1. Lenalidomide (REVLIMID ® ) Celgene Corporation New Drug Application (021880) Oncology Drug Advisory Committee Sept 14, 2005 Lenalidomide Review Team Division of Drug Oncology Products Oncology Drug Advisory Committee Sept 14, 2005 Lenalidomide Review Team Division of Drug Oncology Products Center for Drug Evaluation and Research

2. NDA 21880 Review Team Medical Efficacy: Maitreyee Hazarika, MD Safety: Edvardas Kaminskas, MD Ann Farrell, MD Statistics Yuan Li Shen, DrPH Rajeshwari Sridhara, PhD Pharmacology/Toxicology Pharm Tox: Anwar Goheer, PhD Reproductive Safety: Kimberly Benson, PhD John Leighton, PhD Medical Efficacy: Maitreyee Hazarika, MD Safety: Edvardas Kaminskas, MD Ann Farrell, MD Statistics Yuan Li Shen, DrPH Rajeshwari Sridhara, PhD Pharmacology/Toxicology Pharm Tox: Anwar Goheer, PhD Reproductive Safety: Kimberly Benson, PhD John Leighton, PhD Clinical Pharmacology Gene Williams, PhD Brian Booth, PhD Chemistry Hari Sarker, PhD Nallaperumal Chidambaram, PhD Project Manager Carl Huntley, RPh, MBA

3. Proposed Indication Treatment of patients with transfusion dependent anemia due to low- or intermediate-1 risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities

4. Issues for ODAC Single-arm trial design in a heterogenous disease (MDS) (FDA recommended a randomized controlled trial) ‘8-week transfusion-free’ endpoint to demonstrate clinical benefit Toxicity of 10 mg dose Benefit vs. risk of the drug for this population Implementation of additional risk management measures Single-arm trial design in a heterogenous disease (MDS) (FDA recommended a randomized controlled trial) ‘8-week transfusion-free’ endpoint to demonstrate clinical benefit Toxicity of 10 mg dose Benefit vs. risk of the drug for this population Implementation of additional risk management measures

5. OutlineOutline Drug Approvals for MDS Reproductive Safety Assessment Clinical Review Efficacy Integrated Safety Summary Risk Management Summary Drug Approvals for MDS Reproductive Safety Assessment Clinical Review Efficacy Integrated Safety Summary Risk Management Summary

6. FDA Approval for MDS Azacitidine (Vidaza ® ) injection MDS subtypes: RA, RARS, RAEB, RAEB-t, CMML 1 randomized, controlled trial comparing azacitidine + supportive care (SC) vs. SC (N=191) 2 single-arm studies Response rate (16%) ≥ 4 weeks duration (p<0.0001) based on complete or partial response (CR + PR) of  bone marrow  peripheral blood (all cell counts) MDS subtypes: RA, RARS, RAEB, RAEB-t, CMML 1 randomized, controlled trial comparing azacitidine + supportive care (SC) vs. SC (N=191) 2 single-arm studies Response rate (16%) ≥ 4 weeks duration (p<0.0001) based on complete or partial response (CR + PR) of  bone marrow  peripheral blood (all cell counts)

7. Structural Comparison Lenalidomide Thalidomide Lenalidomide Thalidomide

8. Clinical Pharmacology Metabolism  Not a cytochromes P450 substrate  Presence and identity of circulating metabolites not studied in humans Excretion: Approximately 2/3 eliminated as parent via urine Metabolism  Not a cytochromes P450 substrate  Presence and identity of circulating metabolites not studied in humans Excretion: Approximately 2/3 eliminated as parent via urine

9. Reproductive Safety Assessment

10. Embryo-Fetal Development Study Requirements Study in first species Conduct confirmatory study in second species Study in first species Conduct confirmatory study in second species If results are negative - No evidence of drug- induced embryo-fetal development adverse events

11. Lenalidomide Embryo-Fetal Development Studies Rat Study Methods and Results Pregnant rats dosed during gestational days 6-17 No adverse effects seen on the embryo or fetus, including limb bud effects, at the doses studied Methods and Results Pregnant rats dosed during gestational days 6-17 No adverse effects seen on the embryo or fetus, including limb bud effects, at the doses studied

