Medicare SAF5% claims database  During 3-yr follow-up –Cardiac events were more common in transfused vs nontransfused MDS patients (P =.002) and in MDS patients vs individuals without MDS (P <.001) SAF5%, standard analytic file comprised of randomly selected, 5% sample of all Medicare beneficiaries. Cardiac Events (%) 0 50 90 70 MDS Nontransfused (n = 378) 40 20 No MDS (n = 1,712,797) 80 60 30 10 MDS Transfused (n = 327) 69 42 100 Sanz G, et al. 2008 ASH. Abstract 640.

55. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS MDS Patients With Multiple Transfusions Have an Increased Risk of Diabetes  705 new cases of MDS from January -March 2003 in US Medicare SAF5% claims database  Development of diabetes more common in transfused than in nontransfused MDS patients and total Medicare population during 3-yr follow-up * For comparison of transfused and nontransfused MDS patients. Developed Diabetes (%) 0 30 50 40 MDS Patients (n = 705) 20 10 Overall Medicare Pop (N = 1,713,502) 43 33 P =.0001 Developed Diabetes (%) 0 30 50 40 MDS Transfsd (n = 327) 20 10 48 33 P =.02* 39 Overall Medicare Pop (N = 1,713,502) MDS Nontransfsd (n = 378) Sanz G, et al. 2008 ASH. Abstract 640.

56. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS 050100150200 No ICT ICT Median Survival, mo 40.1 mo (0.7-224) (Not reached at 160 mo) P <.03 For patients with Low and Int-1 MDS, ICT was associated with a significant improvement in overall survival Leitch HA, et al. ASH 2006. Abstract 249. + Improved Survival in MDS Patients Receiving Iron Chelation Therapy (ICT)

57. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Iron Chelation Therapy and Survival in MDS  Survey of 170 patients with MDS referred for RBC transfusion at 18 French treatment centers during 1-month period in 2005 –Assessments: hematologic data, RBC transfusion requirement, iron chelation therapy, and iron overload –Cohort survival prospectively followed and reanalyzed on May 15, 2007  Standard iron chelation therapy –Subcutaneous deferoxamine 40 mg/kg/day for 3-5 days/week: n = 41 –Deferiprone 30-75 mg/kg/day: n = 5 –Subcutaneous deferoxamine + deferiprone: n = 5 –Deferasirox 20-30 mg/kg/day: n = 6  Low-dose iron chelation therapy –Subcutaneous deferoxamine bolus 2-3 g/week: n = 12 –Intravenous deferoxamine 50-100 mg/kg once after RBC transfusion: n = 7 Rose C, et al. ASH 2007. Abstract 249.

58. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Iron Chelation Therapy and Survival in MDS (cont’d)  OS significantly better for patients who received iron chelation therapy  Results consistent across all subgroups analyzed (IPSS low and intermediate-1, sex, age) Rose C, et al. ASH 2007. Abstract 249. Median survival: 63 months (whole group) 115 vs 51 months (P <.0001) CT No CT Diagnosis to Death Time (Mos) 050100150200250 0.00 0.25 0.50 0.75 1.00 Survival Distribution Function

59. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Matched-Pair Analysis of 186 MDS Patients Receiving Iron Chelation Therapy or Transfusion Therapy Only ICT (n=93)BSC (n=93) Median age6367 Median Ferritin1954945 Median survival74 month49 month AML transformation at 2 years10%12%  Two groups were matched for age, WHO subtypes, IPSS  ICT included deferoxamine (n=54), deferiprone (n=5), deferasirox (n=32), deferoxamine followed by deferasirox (n=12) and deferoxamine plus deferiprone (n=4) Fox F, et al. ASH 2009. Abstract 1747.

60. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Month Serum Ferritin, ng/mL EPIC (N = 341) US03 (N = 176) 027303397 323583057 622102802 920762635 1219042501 Deferasirox in MDS: EPIC and US03 Studies  US03 results –HI by IWG criteria: 8/176 (5%) –Erythroid response: 5 –Major platelet response: 1 –Combined platelet + neutrophil response: 1  Both EPIC [1] and US03 [2] studies required –Baseline serum ferritin ≥ 1000 ng/mL –> 20 units red blood cell transfusions  Treatment: deferasirox 10-30 mg/kg daily 1. Gattermann N, et al. ASH 2008. Abstract 633. 2. List AF, et al. ASH 2008. Abstract 634.

61. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Deferasirox Black Box Warning Deferasirox is contraindicated in patients with:  Creatinine clearance 2 times the age-appropriate upper limit of normal  Poor performance status and high-risk myelodysplastic syndromes or advanced malignancies  Platelet counts <50 x 10 9 /L  Known hypersensitivity to deferasirox or any component of drug Deferasirox Prescribing Information

62. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS Screening 1 month 4yr 1yr 2yr Randomization (2:1 = Deferasirox/Placebo) 3yr 5yr Interim analysis (IA) : at 50% of primary composite events (~3yr) at 75% of primary composite events (~4yr) 54% chance to stop the trial depending on IA results IA Placebo N = 210 10 mg/kg/day (1st 2 weeks) 20 mg/kg/day (weeks 2-12) Up to 40 mg/kg/day (after 12 weeks) Deferasirox N = 420 10 mg/kg/day (1st 2 weeks) 20 mg/kg/day (weeks 2-12) Up to 40 mg/kg/day (after 12 weeks) Expected end of study Low or Int-1 risk MDS Serum ferritin >1000 mcg/L and <2500 mcg/L TELESTO STUDY

63. clinicaloptions.com/oncology Individualizing Therapy to Optimize Patient Outcomes in MDS MDS Patients Who Are Likely to Benefit Most From Management Iron Overload CharacteristicNCCN 1 MDS Foundation 2 Transfusion status  Received 20-30 packed RBC units  Continuing transfusions  Transfusion dependent, requiring 2 units/month for > 1 year Serum ferritin level  > 2500 μg/L  1000 μg/L MDS risk  IPSS: Low- or Int-1  WHO: RA, RARS and 5q- Patient profile  Candidates for allografts  Life expectancy > 1 year and no comorbidities that limit progress  A need to preserve organ function  Candidates for allografts 1. NCCN Clinical Practice Guidelines in Oncology. 2. Bennett JM. J Hematol. 2008;83:858-861.

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