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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:Otsuka: Consultancy; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Novartis: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, 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.

β-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with β-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non–transfusion dependent (mean hemoglobin

Diamond-Blackfan Anemia (DBA) is a bone marrow failure disorder characterized by low red blood cell count. Mutations in ribosomal protein genes have been identified in approximately half of all DBA cases. Corticosteriod therapy and bone marrow transplantation are common treatment options for patients; however, significant risks and complications are associated with these treatment options. Therefore, novel therapeutic approaches are needed for treating DBA. Sotatercept (ACE-011, and its murine ortholog RAP-011) acts as an activin receptor type IIA ligand trap, increasing hemoglobin and hematocrit in pharmacologic models, in healthy volunteers, and in patients with β-thalassemia, by expanding late-stage erythroblasts through a mechanism distinct from erythropoietin. Here, we evaluated the effects of RAP-011 in zebrafish models of RPL11 ribosome deficiency. Treatment with RAP-011 dramatically restored hemoglobin levels caused by ribosome stress. In zebrafish embryos, RAP-011 likely stimulates erythropoietic activity by sequestering lefty1 from erythroid cells. These findings identify lefty1 as a signaling component in the development of erythroid cells and rationalize the use of sotatercept in DBA patients.

Introduction: β-thalassemia is an inherited hemoglobinopathy characterized by ineffective erythropoiesis and anemia. Luspatercept is a first-in-class erythroid maturation agent that binds to select TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. We aim to evaluate in detail the number of response episodes, duration of clinical benefit, and safety in luspatercept responders during the phase 3 BELIEVE study (NCT02604433). Methods: Eligible pts were aged ≥ 18 years, with β-thalassemia or hemoglobin (Hb) E/β-thalassemia (compound β-thalassemia mutation and/or multiplication of α-globin genes was allowed), requiring regular transfusions of 6-20 RBC units in the 24 weeks (wks) prior to randomization, with no transfusion-free period > 35 days. Pts were randomized 2:1 to luspatercept 1.0 mg/kg (up to 1.25 mg/kg allowed), or placebo, subcutaneously every 3 wks for ≥ 48 wks. Pts in both treatment arms continued RBC transfusions to maintain baseline Hb level and iron chelation therapy. Achievement and number of response episodes (defined as ≥ 33% reduction in RBC transfusion from baseline over any consecutive 24 wks) were assessed at a median follow-up of 64.1 wks. Duration of clinical benefit, defined as the time of first response (≥ 33% reduction in RBC transfusion over any 24 wks) to discontinuation due to any cause at that episode, was also assessed. Results:A total of 336 pts were randomized. In the ITT population, 224 pts in the luspatercept arm had a median baseline RBC transfusion burden in the 12 wks prior to randomization of 6.12 U RBCs (average 0.51 U/wk; range 3-14) and the 112 pts in the placebo arm had a median baseline transfusion burden of 6.27 U (average 0.52 U/wk; range 3-12). A total of 194 (57.7%) luspatercept and 65 (58%) placebo pts had prior splenectomy. As of the May 11, 2018 cutoff date, 92/224 (41.1%) luspatercept-treated pts and 3/112 (2.7%) placebo-treated pts had achieved ≥ 33% reduction in RBC transfusion over any 24 wks; of these luspatercept responders, 55 (59.8%) had ≥ 2 separate responses (over the treatment period up to data cutoff), 42 (45.7%) had ≥ 3, 29 (31.5%) had ≥ 4, and 19 (20.7%) had ≥ 5. Three (1.3%) pts receiving luspatercept re-responded at the same dose level after initially losing response. Median duration of clinical benefit (as defined above) for luspatercept responders was 53.5 wks (range 24-93.7). Forty-seven (21.0%) pts receiving luspatercept had no loss of response within the entire study period. Five luspatercept responders achieved RBC transfusion independence for ≥ 24 wks (median total duration was 60.1 wks) and 3 achieved RBC transfusion independence for ≥ 48 wks (median duration was 66 wks). The average number of RBC units saved over any 24 wks in all luspatercept responders was 6.55 U (0.27 U/wk) and was 8.16 U (0.34 U/wk) with transfusion burden > 15 U/24 wks, compared to baseline. As of the May 11, 2018 cutoff date, the safety population consisted of 243 pts (including 92 pts who crossed over from the placebo arm to the luspatercept arm). Frequent adverse events (AEs) in the luspatercept and placebo arms included bone pain (19.7% vs 8.3%, respectively), arthralgia (19.3% vs 11.9%), and dizziness (11.2% vs 4.6%). The safety profile for pts who crossed over from placebo to luspatercept was consistent with that observed for pts receiving luspatercept from baseline. The incidence of bone pain, arthralgia, and dizziness was largely non-severe grade 1-2, tended to decrease over time during the study, was not associated with dose level, and was not associated with treatment modification or discontinuation. Pts continue to be monitored for safety outcomes. Conclusions: Most β-thalassemia pts who were luspatercept responders experienced multiple response periods and had durable clinical benefit over the 64.1 wk follow-up period. The incidence of frequent AEs was consistent with the previously reported 48 wk safety profile for luspatercept, was not associated with dose level, and decreased over time with no impact on treatment modification or continuation. Disclosures Viprakasit: Celgene Corporation: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Protagonist: Consultancy, Research Funding; Vifor: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Ionis: Consultancy, Research Funding; La Jolla: Consultancy, Research Funding. Taher:Celgene Corporation: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Abfero: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; La Jolla Pharmaceuticals: Consultancy, Research Funding; Ionis Pharmaceuticals: Consultancy. Hermine:AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene: Research Funding; Novartis: Research Funding. Porter:Vifor: Honoraria; Agios: Consultancy, Honoraria; Protagonist: Honoraria; La Jolla: Honoraria; Bluebird Bio: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria; Silence Therapeutics: Honoraria. Piga:Acceleron Pharma: Research Funding; Celgene Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Coates:agios pharma: Consultancy, Honoraria; celgene: Consultancy, Honoraria, Other: steering committee of clinical study; apo pharma: Consultancy, Honoraria, Speakers Bureau; vifor: Consultancy, Honoraria. Voskaridou:Genesis: Consultancy, Research Funding; Protagonist: Research Funding; Celgene Corporation: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; Addmedica: Membership on an entity's Board of Directors or advisory committees. Perrotta:Acceleron Pharma: Research Funding; Novartis: Honoraria, Research Funding. Kattamis:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apopharma: Honoraria; Vertex: Membership on an entity's Board of Directors or advisory committees; ViFOR: Membership on an entity's Board of Directors or advisory committees; Ionis: Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Shetty:Celgene Corporation: Employment, Equity Ownership. Kuo:Celgene Corporation: Employment, Equity Ownership. Miteva:Celgene International: Employment. Zinger:Celgene Corporation: Employment. Sinsimer:Celgene Corporation: Employment, Equity Ownership. Linde:Acceleron Pharma: Employment, Equity Ownership; Abbott Laboratories, Inc.: Equity Ownership; Fibrogen, Inc.: Equity Ownership. Cappellini:CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Vifor Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

