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1 The Medalist Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Anemia in Patients with Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) TransfusionsClinically Relevant Abstract

Program: General Sessions
Session: Plenary Scientific Session
Hematology Disease Topics & Pathways:
Biological, Diseases, MDS, Myeloid Malignancies
Sunday, December 2, 2018, 2:00 PM-4:00 PM
Hall AB (San Diego Convention Center)

Pierre Fenaux, MD, PhD1, Uwe Platzbecker, MD2, Ghulam J. Mufti3*, Guillermo Garcia-Manero, MD4, Rena Buckstein, MD, FRCPC5, Valeria Santini6, María Díez-Campelo7*, Carlo Finelli, MD8*, Mario Cazzola9, Osman Ilhan, MD10*, Mikkael A. Sekeres, MD, MS11, José F. Falantes12*, Beatriz Arrizabalaga, MD. PhD13*, Flavia Salvi14*, Valentina Giai14*, Paresh Vyas, MRCP FRCP FRCPath15, David Bowen, MD16, Dominik Selleslag, MD17*, Amy E. DeZern, MD18, Joseph G. Jurcic, MD19, Ulrich Germing, MD20*, Katharina S. Götze, MD21, Bruno Quesnel22, Odile Beyne-Rauzy23*, Thomas Cluzeau, MD, PhD24*, Maria Teresa Voso25, Dominiek Mazure26*, Edo Vellenga27, Peter L Greenberg, M.D.28, Eva Hellstrom Lindberg, MD, PhD29, Amer M. Zeidan, MBBS, MHS30*, Abderrahmane Laadem, MD31, Aziz Benzohra32*, Jennie Zhang31*, Anita Rampersad31*, Peter G. Linde33, Matthew L. Sherman33, Rami S. Komrokji, MD34 and Alan F. List, MD34

1Service d’Hématologie Séniors, Hôpital Saint-Louis, Université Paris 7, Paris, France
2University Hospital Dresden, Dresden, Germany
3Department of Haemato-Oncology, King's College London, London, United Kingdom
4Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX
5Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
6MDS Unit, AOU Careggi, University of Florence, Florence, Italy
7Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, Salamanca, Spain
8Department of Oncology and Hematology, S. Orsola-Malpighi University Hospital, Bologna, Italy
9University of Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
10Department of Hematology Science, School of Medicine, Ankara University, Ankara, Turkey
11Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH
12Unidad de Hematología, Hospital Universitario Virgen del Rocío, Seville, Spain
13Department of Hematology, Hospital Universitario Cruces, Vizcaya, Spain
14Hematology Unit, Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy
15Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
16Department of Haematology, Leeds Teaching Hospitals, Leeds, United Kingdom
17Department of Haematology, AZ Sint-Jan, Bruges, Belgium
18The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
19Division of Hematology/Oncology, Columbia University Medical Center, New York, NY
20Klinik für Hämatologie, Onkologie and Klinische Immunologie, Universitätsklinik Düsseldorf, Düsseldorf, Germany
21Department of Medicine III, Technical University of Munich, Munich, Germany
22Service des Maladies du Sang, Hôpital Huriez, Centre Hospitalier Universitaire de Lille, Lille, France
23Médicine Interne, Institute Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
24Départment de Hématologie Clinique, Centre Hospitalier Universitaire de Nice, Nice, France
25Dipartimento di Biopatologia e Diagnostica per Immagini, University of Rome Tor Vergata, Rome, Italy
26Universitair Ziekenhuis Gent, Ghent, Belgium
27Department of Hematology, University Medical Center Groningen, Groningen, Netherlands
28Stanford University Cancer Center, Stanford, CA
29Department of Medicine, Karolinska Institutet, Stockholm, Sweden
30Department of Internal Medicine, Section of Hematology, Yale School of Medicine, New Haven, CT
31Celgene Corporation, Summit, NJ
32Celgene International, Boudry, Switzerland
33Acceleron Pharma, Cambridge, MA
34Moffitt Cancer Center, Tampa, FL

Introduction: MDS is associated with an erythroid maturation defect, characterized by ineffective erythropoiesis leading to anemia and RBC transfusion dependence. Treatment of anemia in lower-risk MDS remains an unmet medical need. Luspatercept is a first‑in‑class erythroid maturation agent which binds to select TGFβ superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis (Suragani RN, et al. Nat Med. 2014;20:408-14). Preliminary clinical studies have shown promising activity in MDS (Platzbecker U, et al. Lancet Oncol. 2017;10:1338-47).

We report the results of a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of luspatercept in patients with anemia due to Revised International Prognostic Scoring System (IPSS-R)-defined Very low-, Low-, or Intermediate-risk MDS with RS who require RBC transfusions. ClinicalTrials.gov identifier: NCT02631070.