12. Lenalidomide Embryo-Fetal Development Studies Rat Study Conclusion  Rat not sensitive species for thalidomide limb bud developmental effects  While this study does provide some information regarding developmental effects, it is inadequate for full assessment of lenalidomide developmental effects Conclusion  Rat not sensitive species for thalidomide limb bud developmental effects  While this study does provide some information regarding developmental effects, it is inadequate for full assessment of lenalidomide developmental effects

13. Lenalidomide Embryo-Fetal Development Studies Rabbit Study Methods and Results Pregnant rabbits dosed during gestational days 7-19 A Thalidomide dose group was also included Acceptable study endpoints (maternal or developmental effects) not achieved Thalidomide caused expected limb deformities, lenalidomide did not Methods and Results Pregnant rabbits dosed during gestational days 7-19 A Thalidomide dose group was also included Acceptable study endpoints (maternal or developmental effects) not achieved Thalidomide caused expected limb deformities, lenalidomide did not

14. Lenalidomide Embryo-Fetal Development Studies Rabbit Study Conclusion This study was inadequate  Drug-related effects on maternal or developmental endpoints in the high dose group did not meet standard study criteria  There was a confounding variable - some rabbits were not eating prior to study onset Conclusion This study was inadequate  Drug-related effects on maternal or developmental endpoints in the high dose group did not meet standard study criteria  There was a confounding variable - some rabbits were not eating prior to study onset

15. ConclusionConclusion Structural similarities of lenalidomide and thalidomide suggests risk Insufficient information to fully determine the effects on embryo-fetal development for lenalidomide  The rat is not an appropriate model for full assessment of embryo-fetal effects of this drug  The rabbit study was inadequate Structural similarities of lenalidomide and thalidomide suggests risk Insufficient information to fully determine the effects on embryo-fetal development for lenalidomide  The rat is not an appropriate model for full assessment of embryo-fetal effects of this drug  The rabbit study was inadequate

16. RecommendationsRecommendations If approved, Pregnancy Category D is recommended, similar to most other oncologic agents Additional studies to fully assess potential developmental effects should be conducted If approved, Pregnancy Category D is recommended, similar to most other oncologic agents Additional studies to fully assess potential developmental effects should be conducted

17. Clinical Review

18. Efficacy Studies StudyStudy DesignEvaluable patients/N DosesPrimary Endpoint MDS-003 Single-arm Open-label Multicenter Phase 2 96/14810 mg daily 10 mg x21d/q28d RBC transfusion independence MDS-001 Pilot, phase 1/2, single-arm, 2- stage, dose- finding 10/4525 mg daily 10 mg daily 10 mg x21d/q28d Major and minor erythroid response MDS-002 Single-arm Open-label Multicenter Phase 2 118/21510 mg daily 10 mg x21d/q28d RBC transfusion independence

19. MDS-003 Efficacy

20. MDS-003 Study Design Single-arm, open-label, multi-center, Phase 2 study Local or central laboratory used to determine eligibility Adjudication by independent hematologic and cytogenetic reviewers Response criteria based on IWG Standardized Response Criteria for MDS (Cheson et al, Blood, 2000) Single-arm, open-label, multi-center, Phase 2 study Local or central laboratory used to determine eligibility Adjudication by independent hematologic and cytogenetic reviewers Response criteria based on IWG Standardized Response Criteria for MDS (Cheson et al, Blood, 2000)

21. Study Endpoints Primary  RBC transfusion independence Secondary endpoints Change of hemoglobin from baseline Duration of response ≥ 50% decrease in RBC transfusion requirements Cytogenetic response Platelet response Neutrophil response Primary  RBC transfusion independence Secondary endpoints Change of hemoglobin from baseline Duration of response ≥ 50% decrease in RBC transfusion requirements Cytogenetic response Platelet response Neutrophil response

22. Eligibility Criteria MDS-003 Low- risk or intermediate- 1- risk MDS  with a del (5q) (q31-33) (del 5q isolated or associated with other cytogenetic abnormalities) RBC transfusion- dependent anemia defined as requiring ≥ 2 units of RBCs within 8 weeks of study treatment Low- risk or intermediate- 1- risk MDS  with a del (5q) (q31-33) (del 5q isolated or associated with other cytogenetic abnormalities) RBC transfusion- dependent anemia defined as requiring ≥ 2 units of RBCs within 8 weeks of study treatment

23. MDS-003MDS-003 Enrolled 148 patients Doses: Oral lenalidomide 10 mg x21 d/q28 d (syncopated) (N=45) 10 mg daily (continuous) (N=103) Enrolled 148 patients Doses: Oral lenalidomide 10 mg x21 d/q28 d (syncopated) (N=45) 10 mg daily (continuous) (N=103)