Introduction: Approximately two-thirds of patients with primary or post-essential thrombocythemia/polycythemia vera myelofibrosis (MF) have anemia, many of whom require red blood cell (RBC) transfusions. In this heavily transfused population there are severely limited treatment options; effective treatment for anemia in MF is a critically unmet medical need. Luspatercept is a first-in-class erythroid maturation agent which binds to select TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. Here we report the interim results of the ongoing open-label, phase 2 trial evaluating luspatercept in patients with MF and anemia. Methods: Seventy-four patients with MF and anemia were enrolled, including 41 not receiving concomitant ruxolitinib at study entry who received either no RBC transfusions (n = 20; Cohort 1) or 2-4 RBC U/28 d in the 12 wks prior to treatment (n = 21; Cohort 2). Thirty-three enrolled patients were receiving a stable dose of ruxolitinib for at least 16 wks, of which 14 were not receiving RBC transfusions (Cohort 3A) and 19 were (Cohort 3B). Patients in Cohorts 3A and 3B received a median dose of ruxolitinib of 20 mg/d (range, 5-50 mg/d) for a median of 41 and 43 wks, respectively. Patients received luspatercept every 21 d at a starting dose of 1.0 mg/kg in doses escalating up to 1.75 mg/kg. The primary endpoint in patients not receiving transfusions was a hemoglobin (Hb) increase ≥ 1.5 g/L at every assessment from baseline for ≥ 12 consecutive wks, within the first 24 wks on study. In patients receiving RBC transfusions, the primary endpoint was RBC transfusion-independence (RBC-TI) for ≥ 12 consecutive wks, within the first 24 wks on study. Additional endpoints included proportion of patients achieving mean Hb increase ≥ 1.5 g/dL in Cohorts 1 and 3A, and ≥ 50% decrease in RBC transfusions (minimum 4 RBC U decrease from baseline) in Cohorts 2 and 3B, with both responses lasting ≥ 12 consecutive wks, within 24 wks of study entry. Intent-to-treat (ITT) data were analyzed as of May 10, 2019. Results: Median age was 71 y (range, 50-88 y) and 42 (57%) were male. Median interval from MF diagnosis to study entry was 3.3 y (range, 19 d-13.5 y). Seven patients were Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, 58 were intermediate-2, and 8 were high risk. Median Hb concentration at study entry was 8.8 g/dL (range, 6.7-9.8 g/dL) for Cohort 1 and 8.6 g/dL (range, 6.7-9.1 g/dL) for Cohort 3A. Patients in Cohort 2 received a median of 2.7 RBC U/28 d (range, 1-5 U/28 d) and patients in Cohort 3B received a median of 2.3 RBC U/28 d (range, 2-4 U/28 d). Patients received a median of 8 cycles of luspatercept (range, 1-24 cycles). Efficacy data are displayed in the Table, per ITT data. Two of twenty (10%) and 3/14 (21%) patients in Cohorts 1 and 3A, respectively, achieved an absolute Hb increase ≥ 1.5 g/dL at every measurement from baseline over any consecutive 12 wks. Two of twenty-one (10%) and 6/19 (32%) patients in Cohorts 2 and 3B, respectively, achieved RBC-TI over any consecutive 12 wks. Median duration of Hb response was 20 wks (range, 12-27 wks) in Cohort 1 and 12 wks (range, 12-13 wks) in Cohort 3A. Median duration of RBC-TI was 23 wks (range, 16-31 wks) in Cohort 2 and 32 wks (range, 12-65 wks) in Cohort 3B. Three (15%) and 8 (57%) patients in Cohorts 1 and 3A, respectively, achieved a mean Hb increase of ≥ 1.5 g/dL. Eight (38%) and 10 (53%) patients in Cohorts 2 and 3B, respectively, achieved a ≥ 50% reduction in RBC transfusion burden from baseline. Ruxolitinib exposure remained stable throughout the 24-wk treatment period in both Cohorts 3A and 3B. There was no difference in spleen size between responders and non-responders. Four (5%) patients had grade 3-4 treatment-related adverse events (AEs). There were no treatment-related deaths. Treatment-related AEs occurring in ≥ 3% of patients were hypertension (11%), bone pain (8%), and diarrhea (4%). Seven (9%) patients had ≥ 1 AE resulting in treatment discontinuation; 23 (31%) remain on study. Conclusions: The initial results from this ongoing study suggest clinically significant activity of luspatercept in patients with MF-associated anemia, including those receiving concomitant ruxolitinib. A minority of AEs were grade 3-4 in severity, consistent with previous studies in MDS and beta-thalassemia. Disclosures Gerds: CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding. Vannucchi:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Passamonti:Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau. Kremyanskaya:La Jolla: Consultancy; Incyte, Celgene, Constellation, Protagonist.: Research Funding. Gotlib:Celgene Corporation: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Promedior: Consultancy, Research Funding; Kartos: Consultancy, Honoraria, Research Funding; CTI Biopharma: Research Funding. Ribrag:BMS: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; argenX: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees. Mead:Celgene: Consultancy, Research Funding; CTI: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; Bristol Myers-Squibb: Consultancy; Pfizer: Consultancy. Harrison:Sierra Oncology: Honoraria; Gilead: Speakers Bureau; CTI: Speakers Bureau; Roche: Honoraria; Promedior: Honoraria; Janssen: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Incyte: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; AOP: Honoraria; Shire: Speakers Bureau. Mesa:Shire: Honoraria; Promedior: Research Funding; Genotech: Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; LaJolla: Consultancy; AbbVie: Research Funding; NS Pharma: Research Funding; CTI: Research Funding; Gilead Sciences: Research Funding; Samus: Research Funding; Baxalta: Consultancy; Galena Biopharma: Consultancy; Celgene Corporation: Research Funding; Sierra Oncology: Consultancy; PharmaEssentia: Research Funding; Genentech: Consultancy; Pfizer: Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; Incyte: Other: travel, accommodations, expenses, Research Funding. Kiladjian:AOP Orphan: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Consultancy. Gale:Celgene Corporation: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Pariseau:Celgene Corporation: Employment. Gerike:Celgene Corporation: Employment. Zhang:Celgene Corporation: Employment, Equity Ownership. Linde:Abbott Laboratories, Inc.: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership; Fibrogen, Inc.: Equity Ownership. Reynolds:Acceleron Pharma: Employment, Equity Ownership. Verstovsek:Gilead: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Roche: Research Funding; Incyte: Research Funding. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

