ASH Review 2018: Update on Myelodysplastic Syndrome Barry Skikne, MD, FACP, FCP(SA) Professor of Medicine University of Kansas Medical Center

CURRENT MDS THERAPY STATUS No new therapies approved for MDS in >10 years Current therapy primarily based on stratification into Lower and Higher Risk disease Only 3 agents approved- 5-azacytidine, decitabine and lenalidomide HSCT only treatment that can potentially cure - but not for all

Gene Mutation Profiling Increased understanding of biology of MDS Knowledge used for: earlier diagnosis more precise risk stratification guide therapy in a rational biologic pathway Promise of effective targeted therapies is real if not yet realized

Fenaux P, et al. ASH 2018. The MEDALIST Trial… The MEDALIST Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Patients With Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) Associated Anemia With Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions Fenaux P, et al. ASH 2018. The MEDALIST Trial…

Background and Rationale Patients with lower-risk (LR) transfusion-dependent MDS have poorer prognosis, greater risk of progression to AML, inferior overall survival compared with transfusion-independent MDS patients RBC transfusion-dependent LR, non-del(5q) MDS may have a transient response to ESAs, risk of iron overload and secondary organ complications Few treatment options exist for patients who are refractory to, or become unresponsive to ESAs Fenaux P, et al. ASH 2018. The MEDALIST Trial…

Fenaux P, et al. ASH 2018. The MEDALIST Trial…

ACE Targets TGF-b Family

Edited from: Fenaux P, et al. ASH 2018. The MEDALIST Trial…

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MEDALIST Trial Patient Population MDS-RS (WHO): ≥ 15% RS or ≥ 5% with SF3B1 mutation < 5% blasts in bone marrow No del(5q) MDS IPSS-R Very Low-, Low-, or Intermediate-risk Prior ESA response Refractory, intolerant ESA naive: EPO > 200 U/L Average RBC transfusion burden ≥ 2 units/8 weeks No prior treatment with disease- modifying agents (e.g. iMIDs, HMAs) Luspatercept 1.0 mg/kg (s.c.) every 21 days n = 153 Randomize 2:1 Dose titrated up to a maximum of 1.75 mg/kg Placebo (s.c.) every 21 days n = 76 Disease & Response Assessment Week 24 & every 6 months Treatment discontinued for lack of clinical benefit or disease progression per IWG criteria; no crossover allowed Fenaux P, et al. ASH 2018. The MEDALIST Trial…

Fenaux P, et al. ASH 2018. The MEDALIST Trial… Study Endpoints Primary endpoint: Red blood cell transfusion independence ≥ 8 weeks Key secondary endpoint: Red blood cell transfusion independence ≥ 12 weeks Additional secondary endpoint: HI-E (IWG 2006 criteria1 ) for any consecutive 56-day period Reduction in red blood cell transfusion burden ≥ 4 RBC units/8 weeks or Mean Hb increase of ≥ 1.5 g/dL/8 weeks Duration of response Hb change from baseline Fenaux P, et al. ASH 2018. The MEDALIST Trial…

Demographics and Baseline Disease Characteristics Luspatercept (n = 153) Placebo (n = 76) Age, median (range), years 71 (40–95) 72 (26–91) Male, n (%) 94 (61.4) 50 (65.8) Time since original MDS diagnosis, median (range), months 44.0 (3–421) 36.1 (4–193) RBC transfusion burden, median (range), units/8 weeks 5 (1–15) 5 (2–20) ≥ 6 units/8 weeks, n (%) 66 (43.1) 33 (43.4) < 6 units/8 weeks, n (%) 87 (56.9) 43 (56.6) Pre-transfusion Hb, median (range), g/dL 7.6 (6–10) 7.6 (5–9) IPSS-R risk category Very Low, Low, n (%) 127 (83.0) 63 (82.9) Intermediate, n (%) 25 (16.3) 13 (17.1) SF3B1 mutation, n (%) 141 (92.2) 65 (85.5) Serum EPO < 200 U/L, n (%) 88 (57.5) ≥ 200 U/L, n (%) 64 (41.8) 26 (34.2) Fenaux P, et al. ASH 2018. The MEDALIST Trial…

Primary and Secondary Endpoints Primary Endpoint: Red Blood Cell Transfusion Independence ≥ 8 Weeks RBC-TI ≥ 8 weeks Luspatercept (n = 153) Placebo (n = 76) Weeks 1–24, n (%) 58 (37.9) 10 (13.2) 95% CI 30.2–46.1 6.5–22.9 P value < 0.0001 Key Secondary Endpoint: Red Blood Cell Transfusion Independence ≥ 12 Weeks RBC-TI ≥ 12 weeks Luspatercept (n = 153) Placebo (n = 76) Weeks 1–24, n (%) 43 (28.1) 6 (7.9) 95% CI 21.14–35.93 2.95–16.40 P value 0.0002 Weeks 1–48, n (%) 51 (33.3) 9 (11.8) 25.93–41.40 5.56–21.29 0.0003 Fenaux P, et al. ASH 2018. The MEDALIST Trial…