24. Disease Characteristics Cytogenetics MDS-003 CytogeneticsITT N=148 (%) 5q deletion148 (100) Isolated 5q del110 (74.3) Del 5q with other abnormality38 (25.7) ≥ 20 metaphases119 (80.4) < 20 metaphases29 (19.6)

25. Disease Characteristics IPSS Risk Score MDS-003 Risk Category10 mg sync N=45 (%) 10 mg cont N=103 (%) ITT N=148 (%) Low13 (28.9)42 (40.8)55 (37.1) Intermediate-125 (55.6)40 (38.8)65 (43.2) Intermediate-22 (4.4)4 (3.9)6 (4.0) High1 (2.2)1 (1.0)2 (1.3) Missing4 (8.9)16 (15.5)20 (13.5)

26. Patient Characteristics RBC Transfusion Dependent Anemia MDS-003 Transfusion Dependence At Baseline ITT N=148 % ≥ 2 RBC units within 8 weeks of start of study drug ≥ 3 RBC units 141 106 95 71.6 0-2 units within 8 weeks4228.4 Median Min, Max 6 0-18

27. Patient Populations MDS-003 PopulationSponsor N (%) FDA N (%) ITT: All enrolled148 (100) MITT: Transfusion dependent anemia (≥ 2 U in each of two 8-week periods) 94 (63.5)Not done FDA Evaluable: Transfusion dependent anemia (≥ 2 U in 8-weeks prior to start of drug) Not done96 (64.9)

28. FDA Evaluable for Efficacy MDS-003 Reasons for ExclusionsPatients N=148 (%) Adjudicated not MDS20 (13.5) Adjudicated no IPSS score20 (13.5) Adjudicated IPSS risk category intermediate-2 or high 8 (5.4) Did not receive ≥ 2 units RBC within 8 weeks7 (4.7) < 20 metaphases analyzed at baseline29 (19.6) Total FDA Evaluable96 (64.9)

29. IWG Response Criteria for MDS Cheson et al, Blood, 2000 Hematologic Improvement-Erythroid Response Major response  for RBC transfusion-dependent patients, transfusion independence  For patients with pretreatment hemoglobin < 11 g/dL, greater than 2 g/dL increase in hemoglobin Minor Response  for RBC transfusion-dependent patients, 50% decrease in transfusion requirements  For patients with pretreatment hemoglobin < 11 g/dL, 1-2 g/dL increase in hemoglobin Hematologic Improvement-Erythroid Response Major response  for RBC transfusion-dependent patients, transfusion independence  For patients with pretreatment hemoglobin < 11 g/dL, greater than 2 g/dL increase in hemoglobin Minor Response  for RBC transfusion-dependent patients, 50% decrease in transfusion requirements  For patients with pretreatment hemoglobin < 11 g/dL, 1-2 g/dL increase in hemoglobin

30. IWG Response Criteria for MDS Cheson et al, Blood, 2000 Hematologic Improvement  Improvements must last at least 2 months in the absence of ongoing cytotoxic therapy Hematologic Improvement  Improvements must last at least 2 months in the absence of ongoing cytotoxic therapy

31. Definition of Response * (Protocol) RBC Transfusion Independence  The absence of the intravenous infusion of any RBC transfusion during any consecutive “rolling” 56 days (8 weeks) during the treatment period  must last ≥ 2 months  ≥ 1.0 g/dL increase in Hgb * Modified IWG MDS Hematologic Improvement Criteria  The absence of the intravenous infusion of any RBC transfusion during any consecutive “rolling” 56 days (8 weeks) during the treatment period  must last ≥ 2 months  ≥ 1.0 g/dL increase in Hgb * Modified IWG MDS Hematologic Improvement Criteria

32. RBC Transfusion Independence Response PopulationTransfusion Independent N (%) 95% CI ITT N=148 99 (66.9)0.59, 0.74 FDA Evaluable N=96 64 (66.7)0.56, 0.76

33. Change in Hemoglobin from Baseline MDS-003 Hemoglobin change  minimum hemoglobin value in the 8 week period preceding first dose of study drug for baseline and the maximum hgb value during the response period, excluding the 30 days after the last transfusion prior to the response period  ITT, Median change 3.3 g/dL  Responders, Median change 5.2 g/dL Hemoglobin change  minimum hemoglobin value in the 8 week period preceding first dose of study drug for baseline and the maximum hgb value during the response period, excluding the 30 days after the last transfusion prior to the response period  ITT, Median change 3.3 g/dL  Responders, Median change 5.2 g/dL