Introduction: Lower-risk MDS is characterized by anemia and ineffective erythropoiesis leading to RBC transfusion dependence. Effective treatment for anemia remains an unmet medical need. Patients with MDS may also experience additional cytopenias that may complicate treatment and contribute to infections and bleeding events. Here, we report hematologic improvement (HI) outcomes for patients in the MEDALIST trial (ClinicalTrials.gov identifier: NCT02631070), a phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of luspatercept, a first-in-class erythroid maturation agent that binds select TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. Methods: Eligible patients in the MEDALIST trial were adults with anemia due to Very low-, Low-, or Intermediate-risk MDS with RS according to the Revised International Prognostic Scoring System; were refractory, intolerant, or ineligible to receive erythropoiesis-stimulating agents (ESAs); and required RBC transfusions. Patients received luspatercept (starting dose of 1.0 mg/kg and titration up to 1.75 mg/kg, if needed) or placebo subcutaneously every 3 weeks for ≥ 24 weeks. Platelet and neutrophil counts were assessed by the central laboratory. Secondary endpoints included HI-neutrophil (HI-N) and -platelet (HI-P) responses, using International Working Group 2006 criteria, over any consecutive 56-day period. Mean changes from baseline in platelets and neutrophils were also evaluated. Results*: A total of 94.8% patients in the luspatercept arm and 97.4% in the placebo arm had refractory cytopenia with multilineage dysplasia and RS at baseline. Mean neutrophil and platelet counts at baseline for patients in the luspatercept arm were 2.8 x 109/L and 259 x 109/L, respectively, and in the placebo arm were 2.7 x 109/L and 252 x 109/L, respectively. Neutropenia (< 1 x 109/L) was confirmed at baseline in 15 (9.8%) and 10 (13.2%) patients in the luspatercept and placebo arms, respectively. Fifty-one (33.3%) patients in the luspatercept arm and 22 (28.9%) in the placebo arm received granulocyte colony-stimulating factor in combination with ESAs prior to randomization. A total of 8 (5.2%) and 6 (7.9%) patients receiving luspatercept and placebo, respectively, had baseline thrombocytopenia (< 100 x 109/L); no patients received prior platelet transfusions. Fifteen (9.8%) and 10 (13.2%) patients in the luspatercept and placebo arms, respectively, were evaluable for HI-N (i.e. baseline neutrophils < 1 x 109/L); 3/15 (20%) of those receiving luspatercept and 1/10 (10%) of those receiving placebo achieved HI-N in Weeks 1-48. Among patients who were evaluable for HI-P (i.e. baseline platelets < 100 x 109/L), 5/8 (62.5%) of those receiving luspatercept and 2/6 (33%) of those receiving placebo achieved HI-P in Weeks 1-48 (Table). None of the luspatercept HI-P responders received platelet transfusions. Mean changes from baseline in neutrophils of 0.94 x 109/L with luspatercept and 0.04 x 109/L with placebo were observed at Week 15, with early increases reported for luspatercept by Day 8 (0.86 vs 0.08 x 109/L for placebo). Mean increases in neutrophils at Day 8 occurred in both luspatercept responders (by MEDALIST primary endpoint; 1.0 x 109/L) and non-responders (0.8 x 109/L). Mean changes from baseline in platelets of 29 x 109/L were observed with luspatercept and 0.9 x 109/L with placebo by Week 12, but early increases were observed with luspatercept by Day 8 (18 vs 3 x 109/L for placebo) and mean increases in platelets at Day 8 occurred in both luspatercept responders (21.4 x 109/L) and non-responders (16.5 x 109/L). No patients in either arm experienced grade 3 or 4 treatment-emergent thrombocytopenia. Treatment-related grade 3 or 4 neutropenia was reported in 1 (0.7%) patient receiving luspatercept and 1 (1.3%) patient receiving placebo. Conclusions: Although only a minority of patients were evaluable for HI-P/HI-N response based on entry criteria for the study, luspatercept treatment resulted in a mean increase from baseline in platelet and neutrophil counts in most patients overall vs placebo, regardless of response status. These improvements were observed early following treatment initiation and then stabilized. Luspatercept did not contribute to the worsening of cytopenias vs placebo. *Data cutoff: May 8, 2018. Disclosures Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Mufti:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding. Buckstein:Takeda: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Santini:Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria. Díez-Campelo:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Finelli:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Ito:Celgene Corporation: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Rampersad:Celgene Corp: Employment, Equity Ownership. Sinsimer:Celgene Corporation: Employment, Equity Ownership. Linde:Fibrogen, Inc.: Equity Ownership; Abbott Laboratories, Inc.: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership. Platzbecker:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Komrokji:Alexion: Speakers Bureau; Incyte: Consultancy; Janssen: Consultancy; Agios: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Jazz: Speakers Bureau; DSI: Consultancy; Novartis: Speakers Bureau. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

Background: Luspatercept is a first-in-class erythroid maturation agent that binds TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. The phase 3 MEDALIST trial evaluated luspatercept in pts with RBC transfusion-dependent, IPSS-R-defined very low-, low-, and intermediate-risk MDS with ring sideroblasts (RS+) who were refractory, intolerant, or ineligible to receive erythropoiesis-stimulating agents. This study explored associations of gene mutations, as analyzed by next-generation sequencing (NGS), with response to luspatercept, as well as dynamics of gene mutations on therapy in MEDALIST pts. Methods: DNA was isolated from bone marrow (BM) mononuclear cells from 222 of 229 pts enrolled in the study (148 luspatercept, 74 placebo) at screening and, when available, following treatment. NGS of 23 MDS-relevant genes was performed at screening and every 24 weeks; mean coverage was 1,000-fold and the variant allele frequency (VAF) cutoff was ≥ 1%. BM cell populations were analyzed by cytomorphology. Response criterion of RBC transfusion independence (RBC-TI) of ≥ 8 weeks within the first 24 weeks of treatment was used for correlative analyses. Results: Mutations in SF3B1 were found in 91.0% of pts analyzed at screening (median VAF 42%, range 6-71%), consistent with the study population being RS+. Overall, a median of 2 (range 0-5) of the 23 MDS-relevant genes analyzed were mutated per pt. In addition to SF3B1, the most frequently mutated genes were TET2 (41.9%), DNMT3A (18.9%), ASXL1 (13.1%), and SRSF2 (8.1%). Mutation profiles were similar to those found in previous studies of refractory anemia with RS (RARS; Malcovati L, et al. Blood. 