1. Guillermo Garcia-Manero, MD University of Texas MD Anderson Cancer Center Houston, Texas Rami S. Komrokji, MD H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida Myelodysplastic Syndromes: Best Practices in Patient Care This program is supported by educational grants from

2. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care 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 Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care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 Myelodysplastic Syndromes: Best Practices in Patient Care Program Chairs Guillermo Garcia-Manero, MD Professor, Division of Cancer Medicine Chief, Section of Myelodysplastic Syndromes Department of Leukemia Division of Cancer Medicine University of Texas M. D. Anderson Cancer Center Houston, Texas Rami S. Komrokji, MD Associate Professor of Oncologic Sciences Department of Oncologic Sciences University of South Florida Clinical Director Malignant Hematology H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida

4. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Faculty Disclosures Guillermo Garcia-Manero, MD, has no significant financial relationships to disclose. Rami S. Komrokji, MD, has disclosed that he has received fees for non-CME/CE services received directly from a commercial interest or their agents (eg, speakers bureaus) from Celgene and Novartis and funds for research support from Celgene and Incyte.

5. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Topics  MDS Diagnosis, Classification, and Risk Stratification  Treatment Options for Lower-Risk MDS  Key Issues in Supportive Care of Patients With MDS  Treatment Options for Higher-Risk MDS

6. MDS Diagnosis, Classification, and Risk Stratification

7. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Myelodysplastic Syndromes  A group of malignant hematopoietic disorders characterized by [1] –Bone marrow failure with resultant cytopenia and related complications –Macrocytic anemia is most common presentation –Dysplastic cytologic morphology is the hallmark of the disease –Tendency to progress to AML  Overall incidence 3.7-4.8/100,000 [2] –≈ 10,000/yr in United States (true estimates ≈ 37,000-48,000) –Median age: 70 yrs; incidence: 34-47/100,000 > 75 yrs [3] 1. Bennett J, et al. In: Clinical oncology. New York NY: Churchill Livingstone; 2004. pp. 2849-2881. 2. SEER data 2000-2009. 3. SEER 18 Data. 2000-2009.

8. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Minimal Diagnostic Criteria for MDS  MDS-related (decisive) criteria* –Dysplasia in ≥ 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. *Prerequisite criteria: constant cytopenia in ≥ 1 of the following: 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

9. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care IPSS Is Most Common Tool for Risk Stratification of MDS Score Value Prognostic Variable 00.51.01.52.0 Bone marrow blasts, %< 55-10--11-2021-30 Karyotype*GoodIntermediatePoor-- Cytopenias † 0/12/3-- *Good = normal, -Y, del(5q), del(20q); intermediate = other karyotypic abnormalities; poor = complex (  3 abnormalities) or chromosome 7 abnormalities. † Hb < 10 g/dL; ANC < 1800/  L; platelets < 100,000/  L. Greenberg P, et al. Blood. 1997;89:2079-2088. Total Score Prognostic Variable 00.51.01.52.0  2.5 RiskLowIntermediate I Intermediate IIHigh Median survival, yrs5.73.5 1.20.4

10. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Revised IPSS: MDS Cytogenetic Scoring System *Data from patients in IWG-PM database, multivariate analysis (n = 7012). † Data from Schanz, et al (n = 2754). Prognostic Subgroups, % Cytogenetic Abnormalities Median Survival,* Yrs Median AML Evolution, 25%,* Yrs HR OS/AML* HR OS/AML † Very good (4%*/3% † ) -Y, del(11q)5.4NR0.7/0.40.5/0.5 Good (72%*/66% † ) Normal, del(5q), del(12p), del(20q), double including del(5q) 4.89.41/1 Intermediate (13%*/19% † ) del(7q), +8, +19, i(17q), any other single or double independent clones 2.72.51.5/1.81.6/2.2 Poor (4%*/5% † ) -7, inv(3)/t(3q)/del(3q), double including -7/del(7q), complex: 3 abnormalities 1.51.72.3/2.32.6/3.4 Very poor (7%*/7% † ) Complex: > 3 abnormalities 0.7 3.8/3.64.2/4.9 Greenberg PL, et al. Blood. 2012;120:2454-2465. Schanz J, et al. J Clin Oncol. 2012;30:820-829.

11. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Revised IPSS: Prognostic Score Values and Risk Categories/Scores Greenberg PL, et al. Blood. 2012;120:2454-2465. Score Value Prognostic Variable 00.51.01.52.03.04.0 Cytogenetics Very good -- Good -- IntermediatePoor Very poor BM blast, %≤ 2 -- > 2 to < 5 -- 5-10> 10 -- Hemoglobin, g/dL≥ 10 -- 8 to < 10< 8 ___ Platelets, x 10 9 /L≥ 100 50 to < 100 < 50 ___ ANC, x 10 9 /L≥ 0.8< 0.8 --___ RiskScore Very low≤ 1.5 Low> 1.5 to 3.0 Intermediate> 3.0 to 4.5 High> 4.5 to 6.0 Very high> 6

12. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care OSTransformation to AML Schanz J, et al. J Clin Oncol. 2012;30:820-829. IPSS-R: OS and Transformation to AML by Risk Group 1.0 0.8 0.6 0.4 0.2 0 Fraction Survival 35050100150200250300 Mos Very good (n = 81; events: 34) Good (n = 1809; events: 890) Intermediate (n = 529; events: 312) Poor (n = 148; events: 109) Very poor (n = 187; events: 158) Log-rank P <.001 1.0 0.8 0.6 0.4 0.2 0 Fraction AML-Free Survival 35050100150200250300 Mos Very good (n = 72; events: 6) Good (n = 1611; events: 284) Intermediate (n = 457; events: 145) Poor (n = 129; events: 56) Very poor (n = 167; events: 47) Log-rank P <.001 0 0

13. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care MDS Is Genetically Complex Papaemmanuil E, et al. Blood. 2013;122:3616-3627.  738 MDS patients sequenced  111 genes  78% had a mutation 200 150 100 50 0 Patients With Mutations (n) RA RARS RARS-T RCMD RCMD-RS RAEB 5q- CMML MDS-MPN MDS-U MDS-AML SF3B1TET2SRFS2ASXL1del(5q) DNMT3A RUNX1 Complex U2AF1TP53EZH2del(7q)del(12)IDH2 STAGE2 ZRSR2 CBLNRASBCORdel20qJAK2 CUX1 IDH1 Rear chr3 +8del(11) del(17p) KRAS EP300 NPM1 PHF6GATA2 PTPN11 CREBBP KIT MLL2MPLNF1 WT1 IRF1 RAD21ATRX CDKN2A ETV6 KDM6A +19 CEBPA FLT3 GNASPTEN SH2B3 BRAFCTNNA1

14. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Bejar R, et al. N Engl J Med. 2011;364:2496-2506. Gene Point Mutations: Independent Predictors of OS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 012345678910111213 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 012345678910111213 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 012345678910111213 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 012345678910111213 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 012345678910111213 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 012345678910111213 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0123456789 10111213 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 012345678910111213 ETV6 (427 wt vs 12 mut ) P =.04 ASXL1 (376 wt vs 63 mut ) P =.003 RUNX1 (401 wt vs 38 mut ) P <.001 IDH2 (430 wt vs 9 mut ) P =.03 TP53 (406 wt vs 33 mut ) P <.001 EZH2 (411 wt vs 28 mut ) P <.001 NRAS (423 wt vs 16 mut ) P =.006 CBL (429 wt vs 10 mut ) P =.02 Hazard Ratios for Death in a Multivariable Model Risk FactorHR (95% CI) P Value Age 55 yrs or older vs younger than 55 yrs 1.81 (1.20-2.73).004 IPSS risk group Intermediate 1 vs low Intermediate 2 vs low High vs low 2.29 (1.69-3.11) 3.45 (2.42-4.91) 5.85 (3.63-9.40) <.001 <.001 <.001 Mutational status TP53 mutation present vs absent EZH2 mutation present vs absent ETV6 mutation present vs absent RUNX1 mutation present vs absent ASXL1 mutation present vs absent 2.48 (1.60-3.84) 2.13 (1.36-3.33) 2.04 (1.08-3.86) 1.47 (1.01-2.15) 1.38 (1.00-1.89) <.001 <.001.03.047.049

