Myelodysplastic Syndromes What is on the horizon? Rami Komrokji, MD - PowerPoint PPT Presentation

Myelodysplastic Syndromes “What is on the horizon?” Rami Komrokji, MD Senior Member & Professor of Oncologic Sciences Section Head – Leukemia & MDS Vice Chair - Malignant Hematology Department H Lee Moffitt Cancer Center & Research Institute Tampa, Florida

Myelodysplastic Syndromes (MDS) • A group of malignant hematopoietic neoplasms characterized by 1 – Bone marrow failure with resultant cytopenia and related complications – Evidence of clonality by cytogenetic abnormalities or somatic gene mutations. – Dysplastic cytologic morphology is the hallmark of the disease – Tendency to progress to AML • Overall incidence 3.7-4.8/100,000 2 – In US (true estimates ≈37,000 -48,000) • Median age: 70 yrs; incidence: 34-47/100,000 >75 yrs 3 AML = acute myeloid leukemia. 1. Bennett J, et al. The myelodysplastic syndromes. In: Abeloff MD, et al, eds. Clinical Oncology . New York, NY: Churchill Livingstone; 2004:2849-2881. 2. SEER data. 2000-2009. 3. SEER 18 data. 2000-2009.

MDS the spectrum? Traditional ICUS MDS by WHO 2016 Non-clonal CHIP CCUS LR-MDS HR-MDS ICUS Clonality + – ++ ++ ++ Dysplasia – /+ – – + ++ Cytopenias – + + + ++ BM Blast % < 5% < 5% < 5% < 5% 5-19% Overall Risk Very Low Very Low Low (?) Low High Are these two the same? Does morphologic dysplasia matter? CCUS = clonal cytopenias of undetermined significance; ICUS = idiopathic cytopenias of undetermined significance; CHIP = clonal hematopoiesis of indeterminate potential; LR = lower risk, HR = higher risk

Risk Groups for the IPSS-R Time until 25% of Risk group Points % of Patients Median survival, years patients develop AML, years Very low ≤ 1.5 19 % 8.8 Not reached Low > 1.5 – 3 38 % 5.3 10.8 Intermediate > 3 – 4.5 20 % 3.0 3.2 High > 4.5 – 6 13 % 1.6 1.4 Very High > 6 10 % 0.8 0.73 Very low Low Int High Very high 100 100 80 80 Patients, % Patients, % 60 60 40 40 20 20 0 0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Overall Survival, years Time to AML Evolution, years Adapted from Greenberg PL, et al. Blood. 1997;89:2079-2088.

Somatic Gene Mutations Improve Precision of the IPSS-R Bejar R. Haematologica 2014; 99: 956.

Summary of Risk Stratification • very low risk R-IPSS +/- 1 HR somatic mutation (SM). • Low risk R-IPSS no HR SM • Very low/low/intermediate R-IPSS with SF3B1 SM. • Low risk R-IPSS + 1 HR SM. • Intermediate risk R-IPSS no HR SM. • Intermediate risk R-IPSS + HR SM • Very high and high risk R-IPSS. • Complex monosomy karyotype. • > 3 HR SM. • P53 mutation.

Anemia Management Algorithm in LR-MDS 2019 Epo<200mU/mL Epo>200mU/mL Del (5q) <2U RBC/mo >2U RBC/mo Iso- or +1 Age ESA Del5q Lenalidomide >60 <60 Non-del5q SF3B1 Mu + No SGM or SF3B1 Mu - MDS > 24 mos HLA-DR15 + ,+8 Non-del5q IST LEN+/- Epo AZA 5 day pathway *SGM, somatic gene mutation. Fenaux P, et al. Lancet Oncol. 2009;10:223-232..

Excess Smad2/3 Signaling Suppresses Late-Stage RBC Maturation in MDS Bone marrow microenvironment 500 cells 8 – 64 cells TGF- β ligands (e.g. GDF15, GDF11, BMP6, activin A) negatively regulate late SCF IL-3 erythropoiesis EPO EPO Luspatercept releases EPO- EPO- responsive dependent maturation block RBC BFU-E Pro-E Baso E Poly E Ortho E Reticulocyte CFU-E Rapid Hb increase Sustained Hb increase • Mobilizes cells from precursor pools into blood • Effect relies on continuous formation of late-stage precursors from earlier progenitors Zhou L, et al. Blood. 2008;112:3434-3443.

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 Pierre Fenaux, Uwe Platzbecker, Ghulam J. Mufti, Guillermo Garcia-Manero, Rena Buckstein, Valeria Santini, María Díez-Campelo, Carlo Finelli, Mario Cazzola, Osman Ilhan, Mikkael A. Sekeres, José F. Falantes, Beatriz Arrizabalaga, Flavia Salvi, Valentina Giai, Paresh Vyas, David Bowen, Dominik Selleslag, Amy E. DeZern, Joseph G. Jurcic, Ulrich Germing, Katharina S. Götze, Bruno Quesnel, Odile Beyne-Rauzy, Thomas Cluzeau, Maria Teresa Voso, Dominiek Mazure, Edo Vellenga, Peter L. Greenberg, Eva Hellström-Lindberg, Amer M. Zeidan, Abderrahmane Laadem, Aziz Benzohra, Jennie Zhang, Anita Rampersad, Peter G. Linde, Matthew L. Sherman, Rami S. Komrokji, Alan F. List