2015;126:233-41) and balanced between luspatercept and placebo arms. Numbers of mutated genes at baseline were distributed similarly in luspatercept responders (R) and non-responders (NR) (Figure A), and comparable response rates were achieved irrespective of number of mutations, with response rates of 36.4%, 34.9%, 42.4%, and 33.3% for pts with 1 mutation, 2 mutations, 3 mutations, and 4 or 5 mutations in the 23 MDS-relevant genes analyzed, respectively. Response to luspatercept was independent of the presence of mutations in any of the genes analyzed individually (Figure B) or when grouped by functional categories (e.g. spliceosome, epigenetic regulation, transcription factor, etc.) (Figure C). Circos plots of co-occurring mutations showed similar mutation profiles in R and NR (Figure D). Response rates were also similar regardless of baseline SF3B1 allelic burden (R: 43%, NR: 42%; P = 0.11). At baseline, BM erythroid precursors were higher in R (R: 32.8%, NR: 26%; P = 0.008; while R and NR had similar levels of RS+ cells [R: 80%, NR: 84%; P = 0.25], Figure E), consistent with the postulated activity of luspatercept on the erythroid lineage. When comparing the frequency of mutation changes in luspatercept- vs placebo-treated pts at week 24 of the study, no statistically significant differences were observed in the frequency of newly acquired mutations (13/126 [10.3%] pts in luspatercept vs 8/64 [12.5%] pts in placebo, P = 0.63) or mutation losses (4/126 [3.2%] in luspatercept vs 5/64 [7.8%] in placebo, P = 0.17). Evaluation of changes in allele burden (median VAF at week 24 vs baseline) for mutations in genes associated with adverse prognosis (ASXL1, SRSF2, U2AF1, NRAS, IDH2, GATA2, TP53, RUNX1, and EZH2; Bejar R. Curr Opin Hematol. 2017;24:73-8) showed no change between luspatercept- or placebo-treated pts (1.01-fold, n = 58 and 0.95-fold, n = 19, respectively, P = 0.69). Conclusions: Pts enrolled in the MEDALIST study had mutations consistent with RS+, lower-risk MDS with a preponderance of SF3B1 mutations; genes associated with poor prognosis (and other genes) were balanced between study arms. RBC-TI responses with luspatercept were achieved regardless of SF3B1 allelic burden, number of baseline mutations, and presence of individual mutations, including adverse mutations, or co-mutations. Disclosures Platzbecker: Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Dunshee:Celgene Corporation: Employment, Equity Ownership. Komrokji:DSI: Consultancy; pfizer: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy; celgene: Consultancy; JAZZ: Speakers Bureau. Mufti:Cellectis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Garcia-Manero:Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding. Buckstein:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. See:Celgene Corporation: Other: Contractor. Tsai:Celgene Corporation: Employment. Risueño:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: Named in Celgene patent filings related to predictive patient response biomarkers in hematological malignancies. Ma:Celgene Corporation: Employment, Equity Ownership. Schwickart:Celgene Corporation: Employment, Equity Ownership. Rampersad:Celgene Corp: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Laadem:Celgene Corporation: Employment, Equity Ownership. Menezes:Celgene Corporation: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership. Linde:Acceleron Pharma: Employment, Equity Ownership; Abbott Laboratories, Inc.: Equity Ownership; Fibrogen, Inc.: Equity Ownership. Reynolds:Acceleron Pharma: Employment, Equity Ownership. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

Introduction: BELIEVE is an ongoing phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of luspatercept, a first-in-class erythroid maturation agent, in adults with β-thalassemia requiring regular RBC transfusions (ClinicalTrials.gov identifier: NCT02604433). Treatment with luspatercept significantly reduced RBC transfusion burden and was associated with a favorable safety profile in this patient (pt) population (Piga A, et al. Blood. 2019;133:1279-89). Here we report iron-related efficacy endpoints of the BELIEVE study, including change from baseline in serum ferritin, liver iron concentration (LIC), and myocardial iron, as determined by T2*-weighted magnetic resonance imaging (MRI), and the effect of baseline iron levels on response to luspatercept. Methods: Adults with β-thalassemia or hemoglobin (Hb) E/β-thalassemia who required regular transfusions of 6-20 RBC units in the 24 weeks (wks) prior to randomization (with no transfusion-free period ≥ 35 days during that period) were randomized 2:1 to luspatercept (starting dose level 1.0 mg/kg; titration up to 1.25 mg/kg) or placebo, administered subcutaneously every 3 wks for ≥ 48 wks. Pts in both arms could receive RBC transfusions and iron chelation therapy (ICT) throughout the study to maintain their baseline Hb levels. Results: 332/336 randomized pts received treatment with luspatercept or placebo; 209/223 (93.7%) and 104/109 (95.4%) pts in the luspatercept and placebo arms had history of iron overload, defined as serum ferritin > 1,000 µg/L or LIC > 7 mg/g dry weight. 97.3% of luspatercept-treated and 97.2% of placebo-treated pts received ICT at baseline; 62.3%, 41.3%, and 37.2% received deferasirox, deferiprone, and deferoxamine, respectively, in the luspatercept arm, vs 57.8%, 36.7%, and 35.8% in the placebo arm. Fewer pts received ICT as combination therapy vs monotherapy (luspatercept arm: 28.6% vs 68.8%; placebo arm: 24.1% vs 72.3%, respectively). Mean baseline serum ferritin, LIC, and myocardial iron (by T2* MRI) for luspatercept vs placebo arms were 2,096.91 vs 1,845.05 μg/L, 12.04 vs 10.09 mg/g, and 33.52 vs 34.76 ms, respectively. As of Jan 7, 2019, 157 (70.4%) continue to receive luspatercept and 92 (84.4%) crossed over from the placebo arm. During the last 12 wks of the 48-wk randomized treatment period, mean change from baseline in serum ferritin was −248.02 μg/L vs +106.62 μg/L for pts in the luspatercept and placebo arms, respectively (least squares mean [LSM] difference: −347.80; P < 0.0001). 