Methods: Eligible patients were aged ≥ 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS according to the WHO 2016 criteria; were refractory, intolerant, or ineligible to receive erythropoiesis-stimulating agents (ESAs); and required RBC transfusions. Patients were randomized 2:1 to receive either luspatercept, at a starting dose level of 1.0 mg/kg with titration up to 1.75 mg/kg, if needed, or placebo, subcutaneously every 3 weeks for ≥ 24 weeks. The primary endpoint was RBC transfusion independence (RBC-TI) for ≥ 8 weeks between week 1 and week 24. A key secondary endpoint was RBC-TI for ≥ 12 weeks between week 1 and 24. Achievement of modified hematologic improvement-erythroid (mHI-E) response using IWG 2006 criteria was also assessed.

Results: A total of 229 patients were randomized and treated. Median age was 71 years (range 26–95), median time from diagnosis was 41.8 months (range 3–421), and 62.9% were male. Overall, patient baseline characteristics were balanced between the treatment groups. Patients received a median of 5 RBC units (range 1–20) transfused over 8 weeks during the 16 weeks prior to treatment (43.2% of patients had ≥ 6 RBC units/8 weeks, 27.9% had ≥ 4 to < 6 RBC units/8 weeks, and 28.8% had < 4 RBC units/8 weeks). At baseline, 138 (60.3%), 58 (25.3%), and 32 (14.0%) patients had serum erythropoietin levels < 200 IU/L, 200–500 IU/L, and > 500 IU/L, respectively. A total of 218 (95.2%) patients had previously received ESAs. Overall, 206 (90.0%) patients had an SF3B1 mutation.

Of 153 patients receiving luspatercept, 58 (37.9%) achieved the primary endpoint of RBC-TI for ≥ 8 weeks compared with 10 of 76 patients (13.2%) receiving placebo (odds ratio [OR] 5.1, P < 0.0001). Of those receiving luspatercept, 43 of 153 (28.1%) achieved the key secondary endpoint of RBC-TI for ≥ 12 weeks (weeks 1–24) compared with 6 of 76 (7.9%) receiving placebo (OR 5.1, P = 0.0002).

Patients receiving luspatercept were more likely to achieve an mHI-E response, defined as a reduction in transfusion of ≥ 4 RBC units/8 weeks or a mean hemoglobin increase of ≥ 1.5 g/dL/8 weeks in the absence of transfusions, compared with patients receiving placebo (52.9% vs 11.8% during weeks 1–24; P < 0.0001).

The safety profile of luspatercept was consistent with that reported in the phase 2 PACE-MDS study (Platzbecker U, et al. Lancet Oncol. 2017;10:1338-47).

Conclusions: Treatment with luspatercept resulted in a significantly reduced transfusion burden compared with placebo in patients with anemia due to IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS, who require RBC transfusions, and was generally well tolerated.

P.F. and U.P. contributed equally to this abstract as lead co-authors. R.S.K. and A.F.L. contributed equally to this abstract as senior co-authors.

As of May 8, 2018, cutoff date.

Disclosures: Fenaux: Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Platzbecker: Celgene: Research Funding. Mufti: Celgene: Research Funding. Buckstein: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Santini: AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Otsuka: Consultancy; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding. Díez-Campelo: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Finelli: Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Research Funding, Speakers Bureau. Ilhan: Alexion: Speakers Bureau; BMS: Speakers Bureau; Roche: Speakers Bureau; Celgene: Speakers Bureau. Sekeres: Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Falantes: Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Giai: Novartis: Consultancy; Pfizer: Consultancy. Selleslag: Kiadis Pharma: Other: Financial support for study-related issues. Jurcic: Actinium Pharmaceuticals, Inc: Research Funding; Daiichi-Sankyo: Research Funding; Astellas: Research Funding; Incyte: Consultancy; AbbVie: Consultancy, Research Funding; Kura Oncology: Research Funding; Genetech: Research Funding; Celgene: Research Funding; Forma Therapeutics: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Syros Pharmaceuticals: Research Funding. Germing: Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Götze: Takeda: Honoraria, Other: Travel aid ASH 2017; Celgene: Honoraria, Research Funding; Novartis: Honoraria; JAZZ Pharmaceuticals: Honoraria. Quesnel: Celyad: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Sunesis: Honoraria. Beyne-Rauzy: Novartis: Research Funding. Cluzeau: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini: Consultancy; Pfizer: Speakers Bureau. Voso: Celgene: Research Funding, Speakers Bureau. Zeidan: Otsuka: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria. Laadem: Celgene: Employment, Equity Ownership. Benzohra: Celgene: Employment, Equity Ownership. Zhang: Celgene: Employment, Equity Ownership. Rampersad: Celgene: Employment, Equity Ownership. Linde: AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership; Fibrogen: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership. Sherman: Acceleron Pharma: Employment, Equity Ownership. Komrokji: Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding. List: Celgene: Research Funding.

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