MEDALIST Trial Luspatercept • Luspatercept is an investigational first-in-class erythroid maturation agent that neutralizes select TGF- β superfamily ligands to inhibit aberrant Smad2/3 signaling and enhance late-stage erythropoiesis in MDS models 1 • In a phase 2 study in LR, non-del(5q) MDS, luspatercept yielded a high frequency of transfusion reduction or RBC-TI in patients with MDS-RS vs other subtypes 2 Luspatercept TGF- β ActRIIB / IgG1 Fc recombinant superfamily fusion protein ActRIIB Modified ligand extracellular P Cytoplasm domain of Smad2/3 Complex ActRIIB Nucleus Human IgG1 Fc domain Erythroid maturation ActRIIB, human activin receptor type IIB; IgG1 Fc, immunoglobulin G1 fragment crystallizable; RBC-TI, red blood cell transfusion independence; RS, ring sideroblasts; TGF- β, transforming growth factor beta . 1. Suragani RN, et al. Nat Med. 2014;20:408-414; 2. Platzbecker U, et. A. Lancet Oncol. 2017; 18:1338.

MEDALIST Trial Study Design – A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Luspatercept 1.0 mg/kg (s.c.) every 21 days n = 153 Patient Population Randomize • MDS- RS (WHO): ≥ 15% RS or ≥ 5% with SF3B1 Dose titrated up to a maximum of 1.75 mg/kg 2:1 mutation • < 5% blasts in bone marrow Placebo (s.c.) every 21 days • No del(5q) MDS n = 76 • IPSS-R Very Low-, Low-, or Intermediate-risk • Prior ESA response – Refractory, intolerant Disease & Response Assessment week 24 & every 6 months – ESA naive: EPO > 200 U/L Treatment discontinued for lack of clinical benefit or disease • Average RBC transfusion burden progression per IWG criteria; no crossover allowed ≥ 2 units/8 weeks • No prior treatment with disease-modifying agents (e.g. iMIDs, HMAs) Subjects followed ≥ 3 years post final dose for AML progression, subsequent MDS treatment and overall survival Data cutoff: May 8, 2018 Includes last subject randomized + 48 weeks. EPO, erythropoietin; HMA, hypomethylating agent; iMID, immunomodulatory drug; IWG, International Working Group; s.c., subcutaneously; SF3B1 , splicing factor 3b subunit 1; WHO, World Health Organization.

MEDALIST Trial Primary Endpoint: Red Blood Cell Transfusion Independence ≥ 8 Weeks Luspatercept Placebo RBC- TI ≥ 8 weeks (n = 153) (n = 76) Weeks 1 – 24, n (%) 58 (37.9) 10 (13.2) 95% CI 30.2 – 46.1 6.5 – 22.9 P value a < 0.0001 a Cochran – Mantel – Haenszel test stratified for average baseline RBC transfusion requirement ( ≥ 6 units vs < 6 units of RBCs/8 weeks) and baseline IPSS-R score (Very Low or Low vs Intermediate). CI, confidence interval.

MEDALIST Trial Duration of RBC-TI Response in Primary Endpoint Responders 1.0 Median duration (weeks) (95% CI): 30.6 (20.6 – 40.6) vs 13.6 (9.1 – 54.9) Probability of Maintaining RBC-TI 0.9 Luspatercept Placebo 0.8 Censored 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Duration of RBC-TI a (week) Number of patients Luspatercept 58 49 37 29 22 18 10 6 3 2 1 1 0 Placebo 10 9 3 2 2 2 0 a During indicated treatment period. Patients who maintained RBC-TI at the time of analysis are censored.

MEDALIST Trial Secondary Endpoint: Erythroid Response (HI-E) Luspatercept Placebo (n = 153) (n = 76) Achieved HI-E a (weeks 1 – 24), n (%) 81 (52.9) 9 (11.8) Reduction of ≥ 4 RBC units/8 weeks 52/107 (48.6) 8/56 (14.3) (baseline transfusion burden ≥ 4 units/8 weeks) Hb increase of ≥ 1.5 g/dL 29/46 (63.0) 1/20 (5.0) (baseline transfusion burden < 4 units/8 weeks) 95% CI 44.72 – 61.05 5.56 – 21.29 P value b < 0.0001 Achieved HI-E a (weeks 1 – 48), n (%) 90 (58.8) 13 (17.1) Reduction of ≥ 4 RBC units/8 weeks 58/107 (54.2) 12/56 (21.4) (baseline RBC transfusion burden ≥ 4 units/8 weeks) Hb increase of ≥ 1.5 g/dL 32/46 (69.6) 1/20 (5.0) (baseline RBC transfusion burden < 4 units/8 weeks) 95% CI 50.59 – 66.71 9.43 – 27.47 P value b < 0.0001 a Defined as the proportion of patients meeting the HI-E criteria per IWG 2006 criteria (Cheson et al. 2006) sustained over a consecutive 56-day period during the indicated treatment period. b Luspatercept compared with placebo, Cochran – Mantel – Haenszel test.