158/224 (70.5%) and 33/112 (29.5%) pts in the luspatercept and placebo treatment arms achieved a ≥ 33% reduction in RBC transfusion burden of ≥ 2 RBC units during any 12-wk interval. Among the responders, mean change from baseline in serum ferritin was −343.22 μg/L and +47.30 μg/L for pts receiving luspatercept and placebo, respectively (LSM difference: −389.50; P = 0.0047). Of 140 luspatercept-treated pts with baseline ferritin ≥ 1,000 μg/L, 29 (20.7%) achieved post baseline ferritin of < 1,000 μg/L when assessed over the entire treatment period; results were similar in responders and non-responders. During the treatment phase, mean change in myocardial MRI iron signal (T2*) from baseline to Wk 48 was −1.83 ms for luspatercept and +0.02 ms for placebo (LSM difference: −2.39; P = 0.0391). Over 96 wks, 6 (20%) luspatercept-treated pts with baseline myocardial iron ≤ 20 ms had post-baseline results > 20 ms; results were similar between responders and non-responders. Mean LIC changes from baseline to Wk 48 (mg/g dry weight) were +0.10 and +0.08 for luspatercept and placebo arms, respectively (LSM difference: +0.11; P = 0.8685). Over 96 wks, mean change in LIC among luspatercept-treated patients overall was −0.5 mg/g and −1.1 mg/g among responders. When assessing impact of baseline iron loading there was a general consistency in achievement of ≥ 33% reduction in RBC transfusion with luspatercept over any 12 wks, regardless of iron loading subgroup (baseline serum ferritin, LIC, and myocardial iron) (Table). Conclusions: Luspatercept treatment resulted in clinically meaningful reductions in serum ferritin levels. Baseline iron overload did not seem to affect response to luspatercept; treatment resulted in clinically meaningful reductions in RBC transfusion burden regardless of baseline serum ferritin level, LIC, or myocardial iron loading. Disclosures Porter: Celgene Corporation: Consultancy, Honoraria; Protagonist: Honoraria; Vifor: Honoraria; La Jolla: Honoraria; Agios: Consultancy, Honoraria; Silence Therapeutics: Honoraria; Bluebird Bio: Consultancy, Honoraria. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees. Coates:apo pharma: Consultancy, Honoraria, Speakers Bureau; agios pharma: Consultancy, Honoraria; celgene: Consultancy, Honoraria, Other: steering committee of clinical study; vifor: Consultancy, Honoraria. Hermine:AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Novartis: Research Funding; Celgene: Research Funding. Viprakasit:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Research Funding; Protagonist: Consultancy, Research Funding; Vifor: Consultancy, Research Funding; Ionis: Consultancy, Research Funding; La Jolla: Consultancy, Research Funding. Voskaridou:Genesis: Consultancy, Research Funding; Protagonist: Research Funding; Celgene Corporation: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; Addmedica: Membership on an entity's Board of Directors or advisory committees. Perrotta:Acceleron Pharma: Research Funding; Novartis: Honoraria, Research Funding. Kattamis:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apopharma: Honoraria; Vertex: Membership on an entity's Board of Directors or advisory committees; ViFOR: Membership on an entity's Board of Directors or advisory committees; Ionis: Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Shetty:Celgene Corporation: Employment, Equity Ownership. Kuo:Celgene Corporation: Employment, Equity Ownership. Miteva:Celgene International: Employment. Zinger:Celgene Corporation: Employment. Linde:Acceleron Pharma: Employment, Equity Ownership; Fibrogen, Inc.: Equity Ownership; Abbott Laboratories, Inc.: Equity Ownership. Sinsimer:Celgene Corporation: Employment, Equity Ownership. Taher:Protagonist Therapeutics: Consultancy, Research Funding; La Jolla Pharmaceuticals: Consultancy, Research Funding; Celgene Corporation: Research Funding; Abfero: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Ionis Pharmaceuticals: Consultancy. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

Introduction: Few treatment options are available to RBC transfusion-dependent pts with lower-risk MDS (LR-MDS) who are refractory/ineligible for erythropoiesis-stimulating agents (ESAs). Luspatercept is a first-in-class erythroid maturation agent that binds select TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. In the phase 3, randomized, double-blind, placebo-controlled MEDALIST study (NCT02631070), luspatercept significantly reduced transfusion burden vs placebo. Longer-term efficacy analyses of the MEDALIST study (data cutoff Jan 7, 2019), including multiple responses, and safety are presented here. Methods: Eligible pts were ≥ 18 years of age with IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS (World Health Organization 2016 criteria); were refractory, intolerant, or unlikely to respond to ESAs (serum erythropoietin > 200 U/L); and required regular RBC transfusions. Pts were randomized 2:1 to luspatercept (1.0 mg/kg titrated up to 1.75 mg/kg, if needed) or placebo, subcutaneously every 3 weeks (wks). This analysis assessed the achievement and number of individual response periods of RBC transfusion independence (RBC-TI) ≥ 8 wks. Clinical benefit, defined as achieving RBC-TI ≥ 8 wks and/or modified hematologic improvement-erythroid (HI-E) response per International Working Group 2006 criteria, was also assessed, along with total duration of clinical benefit (time from achieving clinical benefit to discontinuation due to loss of benefit, adverse events [AEs], or other reasons). Longer-term efficacy and safety were also evaluated. Results: Pts were assessed for RBC transfusion burden/8 wks in the 16 wks before randomization: 66 pts received 2 to < 4 U RBCs (30.1% and 26.3% of pts receiving luspatercept and placebo, respectively), 64 received ≥ 4 to < 6 U (26.8% and 30.2%, respectively), and 99 received ≥ 6 U (43.1% and 43.4%, respectively); both arms had a median baseline burden of 5 RBC U/8 wks. Compared with our previous analysis and earlier data cutoff of May 8, 2018 (Fenaux P, et al. Blood. 2018;132:1), we now report that as of Jan 7, 2019, 72 (47.1%) pts treated with luspatercept and 12 (15.8%) treated with placebo achieved RBC-TI ≥ 8 wks. Analysis of multiple response periods of RBC-TI ≥ 8 wks in the luspatercept responders (i.e. initial RBC-TI ≥ 8 wks, followed by transfusion, followed by another period of RBC-TI ≥ 8 wks) demonstrated that 48 (66.7%) pts had ≥ 2 separate response periods, 22 (30.6%) had ≥ 3, 12 (16.7%) had ≥ 4 , and 7 (9.7%) had ≥ 5. Of the 12 pts achieving RBC-TI ≥ 8 wks with placebo, 4 (33.3%) had ≥ 2 responses; none had > 3. Overall, 48 (31.4%) pts receiving luspatercept and none receiving placebo remained on treatment as of the Jan 7, 2019 data cutoff. Median treatment duration was 50.9 (range 5.9-147.0) wks in pts receiving luspatercept vs 24.0 (range 7.4-103.0) wks in pts receiving placebo. Median duration of the longest period of RBC-TI ≥ 8 wks during Wks 1-48 was 30.6 (95% confidence interval [CI] 20.6-50.9) wks with luspatercept and 18.6 (95% CI 10.9-not evaluable) wks with placebo. Median total duration of clinical benefit was 83.6 and 26.8 wks for pts responding to luspatercept (n = 97) and placebo (n = 20), respectively. Of the 97 luspatercept-treated pts evaluable for clinical benefit, median duration of clinical benefit in pts with baseline transfusion burden of 4 to < 6 U/8 wks was 87.9 (range 13-125) wks, of < 4 U/8 wks was 84.7 (range 21-147) wks, and of ≥ 6 U/8 wks was 64.9 (range 