34. ≥50% Decrease in Transfusion Requirements Population≥ 50% decrease N (%) 95% CI ITT N=148 112 (75.7)0.68, 0.82 FDA Evaluable N=96 73 (76.0)0.66, 0.84

35. Duration of Transfusion Independence in Responders (weeks) (N=99) MDS-003 Response duration Measured from end of the consecutive 56 days during which patient was free of RBC transfusions to the date of first RBC transfusion Median 52.3 weeks (Min, Max 8.1- 74.6) Response duration Measured from end of the consecutive 56 days during which patient was free of RBC transfusions to the date of first RBC transfusion Median 52.3 weeks (Min, Max 8.1- 74.6)

36. Relapsed Patients Relapses from transfusion independent to transfusion dependent : 32/99 patients Relapses occurred within treatment period: 13/32 patients Relapses from transfusion independent to transfusion dependent : 32/99 patients Relapses occurred within treatment period: 13/32 patients

37. IWG Response Criteria for MDS Cheson et al, Blood, 2000 Major Cytogenetic Response  Major: No detectable cytogenetic abnormality if preexisting abnormality was present (Requires 20 analyzable metaphases using conventional cytogenetic techniques) Major Cytogenetic Response  Major: No detectable cytogenetic abnormality if preexisting abnormality was present (Requires 20 analyzable metaphases using conventional cytogenetic techniques)

38. Major Cytogenetic Response MDS-003 PopulationMajor Response N (%) 95% CI ITT N=120 52 (43.3)17.6, 33.7 FDA Evaluable N=58 26 (44.8)31.7, 58.5

39. Major Platelet Response MDS-003 Definition (IWG MDS Response criteria):  For patients with pre-treatment platelet count less than 100,000/mm 3 an absolute increase of 30,000 or more  for platelet transfusion-dependent patients, stabilization of platelet counts and platelet transfusion independence Major platelet response rate: 0/14 Definition (IWG MDS Response criteria):  For patients with pre-treatment platelet count less than 100,000/mm 3 an absolute increase of 30,000 or more  for platelet transfusion-dependent patients, stabilization of platelet counts and platelet transfusion independence Major platelet response rate: 0/14

40. Major Neutrophil Response MDS-003 Definition (IWG MDS Response Criteria):  For ANC less than 1500/mm 3 before therapy, at least a 100% increase, or  an absolute increase of more than 500/mm 3, whichever is greater Major neutrophil response: 1/6 Definition (IWG MDS Response Criteria):  For ANC less than 1500/mm 3 before therapy, at least a 100% increase, or  an absolute increase of more than 500/mm 3, whichever is greater Major neutrophil response: 1/6

41. MDS-001 Efficacy

42. MDS-001 Study Design Dose-finding, phase 1/2, single-arm, single-center study Primary endpoint: patients with major or minor erythroid response (modified from the IWG MDS Response Criteria) Enrolled 45 patients Doses: 25 mg daily (N=13) 10 mg q21 d/28 d (syncopated) (N=18) 10 mg daily (continuous) (N=12) Dose-finding, phase 1/2, single-arm, single-center study Primary endpoint: patients with major or minor erythroid response (modified from the IWG MDS Response Criteria) Enrolled 45 patients Doses: 25 mg daily (N=13) 10 mg q21 d/28 d (syncopated) (N=18) 10 mg daily (continuous) (N=12)

43. Study Endpoints Primary Major or minor erythroid response Secondary cytogenetic response neutrophil response platelet count response Primary Major or minor erythroid response Secondary cytogenetic response neutrophil response platelet count response

44. Eligibility Criteria MDS-001 De novo MDS: RA, RARS, RAEB, RAEB-t, CMML RBC transfusion- dependent anemia defined as requiring ≥ 4 units of RBCs within 8 weeks of study treatment, or Baseline mean hemoglobin < 10 g/dL (untransfused) De novo MDS: RA, RARS, RAEB, RAEB-t, CMML RBC transfusion- dependent anemia defined as requiring ≥ 4 units of RBCs within 8 weeks of study treatment, or Baseline mean hemoglobin < 10 g/dL (untransfused)