15. Treatment Options for Lower-Risk MDS

16. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Anemia Management Algorithm 2014: Low- or Intermediate 1–Risk MDS  Assess potential causes of anemia  RBC transfusion support for symptomatic patients Lenalidomide ESA ± G-CSF del(5q) EPO ≤ 500 mU/mL < 2 U RBC/mo EPO > 500 mU/mL; RCMD; ≥ 2 U RBC/mo ≤ 60 yrs of age, hypocellular marrow, HLA-DR15+, PNH+ IST AZA/DAC Lenalidomide Clinical trial Yes No NCCN. Clinical practice guidelines in oncology: myelodysplastic syndromes. v.2.2014. No response or failure of therapy AZA/DAC Clinical trial

17. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care 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.

18. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care 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 CRStable Hb > 11.5 g/dL PRIncrease in Hb with > 1.5 g/dL or total stop in RBC transfusions S-EPO U/L < 100 100-500 > 500 +2 +1 -3 Transf U RBC/mos < 2 units/mo ≥ 2 units/mo +2 -2 Hellström-Lindberg E, et al. Br J Hematol. 2003;120:1037-1046.

19. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Lenalidomide  Thalidomide analogue with immunomodulatory, antiangiogenic, and antineoplastic properties  Approved for use –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 received at least 1 previous therapy

20. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care  Primary endpoint: transfusion independence  Secondary endpoints: duration of TI, cytogenetic response, minor erythroid response, pathologic response, safety MDS-003: Lenalidomide in MDS With 5q Deletion 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.

21. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care 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: 5.4 g/dL  Time to response: 4.6 wks  Duration of response: > 2 yrs

22. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care  Primary endpoint: TI, Hb response  Secondary endpoints: cytogenetic response, safety MDS-002: Phase II Study of Lenalidomide in RBC-Dependent Non-del(5q) MDS 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 al. Blood. 2008;111:86-93. RESPONSERESPONSE R E G I S T E R

23. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care 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: 3.2 g/dL  Time to response: 4.8 wks  Median duration of response: 41 wks Raza A, et al. Blood. 2008;111:86-93.

24. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care 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.

25. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Azacitidine Treatment for Low- or Intermediate 1–Risk MDS  Pyrimidine nucleoside analogue of cytidine  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 Silverman LR, et al. Nat Clin Pract Oncol. 2005;2(suppl 1):S12-S23. Azacitidine [package insert]. 2012.

26. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care 5-2-2: 75 mg/m 2 (n = 50) 5-2-5: 50 mg/m 2 (n = 51) 5: 75 mg/m 2 (n = 50) x 6 IWG 2000 HI 12 Cycles AZA x 5 days q4-6 wks Study Design (N = 151) Lyons RM, et al. J Clin Oncol. 2009;27:1850-1856. Eligibility  All FAB  Cytopenia  ECOG PS: 0-3 Randomized Phase II Study of Alternative Azacitidine Dose Schedules

27. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care *IWG 2000 criteria. Lyons RM, et al. J Clin Oncol. 2009;27:1850-1856. Alternate Azacitidine Dose Schedule Study: Frequency of Major HI Parameters in Evaluable Pts,* n/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 > grade 333/50 (66)24/48 (50)17/50 (34) AE Tx delay34/50 (68)30/48 (63)17/50 (34)

28. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Hypomethylating Agent Failure in Low- Risk and Intermediate 1–Risk MDS  N = 423 patients with IPSS low-risk (32%) and intermediate 1–risk (68%) MDS prior to failure of azacitidine and/or decitabine  Outcomes are poor after HMA failure in lower-risk MDS –Median OS: 17 mos; median TFS: 15 mos Jabbour E, et al. ASH 2013. Abstract 388. Scoring SystemOS n (%)Median, Mos1 Yr, %3 Yrs, % IPSS Low Intermediate 1 Intermediate 2 High 69 (24) 155 (53) 43 (15) 23 (8) 33 26 7 8 90 77 37 39 62 38 10 0 R-IPSS Very low Low Intermediate High Very high 31 (11) 88 (30) 84 (29) 58 (20) 29 (10) 51 31 22 9 7 82 79 68 38 36 62 47 38 10 MDGSSLow Intermediate 1 Intermediate 2 Poor 51 (17) 104 (37) 85 (29) 50 (17) 36 29 12 8 77 75 60 32 60 51 21 10