8-122) wks. Twelve luspatercept-treated pts did not require a transfusion after the first dose of luspatercept up to Wk 48 or until time of analysis; as of Jan 7, 2019 data cutoff, 3 (25%) of those pts maintained response. AEs occurring more frequently with luspatercept vs placebo (fatigue, diarrhea, asthenia, dizziness) occurred early (Cycles 1-4), were mainly grade 1 or 2, decreased over time, and were not associated with a higher dose level. Progression to acute myeloid leukemia was similar in pts receiving luspatercept (n = 3 [2.0%]) and those receiving placebo (n = 1 [1.3%]). Conclusions: Most LR-MDS pts achieving RBC-TI and/or HI-E with luspatercept in the MEDALIST study had multiple responses with durable clinical benefit superior to that of pts receiving placebo, including those with a high baseline transfusion burden. AEs were mainly grade 1 or 2, decreased over time, and were not correlated with a higher dose level. Disclosures Fenaux: Aprea: Research Funding; Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Mufti:Cellectis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Buckstein:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Finelli:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Ilhan:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Komrokji:DSI: Consultancy; JAZZ: Consultancy; celgene: Consultancy; Agios: Consultancy; pfizer: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; Incyte: Consultancy. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zeidan:Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Verma:Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria; BMS: Research Funding; Janssen: Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Ito:Celgene Corporation: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Rampersad:Celgene Corp: Employment, Equity Ownership. Sinsimer:Celgene Corporation: Employment, Equity Ownership. Linde:Acceleron Pharma: Employment, Equity Ownership; Fibrogen, Inc.: Equity Ownership; Abbott Laboratories, Inc.: Equity Ownership. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Platzbecker:Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

Introduction: β-thalassemia is an inherited hemoglobinopathy associated with an erythroid maturation defect characterized by ineffective erythropoiesis and impaired RBC maturation. Luspatercept is a first-in-class erythroid maturation agent under development to treat patients with β-thalassemia. Luspatercept 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). We report the results of a phase 3, randomized, double-blind, placebo-controlled study to determine the efficacy and safety of luspatercept in adult β-thalassemia patients requiring regular RBC transfusions. ClinicalTrials.gov identifier: NCT02604433. Methods: Eligible patients were aged ≥ 18 years; had β-thalassemia or hemoglobin (Hb) E/β-thalassemia (compound β-thalassemia mutation and/or multiplication of α-globin genes was allowed); and required regular transfusions of 6-20 RBC units in the 24 weeks prior to randomization with no transfusion-free period ≥ 35 days during that time. Patients were randomized 2:1 to receive either luspatercept, at a starting dose level of 1.0 mg/kg with titration up to 1.25 mg/kg, or placebo, subcutaneously every 3 weeks for ≥ 48 weeks. Patients in both treatment arms continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline Hb level. The primary endpoint was a ≥ 33% reduction in transfusion burden (with a reduction of ≥ 2 RBC units) during weeks 13-24, when compared with a 12-week baseline period. Key secondary endpoints included: ≥ 33% reduction in RBC transfusion burden at weeks 37-48, ≥ 50% reduction in transfusion burden at weeks 13-24, ≥ 50% reduction in transfusion burden at weeks 37-48, and mean change in transfusion burden at weeks 13-24. Achievement of ≥ 33% reduction in RBC transfusion burden over any consecutive 12 weeks on study was also evaluated. Results: † A total of 336 patients were randomized, of whom 332 were treated. Median age was 30 years (range 18-66) and 58% of patients were female. Patients received a median of 6 RBC units in the 12 weeks prior to treatment. 58% of patients in each arm had undergone splenectomy. B0/B0 genotype (classification according to the HbVar database) was observed in 68 of 224 (30.4%) and 35 of 112 (31.3%) patients in the luspatercept and placebo arms, respectively. 48 of 224 (21.4%) patients in the luspatercept arm achieved the primary endpoint versus 5 of 112 (4.5%) patients receiving placebo (odds ratio 5.79, P < 0.0001). 44 of 224 (19.6%) patients receiving luspatercept achieved a ≥ 33% reduction in RBC transfusion burden at weeks 37-48 compared with 4 of 112 (3.6%) patients receiving placebo (P < 0.0001). Of 224 patients receiving luspatercept, 17 (7.6%) and 23 (10.3%) achieved a ≥ 50% reduction in RBC transfusion burden at weeks 13-24 and 37-48, respectively, compared with 2 (1.8%) and 1 of 112 (0.9%) patients receiving placebo (P = 0.0303 and P = 0.0017, respectively). The difference of mean change from baseline in transfusion burden from week 13 to week 24 was 1.35 units (P < 0.0001). 158 of 224 (70.5%) patients receiving luspatercept achieved a ≥ 33% RBC transfusion reduction over any consecutive 12 weeks compared with 33 of 112 (29.5%) patients receiving placebo (P < 0.0001); statistically significant differences were also noted for all other transfusion burden reduction endpoints. Adverse events (AEs) observed in the study were generally consistent with previously reported phase 2 data. Treatment-emergent AEs leading to dose delay or dose reduction were similar between treatment arms. No patient deaths were reported for those treated with luspatercept. Conclusions: Treatment with luspatercept resulted in significant reductions in RBC transfusion burden in adults with transfusion-dependent β-thalassemia. Luspatercept was generally well tolerated in this patient population. † As of May 11, 2018, cutoff date. Disclosures Cappellini: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Sanofi/Genzyme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Vifor: Membership on an entity's Board of Directors or advisory committees. Viprakasit:F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Protagonist Therapeutics: Consultancy, Research Funding. Taher:Protagonist Therapeutics: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Ionis Pharmaceuticals: Consultancy; La Jolla Pharmaceutical: Research Funding; Celgene Corp.: Research Funding. Georgiev:Alnylam: Consultancy. Coates:Celgene Corp.: Consultancy; ApoPharma: Consultancy, Honoraria; Vifor Pharma: Consultancy; Sangamo: Consultancy, Honoraria. Voskaridou:Acceleron: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding. Forni:Novartis: Research Funding; Roche: Research Funding; Celgene: Research Funding. Perrotta:Acceleron Pharma: Research Funding; Novartis: Research Funding. Lal:Celgene Corporation: Research Funding; Bluebird Bio: Research Funding; La Jolla Pharmaceutical Company: Consultancy, Research Funding; Insight Magnetics: Research Funding; Novartis: Research Funding; Terumo Corporation: Research Funding. Kattamis:ApoPharma: Honoraria; Vifor Pharma: Consultancy; CELGENE: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Vlachaki:Novartis: Honoraria. Origa:Cerus Corporation: Research Funding; Bluebird Bio: Consultancy; Novartis: Honoraria; Apopharma: Honoraria. Aydinok:TERUMO: Research Funding; Protagonist: Other: SSC; CRISPR Tech: Other: DMC; Cerus: Honoraria, Research Funding; La Jolla Pharmaceuticals: Research Funding; Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding. Ho:Takeda: Honoraria, Other: travel to meeting; Novartis: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Celgene: Other: Travel to meeting. Chew:Celgene: Research Funding. Tantiworawit:Celgene: Honoraria, Research Funding, Speakers Bureau. Shah:Novartis: Honoraria, Speakers Bureau; Sobi/Apotex: Honoraria; Celgene Corp: Other: Steering committee; Roche: Other: Advisory board meeting. Neufeld:Celgene Corp.: Consultancy, Other: Steering committee; Acceleron Pharma: Consultancy. Laadem:Celgene: Employment, Equity Ownership. Shetty:Celgene: Employment, Equity Ownership. Zou:Celgene Corporation: Employment, Equity Ownership. Miteva:Celgene Corporation: Employment, Other: grants. Zinger:Celgene Corporation: Employment. Linde:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership; Fibrogen: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Hermine:AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene Corporation: Research Funding; Hybrigenics: Research Funding; Erythec: Research Funding; Novartis: Research Funding. Porter:Cerus: Honoraria; Agios: Honoraria; Novartis: Consultancy. Piga:La Jolla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Honoraria; Apopharma: Honoraria, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Acceleron: Research Funding.

Background The hemoglobin (Hb) response to the activin receptor type IIA ligand trap ACE-011 (Sotatercept) in non-transfusion-dependent thalassemia (NTDT), and the transfusion requirement response in TDT are described, but the mechanisms of action, clinical predictors and markers of response, are unclear. In principle, ACE-011 may act on early and/or late erythroblasts to decrease ineffective erythropoiesis (IE), both in healthy subjects and in thalassemia. As erythropoiesis intimately links to iron metabolism, changes in markers of iron metabolism relative to those of erythropoiesis may inform the mechanisms and developmental stage at which ACE-011 acts. Methods Markers of IE and iron metabolism in 46 thalassemia patients (30 NTDT, 16 TDT) were taken before and during a median follow up of 722.5 days, (IQR 830.5, range 152-1427) of escalating doses of ACE-011 (3-weekly 0.1 to 1.0 mg/kg s.c. injections), depending on the protocol, as part of the approved study (Cappellini, et al. 2018 under review). Markers of erythropoiesis included Hb, Reticulocytes (Ret), soluble transferrin receptor 1 (sTfR), growth differentiation factor 11 and 15 (GDF11, GDF15), erythroferrone (ERFE). Markers of iron metabolism included plasma hepcidin, serum ferritin (SF), transferrin saturation (TSAT), and non-transferrin-bound iron (NTBI). Data were analyzed using longitudinal multilevel model for change (LMMC) on STATA (Version 14) as generalized linear mixed model with random and fixed effects to account for repeated measures and highly complex temporal data structure. Final LMMCs were built to explain the change in Hb from baseline and the behavior of key biomarkers. Independent variables were entered into the models based on the study design (predictors from design) and theoretical background (predictors of interest and control variables). P value Results Predictors of response. In NTDT, Hb response associated positively with dose and duration of exposure (both at p Biomarker changes with time In NTDT, significant changes with time on study were increases in Hb, sTfR, ERFE and Ret and decreases in hepcidin, bilirubin, and NTBI. GDF15 showed no change. In TDT, GDF15, sTfR and ERFE increased, whereas hepcidin decreased. The Hb change was insignificant in TDT (as expected per protocol) and was dose-independent, however the mean 41% reduction in transfusion iron load rate (ILR) was dose dependent, implying an equivalent net production of Hb in TDT (Table 1). Other significant relationships Absolute hepcidin level in NTDT and TDT was negatively predicted by ERFE (p Interpretation and conclusions NTDT patients allow a cleaner interpretation of biomarker changes as these are confounded in TDT by increased bone marrow stress from less transfusion. In NTDT, sTfR and ERFE (total erythropoiesis) increase on study while GDF15 (IE) and EPO do not. Thus Hb gain may result from increased effectiveness of late stage erythropoiesis (sTfR+ and ERFE+) possibly from decreased apoptosis and more rapid maturation (Carrancio et al, BJH 2014) in this compartment. We speculate that increased survival of those erythroid progenitor cells expressing TfR (and hence sTfR) and ERFE (hence increased ERFE) also explains the observed hepcidin reduction. Despite exposure to lower hepcidin, there is no iron loading: NTBI falls against stable SF in NTDT, consistent with shunting of iron into the sink of effective erythropoiesis. The reduction in GDF11 in vivo, not previously reported for ACE-011, is also consistent with increased apoptosis of the early progenitor pool and with improved erythroblast differentiation relative to proliferation as suggested in murine β-thalassemia treated with ACE-011 (Dussiot, et al. Nat Med 2014). Disclosures Garbowski: Vifor: Consultancy. Hermine:Erythec: Research Funding; AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene Corporation: Research Funding; Hybrigenics: Research Funding; Novartis: Research Funding. Cappellini:Sanofi/Genzyme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Vifor: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Origa:Bluebird Bio: Consultancy; Novartis: Honoraria; Cerus Corporation: Research Funding; Apopharma: Honoraria. Forni:Celgene: Research Funding; Novartis: Other: travel expenses, Research Funding; Shire: Research Funding; Roche: Consultancy; Apopharma: Other: DSM Board. Voskaridou:Acceleron: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding. Galactéros:Addmedica: Other: grant; Novartis: Other: grant. Taher:Novartis: Consultancy, Honoraria, Research Funding; La Jolla Pharmaceutical: Research Funding; Protagonist Therapeutics: Consultancy; Celgene Corp.: Research Funding; Ionis Pharmaceuticals: Consultancy. Ribeil:bluebird bio: Consultancy; Vitalaire: Other: grant; Addmedica: Other: grant; Cydan: Consultancy; Novartis: Consultancy. Laadem:Celgene: Employment, Equity Ownership. Miteva:Celgene Corporation: Employment, Other: grants. Zou:Celgene Corporation: Employment, Equity Ownership. Zinger:Celgene Corporation: Employment. Schwickart:Celgene Corporation: Employment, Equity Ownership. Sung:Celgene Corporation: Employment, Equity Ownership. Porter:Novartis: Consultancy; Cerus: Honoraria; Agios: Honoraria.