Duration of RBC-TI Response in Primary Endpoint Responders Fenaux P, et al. ASH 2018. The MEDALIST Trial…

Secondary Endpoint: Erythroid Response (HI-E) Luspatercept (n = 153) Placebo (n = 76) Achieved HI-E (weeks 1–24), n (%) 81 (52.9) 9 (11.8) Reduction of ≥ 4 RBC units/8 weeks (baseline transfusion burden ≥ 4 units/8 weeks) 52/107 (48.6) 8/56 (14.3) Hb increase of ≥ 1.5 g/dL (baseline transfusion burden < 4 units/8 weeks) 29/46 (63.0) 1/20 (5.0) 95% CI 44.72–61.05 5.56–21.29 P Value < 0.0001 Achieved HI-E (weeks 1–48), n (%) 90 (58.8) 13 (17.1) 58/107 (54.2) 12/56 (21.4) 32/46 (69.6) 50.59–66.71 9.43–27.47 Fenaux P, et al. ASH 2018. The MEDALIST Trial…

Fenaux P, et al. ASH 2018. The MEDALIST Trial… Safety Summary Luspatercept (n = 153) Placebo (n = 76) Patients with ≥ 1 TEAE, n (%) 150 (98.0) 70 (92.1) Patients with ≥ 1 serious TEAE 48 (31.4) 23 (30.3) Patients with ≥ 1 Grade 3 or 4 TEAE 65 (42.5) 34 (44.7) Patients with TEAEs leading to death 5 (3.3) 4 (5.3) Patients with ≥ 1 TEAE causing discontinuation, n (%) 13 (8.5) 6 (7.9) TEAEs were balanced between the arms Progression to AML occurred in 4 patients (3/153 [2.0%] in the luspatercept arm; 1/76 [1.3%] in the placebo arm) Fenaux P, et al. ASH 2018. The MEDALIST Trial…

Fenaux P, et al. ASH 2018. The MEDALIST Trial… MEDALIST Conclusions Treatment with luspatercept in lower-risk RARS MDS, resulted in a significantly higher percentage of RBC-TI, major RBC transfusion reduction, or hemoglobin increase, compared with placebo Erythroid responses durable, ~40% of patients achieving RBC-TI sustained at 12 months of treatment Generally well tolerated Potential new therapy for lower-risk RARS MDS with RBC transfusion-dependent anemia Fenaux P, et al. ASH 2018. The MEDALIST Trial…

Sallman D, et al. H Lee Moffitt Cancer Center Clonal Suppression of TP53 Mutant MDS/Oligoblastic AML (blasts <30%)with Hypomethylating Agent Therapy Improves Overall Survival Sallman D, et al. H Lee Moffitt Cancer Center

TP53 mutations occur in 5-10% patients with MDS Conflicting response rates/outcomes in TP53 mutant MDS patients azacytidine vs decitabine (Welch NEJM 2016; Garcia-Manero NEJM 2017) TP53 mutant patient numbers - small, heterogenous – treatment naïve and or relapsed/refractory Evaluated outcomes of TP53 mutant (by NGS) MDS patients who received frontline HMA therapy

71 patients with TP53 mutation 63 with TP53 WT 14 had multiple mutations in TP53 gene Age 68(39-82) 58 treated with 5-azacytidine 51 with aza monotherapy 7 with aza in combination (2 lenalidomide, 5 other) 13 with decitabine Median number of treatment cycles 4(1-33), 13 proceeded to allogeneic BMT Median follow-up 20 months, median OS 9.7 months 13(18%) achieved CR, 28(39%) ORR Transplanted patients OS 14.5 months vs 7.9 months (if VAF <5% OS 16.3 months)

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VAF < 5% VAF ≥ 5% 14.5 mnths 7.5 mnths Sallman D

TP53 MT TP53 WT CR 18% 14% ORR 39% 40% 15.4 mnths 9.7 mnths Sallman D

Conclusions TP53 MT patients have inferior OS to TP53 WT with HMA therapy BUT have similar response rates No OS difference according to specific HMA used TP53 MT patients with max clonal suppression (VAF<5%) have improved OS as well as improved outcome with HSCT Need new therapies targeting TP53 mutant MDS/AML APR-246 - reactivates mutant TP53 to induce programmed cell death Phase 1b/2 safety/efficacy study with azacytidine ongoing Sallman D

Phase 1b/2 Combination Study of APR-246 and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) David Sallman, et al.

Safety, AEs, DLTs and Response Hypomethylator naïve mTP53 MDS and oligoblastic AML (RAEB-T) APR-246 given IV in 3+3 regimen, escalation dose – 50, 75, 100 mg/kg/d x 4 THEN same dose, d 1-4 followed by Vidaza 75mg/m2 x 7 d - 28 day cycles Serial NGS and TP53 by IHC evaluation- clonal suppression and remission depth, MRD, nanostring RNA expression Sallman D

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