29. Key Issues in Supportive Care of Patients With MDS

30. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Serum Ferritin Level Is Predictive of Survival and Risk of AML in MDS  Development of transfusional iron overload is a significant independent prognostic factor for OS and transformation 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 µg/L Ferritin ≥ 1000 µg/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

31. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Prospective Chelation Study in Lower-Risk MDS: 48-Mo Update—OS  5-yr noninterventional registry study of 599 patients with lower-risk MDS and transfusional iron overload treated with or without chelation  At 48 mos, chelated patients had significantly longer OS vs nonchelated Lyons RM, et al. ASH 2013. Abstract 2775. Median OS From Diagnosis, Mos Nonchelated (n = 330): 48.7 Chelated (n = 269): 96.8 Chelated ≥ 6 mos (n = 202): 102.5 P <.0001 for chelated vs nonchelated Mos Survival Distribution Function 1.00 0.75 0.50 0.25 0 0100200300 400 500

32. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Prospective Chelation Study in Lower-Risk MDS: 48-Mo Update—AML Transformation  At 48 mos, chelated patients had significantly longer time to AML transformation vs no chelation –Percentages of patients who progressed to AML similar in both groups (~ 7% to 10%) Lyons RM, et al. ASH 2013. Abstract 2775. Median Time to AML Progression, Mos Nonchelated (n = 330): 45.6 Chelated (n = 269): 67.6 Chelated ≥ 6 mos (n = 202): 77.0 P <.0001 for chelated vs nonchelated Proportion Progressing to AML 1.00 0.75 0.50 0.25 0 Mos 0100200300 400 500

33. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Mo Serum Ferritin, ng/mL EPIC (N = 341) US03 (N = 176) 027303397 323583057 622102802 920762635 1219042501 Deferasirox in MDS: EPIC and US03 Studies  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/day 1. Gattermann N, et al. Leuk Res. 2010;34:1143-1150. 2. List AF, et al. ASH 2008. Abstract 634.

34. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Deferasirox Black Box Warning Deferasirox is contraindicated in patients with  Creatinine clearance 2 times the age-appropriate ULN  Poor performance status and high-risk MDS or advanced malignancies  Platelet counts < 50 x 10 9 cells/L  Known hypersensitivity to deferasirox or any component of drug Deferasirox [package insert]. January 2013.

35. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Screening 1 mo 4 yrs1 yr2 yrs Randomization (2:1 = Deferasirox/Placebo) 3 yrs5 yrs Interim analysis: At 50% of primary composite events (~ 3 yrs) At 75% of primary composite events (~ 4 yrs) 54% chance to stop the trial depending on IA results IA Placebo (n = 210) 10 mg/kg/day (1st 2 wks) 20 mg/kg/day (Wks 2-12) Up to 40 mg/kg/day (after 12 wks) Deferasirox (n = 420) 10 mg/kg/day (first 2 wks) 20 mg/kg/day (Wks 2-12) Up to 40 mg/kg/day (after 12 wks) Expected end of study Low- or int 1–risk MDS Serum ferritin > 1000 µg/L and < 2500 µg/L TELESTO Study Design ClinicalTrials.gov. NCT00940602.

36. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care MDS Patients Who Are Likely to Benefit Most From Management Iron Overload CharacteristicNCCN [1] MDS Foundation [2] Transfusion status  Received > 20 RBC transfusions  Continuing transfusions  Transfusion dependent, requiring 2 units/mo for > 1 yr Serum ferritin level  > 2500 μg/L  1000 μg/L MDS risk  IPSS: low or intermediate 1 risk  IPSS: low- or int 1  WHO: RA, RARS and 5q- Patient profile  Candidates for allografts  Life expectancy > 1 yr and no comorbidities that limit progress  Need to preserve organ function  Candidates for allografts 1. NCCN. Clinical practice guidelines in oncology: MDS. v2.2014. 2. Bennett JM. J Hematol. 2008;83:858-861.

37. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care 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

38. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care List AF, et al. J Clin Oncol. 2012;30:2134-2139. Serum Ferritin Levels Labile Plasma Iron Levels 0 1000 3500 Baseline 2000 2500 3000 Wks 1500 500 133753 *P =.6063 *P <.001 Median Serum Ferritin (μg/L) Pts at Risk, n Median change from baseline (μg/L) 9594 -48 90 -574 91 -561 0 0.4 1.2 Baseline 0.8 1.0 Wks 0.6 0.2 132549 Mean LPI (μmol/L) Pts at Risk, n 6847 37 43 Threshold of normal LPI (< 0.5 μmol/L) US03 Phase II Trial: Deferasirox in Lower- Risk Transfusion-Dependent MDS  N = 173 patients with IPSS low- to intermediate-1 risk, serum ferritin ≥ 1000 μg/L, and ≥ 20 units RBC with ongoing need for transfusions  Treatment: deferasirox 20 mg/kg/day with dose escalation to 40 mg/kg

39. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Risk of Cardiac Events in MDS Patients With Multiple Transfusions  513 new cases of MDS from January-March 2003 in the US Medicare SAF5% claims database –SAF5%, standard analytic file comprised randomly selected, 5% sample of all Medicare beneficiaries  During a 3-yr follow-up, cardiac events were more common in transfused vs nontransfused MDS patients (P <.001) and in MDS patients vs individuals without MDS (P <.001) Cardiac Events (%) 0 MDS Nontransfused (n = 307) 40 20 Overall Medicare SAF5% Population (N = 1,379,185) 82.4 80 60 MDS Transfused (n = 205) 67.1 54.5 100 Goldberg SL, et al. J Clin Oncol. 2010;28:2847-2852.

40. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Risk of Diabetes in MDS Patients With Multiple Transfusions  Development of diabetes was more common in transfused than in nontransfused MDS patients and overall SAF5% Medicare population during a 3-yr follow-up *For comparison of transfused and nontransfused MDS patients. Developed Diabetes (%) 0 30 50 40 MDS Patients (n = 513) 20 10 Overall Medicare SAF5% Population (N = 1,379,185) 40.0 33.1 P <.0001 Developed Diabetes (%) 0 30 50 40 MDS Transfused (n = 205) 20 10 P =.02* Overall Medicare SAF5% Population (N = 1,379,185) MDS Non- transfused (n = 307) Goldberg SL, et al. J Clin Oncol. 2010;28:2847-2852. 33.1 37.1 44.4

41. Treatment Options for High-Risk MDS

42. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care SCT candidate No donor Allogeneic donor  Continue azanucleosides  High-intensity chemotherapy Investigational SCT Favorable  Comorbidities  Functional status Unfavorable Treatment Algorithm 2014: Intermediate 2–Risk/High-Risk MDS Adapted from NCCN. Clinical practice guidelines in oncology. MDS. v.2.2014. Start azanucleosides

43. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Role of RIC Allogeneic HCT in Older Patients With De Novo MDS Koreth J, et al. J Clin Oncol. 2013;31:2662-2671. Low/Intermediate-1 IPSS MDSIntermediate-2/High IPSS MDS 1.0 0.8 0.6 0.4 0.2 0 Probability of OS P <.001 140020406080100120 Mos Nontransplantation therapy RIC transplantation 1.0 0.8 0.6 0.4 0.2 0 P <.001 140020406080100120 Mos Nontransplantation therapy RIC transplantation Probability of OS

44. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Pretransplantation Treatment With AZA and ICT for MDS Damaj G, et al. J Clin Oncol. 2012;30:4533-4540. 1.0 0.8 0.6 0.4 0 02004006008001000 Days Probability of OS AZA: HR = 1 ICT vs AZA: HR = 1.41 (95% CI: 0.83-2.42; P = NS) ICT-AZA vs AZA: HR = 3.08 (95% CI: 1.38-6.85; P =.006) 1.0 0.8 0.6 0.4 0 02004006008001000 Days Probability of Event-Free Survival AZA: HR = 1 ICT vs AZA: HR = 1.48 (95% CI: 0.90-2.44; P = NS) ICT-AZA vs AZA: HR = 2.72 (95% CI: 1.38-5.34; P =.01) 1.0 0.8 0.6 0.4 0 02004006008001000 Days Probability of 3-Yr Relapse AZA: HR = 1 ICT vs AZA alone: HR = 1.35 (95% CI: 0.73-2.46; P = NS) ICT-AZA vs AZA: HR = 1.87 (95% CI: 0.69-5.06; P = NS) 1.0 0.8 0.6 0.4 0 02004006008001000 Days Probability of 3-Yr NRM Survival AZA: HR = 1 ICT vs AZA: HR = 1.23 (95% CI: 0.55-2.76);P = NS) ICT-AZA vs AZA: HR = 2.50 (95% CI: 0.89-7.05; P =.08)

45. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care 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 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

46. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care 0 1.0 510152025303540 Mos From Randomization 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 15.0 mos Fenaux P, et al. Lancet Oncol. 2009;10:223-232. AZA-001 Trial: Azacitidine Significantly Improves OS

47. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care AZA-001: Grade 3/4 Adverse Events (≥ 2% of Patients)* Adverse Events, n (%)Azacitidine (n = 175) BSC Only (n = 102) Neutropenia159 (91)70 (69) Thrombocytopenia149 (85)72 (71) Leukopenia26 (15)1 (1) Anemia100 (57)67 (66) Febrile neutropenia22 (13)7 (7) Pyrexia8 (5)1 (1) Abdominal pain7 (4)0 Dyspnea6 (3)2 (2) Fatigue6 (3)2 (2) Hematuria4 (2)1 (1) Hypertension2 (1)2 (2) *When any grade of the reactions occurs in ≥ 5% of azacitidine-treated patients. Fenaux P, et al. Lancet Oncol. 2009;10:223-232.

48. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Outcome After Azanucleoside Failure in Higher-Risk MDS and CMML InstitutionNAZA Failures, n AML Progression, n (%) Median OS, Mos OS at 12 Mos, % Moffitt [1] 1515912 (20.3)5.830 GFM* [2] 435NR 5.629 MDACC †[3] NR8725 (29)4.328 *Includes AZA001, J9950, J0443 studies. † Decitabine only. 1. Duong V, et al. Clin Lymph Myel Leuk. 2013;13:711-715. Abstract 2913. 2. Prebet T, et al. J Clin Oncol. 2011;29:3322-3327.3. Jabbour E, et al. Cancer. 2010;116:3830-3834.

49. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Type of Salvage NORRMedian OS, Mos Unknown 165NA3.6 Best supportive care 122NA4.1 Low-dose chemotherapy 320/187.3 Intensive chemotherapy 353/228.9* Investigational therapy 444/3613.2* † Allogeneic transplantation 3713/1919.5* † Prébet T, et al. J Clin Oncol. 2011;29:3332-3327. *Log-rank comparison of BSC vs intensive CT (P =.04), investigational therapy (P <.001), or alloSCT (P <.001). † Comparison of intensive CT vs investigational therapy (P =.05), intensive CT vs ASCT (P =.008), or IT vs ASCT (P =.09). Salvage Therapy After Azacitidine Failure: GFM and AZA001 Studies 100 75 50 25 0 036573010951460 OS (%) Days Since AZA Failure Investigational Allo-SCT

50. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Azacitidine Azacitidine + Lenalidomide Azacitidine + Vorinostat Patients with higher-risk MDS or CMML (IPSS > 1.5 or blasts > 5%) (Planned N = 267) Phase II SWOG-S1117 Study: Aza + Len or Vorinostat in Higher-Risk MDS/CMML  Primary endpoint: 20% RR improvement (2006 IWG criteria)  Secondary endpoints: OS, RFS, LFS, toxicity, cytogenetic responses  81% power (P =.05 for each combination arm vs azacitidine alone) Groups: SWOG, ECOG, CALGB, NCIC Anticipated time: 2.5 yrs ClinicalTrials.gov. NCT01522976.

51. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Phase III ONTIME: Rigosertib in Higher- Risk MDS After Azanucleoside Failure  Rigosertib: PLK and PI3K inhibitor; a novel synthetic benzyl styryl sulfone that is cytotoxic against a variety of human tumor cell lines  Primary endpoint: OS (HR: 0.62)  Secondary endpoints: IWG response, transformation to AML, infection, bleeding, QoL Komrokji RS, et al. Br J Hematol. 2013;162:517-524. ClinicalTrials.gov. NCT01241500. Patients with higher-risk MDS (FAB, RAEB/t, CMML), relapsed/refractory after azacitidine or decitabine (planned N = 270) Continue treatment q4w until progression Rigosertib (ON 01910.Na) + BSC 1800 mg/d x 3 days q2w (n = 180) Best Supportive Care LoDAC, hydrea, GFs (n = 90) Stratified by blast % (5% to 19% vs 20% to 30% Wk 16

52. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care 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

53. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care ADOPT Trial: Study Design  Patients (N = 99) with de novo or secondary MDS of any FAB subtype and IPSS score ≥ 0.5  Decitabine 20 mg/m 2 /day IV for 5 days  Primary endpoint: ORR by IWG 2006 criteria  Secondary endpoints: cytogenetic response, hematologic improvement, response duration, survival, safety Steensma DP, et al. J Clin Oncol. 2009;27:3842-3848.

54. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care ADOPT Trial: Responses Response (IWG 2006 Criteria)Patients, n (%) (N = 99) Overall CR rate (CR + mCR)32 (32) PRR (CR + mCR + PR)32 (32) Overall improvement rate (CR + mCR + PR +HI)50 (51) Rate of SD or better (CR + mCR + PR + HI +SD)74 (75) CR17 (17) mCR15 (15) PR0 (0) HI18 (18) SD24 (24) PD10 (10) Not assessable15 (15) Steensma DP, et al. J Clin Oncol. 2009;27:3842-3848.

55. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care ADOPT: Survival Patients Stratified by FAB Subtype Steensma DP, et al. J Clin Oncol. 2009;27:3842-3848. Patients Stratified by IPSS Score RA (n = 20) RARS (n = 17) RAEB (n = 45) RAEB-T (n = 6) CMML (n = 11) Survival (%) Days 100 90 80 70 60 50 40 30 20 10 0 1,0000100200300400500600800900700 Survival (%) Days 100 90 80 70 60 50 40 30 20 10 0 1,0000100200300400500600800900700 Low ( n = 1) Intermediate 1 (n = 52) Intermediate 2 (n = 23) High risk (n = 23)

56. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care EORTC-06011 Decitabine Phase III Trial: Study Design  Open-label, multicenter, 1:1 randomized study  IPSS: int-1, -2, and high-risk MDS; ≥ 60 yrs (n = 223)  Primary endpoint: survival Stratification  Cytogenics risk group  IPSS  Primary vs secondary  Study center RANDOMIZERANDOMIZE Decitabine 15 mg/m 2 IV x 4 hrs q8h x 3 days q6w (max 8 cycles) (n = 119) Best Supportive Care (n = 114) Response assessment q2 cycles; HI, CR, PR, and SD continue for up to 8 cycles Exception: CR—2 additional cycles Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996. 20 mg/m 2 /day IV recommended in PI

57. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care *HI: 3 lineage (n = 7), 2 lineage (n = 5), 1 lineage (n = 6). Median number of courses: 4 Patients (%) 0 5 16 25 10 20 CRPRHISD 13 6 00 15* 2 14 22 Decitabine (n = 119) Supportive care (n = 114) EORTC-06011: Best IWG 2000 Response Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996.

58. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Decitabine Supportive care Median PFS: 6.6 vs 3.0 mos HR: 0.68 (95% CI: 0.52-0.88; Log-rank P =.004) Mos 061218243036 0 10 20 30 40 50 60 70 80 90 100 EORTC-06011: PFS With Decitabine Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996. PFS (%)

59. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care EORTC-06011: OS With Decitabine Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996. 0 1.0 0 20 40 60 80 OS (%) 61218243036 Mos Pts at Risk, n BSC Decitabine 71 83 38 53 22 24 10 15 6464 BSC Decitabine Log-rank test P =.38

60. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Combination Therapy: Lenalidomide + Azacitidine in Higher-Risk MDS  Multicenter, single-arm open-label phase II continuation study (N = 36)  Patient eligibility –Higher-risk MDS: CMML-2, RAEB-1 or -2, IPSS intermediate 2 or high (score ≥ 1.5), or revised IPSS score 4 or 5 –No previous treatment with lenalidomide or azacitidine  Maximum of seven 28-day treatment cycles administered –Lenalidomide 10 mg on Days 1-21 –Azacitidine 75 mg/m 2 on Days 1-5 –After 7 cycles, patients could continue azacitidine monotherapy off study  Median patient follow-up: 12 mos (range: 3-55) Sekeres MA, et al. Blood. 2012;120:4945-4951.

61. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Lenalidomide + Azacitidine in Patients With Higher-Risk MDS: Results  Median CR duration: 17+ mos (range: 3-39+)  Median OS among CR: 37+ mos (range: 7-55+)  8 patients evolved to AML at median of 18 mos after CR  Treatment well tolerated; FN was most common grade 3/4 AE (22%)  Randomized trial planned to compare azacitidine vs lenalidomide/azacitidine vs azacitidine/vorinostat in higher- risk MDS 0 10 20 30 40 50 60 70 80 90 100 Lenalidomide/ Azacitidine (N = 36) Response Rate (%) CR Hematologic improvement 44 28 Sekeres MA, et al. Blood. 2012;120:4945-4951.

62. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Phase III ECOG 2905 Study: Lenalidomide ± Epoetin Alfa in Lower-Risk MDS  Primary endpoint: major erythroid response by IWG 2006 criteria  Secondary endpoints: time to MER, DOR, MER to salvage combination therapy  Randomization note: patients with del(5q31.1) assigned to lenalidomide monotherapy, all other patients randomized between arms Patients with IPSS low- to int-1 MDS, Hgb < 9.5 g/dL, failed or poor response to EPO (Planned N = 262) Lenalidomide 10 mg/day on Days 1-21 of 28-day cycles Lenalidomide 10 mg/day on Days 1-21 Epoetin Alfa 60,000 U/wk 28-day cycles MER: treat until relapse Failure: add epoetin or discontinue MER: treat until relapse Failure: discontinue Wk 16 response assessment Stratified by sEPO ( 500 mU/mL), previous EPO/DA vs none ClinicalTrials.gov. NCT00843882.

63. clinicaloptions.com/oncology Myelodysplastic Syndromes: Best Practices in Patient Care Patients with IPSS low- to int-1 MDS, RBC ≥ 2 U/28 d x ≥ 84 d, Hb ≤ 9 g/dL prior to transfusion, plt ≤ 50 x 10 9 /L (Planned N = 386) Oral Azacitidine 300 mg/day x 21/28 days + BSC (n = 193) Placebo x 21/28 days + BSC (n = 193) Yes: treat until progression (24 mos) No: discontinue Wk 24 response assessment ClinicalTrials.gov. NCT01566695. Phase III Study: Oral Azacitidine in Lower- Risk TD MDS With Thrombocytopenia  Primary endpoint: RBC transfusion independence for ≥ 84 days  Secondary endpoints: HI-P, OS, duration of transfusion independence, AML

64. Go Online for More CCO Coverage of Myelodysplastic Syndromes and Acute Leukemias Expert Analysis: A text module with large embedded slide graphics Downloadable Slideset: Highlights of key studies with expert perspective in the notes Capsule Summaries of the key data identified by CCO’s expert faculty clinicaloptions.com/oncology