45. Population (N=10) MDS-001 Transfusion dependent anemia (≥ 2 U/8 weeks) low- or intermediate-1 risk MDS with del 5 q

46. Major Erythroid Response MDS-001 Major erythroid response  7/10 (70%) (95% CI [35, 93]) Minor erythroid response  none Major erythroid response  7/10 (70%) (95% CI [35, 93]) Minor erythroid response  none

47. Efficacy Analyses (cont’d) MDS-001 Duration of response (7 responders) Median: 41.4 weeks (Range: 31- 88.1 weeks) Median change in hemoglobin values : 5.3 g/dL Major cytogenetic response: 9/10 Major platelet response: 1/1 Major neutrophil response: 1/2 Duration of response (7 responders) Median: 41.4 weeks (Range: 31- 88.1 weeks) Median change in hemoglobin values : 5.3 g/dL Major cytogenetic response: 9/10 Major platelet response: 1/1 Major neutrophil response: 1/2

48. MDS-002 Efficacy

49. MDS-002 Study Design MDS-002 identical to MDS-003 except Study Population  Patients without del 5q cytogenetic abnormality Enrolled 215 patients 2 doses: Dose 10 mg syncopated (115) Dose 10 mg continuous (100) MDS-002 identical to MDS-003 except Study Population  Patients without del 5q cytogenetic abnormality Enrolled 215 patients 2 doses: Dose 10 mg syncopated (115) Dose 10 mg continuous (100)

50. Efficacy Analyses MDS-002 ITT PopulationResults RBC Transfusion Independence (N=215) 46 (21.4 %) Change in Hgb in responders (N=46)3 g/dL (Range: 1.3-8.3) Duration in responders (N=46) 18.9 weeks (Range: 8-36)

51. Integrated Safety Summary

52. Patient Exposure Data Sources 408 MDS patients 13 patients 25 mg/day starting dose 215 patients 10 mg/day starting dose 180 patients 10 mg x 21 days q28 day cycle Data Sources 408 MDS patients 13 patients 25 mg/day starting dose 215 patients 10 mg/day starting dose 180 patients 10 mg x 21 days q28 day cycle

53. Dose Modifications due to Adverse Events Dose reduced or interrupted MDS-003 10 mg N = 148 MDS-001 25 mg N = 13 MDS-001 10 mg N = 32 MDS-002 10 mg N = 215 Any dose reduced or interrupted 118 (80%)8 (62%)12 (38%)102 (47%) ≥ 2 doses reduced or interrupted 50 (34%)7 (54%)049 (23%)

54. Grade 3 and 4 Adverse Events (AEs) 10 mg Starting Dose Are AEs due to MDS or lenalidomide or both? All patients had grade 1 to 4 AEs 80% had one or more grade 3 or 4 AEs Neutropenia - 39% Thrombocytopenia - 34% Pneumonia, Sepsis and Other Infections – 9% Anemia – 7% Fatigue – 6% Rash – 5% Diarrhea – 4% Febrile neutropenia – 3% DVTs – 2% Single grade 4 bleeding events – subarachnoid, subdural, GI, hematuria Are AEs due to MDS or lenalidomide or both? All patients had grade 1 to 4 AEs 80% had one or more grade 3 or 4 AEs Neutropenia - 39% Thrombocytopenia - 34% Pneumonia, Sepsis and Other Infections – 9% Anemia – 7% Fatigue – 6% Rash – 5% Diarrhea – 4% Febrile neutropenia – 3% DVTs – 2% Single grade 4 bleeding events – subarachnoid, subdural, GI, hematuria

55. Confounding Issue Neutropenia or thrombocytopenia due to MDS or to lenalidomide, especially in a trial without a control?

56. Serious Adverse Events (SAEs) with 10 mg Dose SAEs occurred in 38% in all 3 studies Blood (13%) Infections (8%) General (4%) Respiratory (3%) Cardiac (3%) GI (2%) Metabolic (2%) Vascular (1%) SAEs occurred in 38% in all 3 studies Blood (13%) Infections (8%) General (4%) Respiratory (3%) Cardiac (3%) GI (2%) Metabolic (2%) Vascular (1%)

57. DeathsDeaths In the 3 studies, 28 on-study deaths, and 14 deaths in patients with continuing toxicity Pneumonia/sepsis with neutropenia (9) AML (9) Bleeding with thrombocytopenia (5) Cardiac (5) Liver failure (2) Perforated bowel & sepsis (2) Multiorgan failure with pancytopenia (1) Lung cancer (1) Angiodysplasia and bleeding (1) Cause unknown (7) In the 3 studies, 28 on-study deaths, and 14 deaths in patients with continuing toxicity Pneumonia/sepsis with neutropenia (9) AML (9) Bleeding with thrombocytopenia (5) Cardiac (5) Liver failure (2) Perforated bowel & sepsis (2) Multiorgan failure with pancytopenia (1) Lung cancer (1) Angiodysplasia and bleeding (1) Cause unknown (7)

58. Safety Summary 408 MDS patients treated with starting doses of 25 mg/day or 10 mg/day lenalidomide Excessive toxicity observed - 10 mg/day dose reduced and/or interrupted in 80% Single-arm trial does not permit attribution of AEs to MDS or to the drug or to both 80% of patients had grade 3 or 4 AEs 38% of patients had SAEs 408 MDS patients treated with starting doses of 25 mg/day or 10 mg/day lenalidomide Excessive toxicity observed - 10 mg/day dose reduced and/or interrupted in 80% Single-arm trial does not permit attribution of AEs to MDS or to the drug or to both 80% of patients had grade 3 or 4 AEs 38% of patients had SAEs

59. Safety Summary (cont’d) Most common gr. 3/4 AEs and SAEs were neutropenia, thrombocytopenia, and infections. Most common reasons for discontinuations from studies were adverse events: hematologic, GI, and dermatologic. Most deaths were due to: infections, AML, bleeding, and cardiac. Benefits of RBC transfusion independence vs. risks of neutropenia and thrombocytopenia need to be assessed. Most common gr. 3/4 AEs and SAEs were neutropenia, thrombocytopenia, and infections. Most common reasons for discontinuations from studies were adverse events: hematologic, GI, and dermatologic. Most deaths were due to: infections, AML, bleeding, and cardiac. Benefits of RBC transfusion independence vs. risks of neutropenia and thrombocytopenia need to be assessed.

60. Ongoing Phase 3 Study

61. Planned Phase 3 Study Ongoing in Europe Del 5q patients Randomized, double-blind, 3-arm trial  5 mg daily  10 mg x21d/q28 d  placebo Primary endpoint  RBC transfusion independence for ≥26 weeks Ongoing in Europe Del 5q patients Randomized, double-blind, 3-arm trial  5 mg daily  10 mg x21d/q28 d  placebo Primary endpoint  RBC transfusion independence for ≥26 weeks

62. Risk Management

63. Major safety concern  Teratogenicity Major goal  Prevention of fetal exposure to lenalidomide Major safety concern  Teratogenicity Major goal  Prevention of fetal exposure to lenalidomide

64. Risk Management Plan Examples of other drugs with teratogenic potential and risk management plans  Thalidomide/ S.T.E.P.S ® Program  Isotretinoin/ iPLEDGE ® Examples of other drugs with teratogenic potential and risk management plans  Thalidomide/ S.T.E.P.S ® Program  Isotretinoin/ iPLEDGE ®

65. Summary Comparison AzacitidineLenalidomide Study Designrandomizedsingle-arm PopulationRA, RARS, RAEB, RAEB-t, CMML low or int-1 risk MDS, transfusion dependent anemia, del 5q Response Criteria CR + PR (Bone marrow, peripheral blood) transfusion independence, change in hemoglobin

66. SummarySummary Embryo-fetal development not adequately addressed Single arm study for efficacy  transfusion entry criteria; median 6 units/8 weeks  a rolling 56 day transfusion free period RBC transfusion independence response (67%) with ≥ 1 g/dL increase in hemoglobin Median duration of transfusion independence in responders (52 wks) Major cytogenetic response (43%) Embryo-fetal development not adequately addressed Single arm study for efficacy  transfusion entry criteria; median 6 units/8 weeks  a rolling 56 day transfusion free period RBC transfusion independence response (67%) with ≥ 1 g/dL increase in hemoglobin Median duration of transfusion independence in responders (52 wks) Major cytogenetic response (43%)

67. SummarySummary All patients had AEs, 80% grade 3/4 AEs Dosing reduced in 80% patients Excessive toxicity at 10 mg Absence of control arm makes attribution of AEs and deaths difficult All patients had AEs, 80% grade 3/4 AEs Dosing reduced in 80% patients Excessive toxicity at 10 mg Absence of control arm makes attribution of AEs and deaths difficult