Background: Significant increase in life expectancy has been observed in patients with β-thalassemia in recent years. The improved survival, however, is accompanied by significant ongoing healthcare needs related to the chronic condition; therefore, quality of life (QoL) has emerged as a fundamental focus of comprehensive patient care. We compared QoL outcomes between transfusion-dependent (TD) and non-transfusion-dependent (NTD) patients with β-thalassemia in the routine clinical care setting. Method: Adult patients with β-thalassemia were prospectively enrolled in an observational study in Italy, Greece, Lebanon, and Thailand. All patients completed Short Form 36 Health Survey version 2 (SF-36v2) and Functional Assessment of Cancer Therapy (FACT)-Anemia (An) questionnaires at baseline, and then once every 3 weeks using a hand-held electronic device. This analysis evaluated QoL between TD and NTD patients at study entry. Transfusion dependent was defined as receiving ≥ 6 red blood cell (RBC) units in the 24 weeks prior to study entry and no transfusion-free period for ≥ 35 days during that period. Results: A total of 102 patients with β-thalassemia were enrolled, of which 52 were TD and 50 NTD. The mean age of patients was 31.2 years and 70 (68.6%) were females. On average, patients with TD β-thalassemia were 3.6 years younger (P= 0.06) and had moderately higher hemoglobin values at baseline (8.8 vs 8.2 g/dL; P= 0.02). At study entry, all (100%) patients with TD β-thalassemia had received RBC transfusions within the 24 weeks prior to study entry, as per inclusion criteria, versus 5 (10%) patients with NTD β-thalassemia who had received RBC transfusions during the same time period. Patients with NTD β-thalassemia reported lower QoL on all domains and summary scores as captured by the SF-36v2 questionnaire, except for Role-Physical. On average, patients with NTD β-thalassemia experienced statistically significant lower QoL versus their TD counterparts on the domains of General Health (39.5 vs 44.0; P= 0.01), Vitality (49.3 vs 53.7; P= 0.01), and Mental Health (46.8 vs 50.8; P= 0.01), and in the Mental Component Summary Score (46.5 vs 50.8; P= 0.01). Similarly, patients with NTD β-thalassemia reported worse QoL scores from the FACT-An questionnaire on all domains and statistically significant differences were observed for Emotional Well-Being (18.5 vs 20.0; P= 0.02), Functional Well-Being (20.0 vs 23.2; P < 0.01), and FACT-General (82.9 vs 89.4; P= 0.01). Conclusions: In the routine clinical care setting, there are critical unmet medical needs for patients with NTD β-thalassemia as they experience worse QoL on many domains compared with patients with TD β-thalassemia. There is a need for new interventions to treat patients with NTD β-thalassemia and reduce their burden of disease. Disclosures Cappellini: Vifor: Honoraria; Novartis: Speakers Bureau; Celgene: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding, Speakers Bureau. Kattamis: National and Kapodistrian University of Athens: Employment; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy. Viprakasit: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Siriraj Hospital: Employment; Shire: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding. Sutcharitchan: Celgene: Research Funding; Chulalongkorn University: Consultancy, Employment. Mahmoud: Celgene: Employment. Pariseau: Celgene: Employment. Laadem: Celgene: Employment, Equity Ownership. Khan: Nathan S. Kline Institute for Psychiatric Research; Manhattan Psychiatric Center: Employment. Hu: Celgene: Employment, Equity Ownership. Taher: Novartis Pharmaceuticals: Honoraria, Research Funding; Celgene: Research Funding.

Background.Luspatercept (ACE-536) is a modified activin receptor type IIB fusion protein that promotes late-stage erythroid differentiation. In beta-thalassemia, imbalanced production of alpha and beta globin chains in erythroid precursors causes ineffective erythropoiesis (IE) leading to anemia and dysregulated iron homeostasis. In a mouse model of beta-thalassemia, luspatercept corrected the effects of ineffective erythropoiesis and in a phase 1 clinical study with healthy volunteers, was well tolerated and increased hemoglobin (Suragani R, Nat Med, 2014; Suragani R, Blood, 2014; Attie K, Am J Hematol, 2014). Aims.This is an ongoing, phase 2, multicenter, open-label, dose-finding study followed by a long-term extension study to evaluate the effects of luspatercept in patients (pts) with either transfusion-dependent (TD) or non-transfusion dependent (NTD) beta-thalassemia with the following key endpoints: erythroid response (including Hgb increase) and patient-reported quality-of-life (QoL) measures in NTD patients, and reductions in RBC transfusion burden in TD patients. Methods.Inclusion criteria included age ≥ 18 yr and either TD (defined as ≥ 4 RBC units transfused in the 8 weeks prior to first dose, confirmed over 6 months) or NTD (defined as < 4 RBC units transfused in the 8 weeks prior to first dose with baseline Hgb < 10.0 g/dL). Luspatercept was administered subcutaneously every 3 weeks for up to 5 doses over 12 weeks with an 8 week follow-up (20 weeks total). Six cohorts (n=35) were treated at dose levels from 0.2-1.25 mg/kg. Pts in the expansion cohort (n=29) and all pts who rolled over to the extension study (n=51) were treated at ≥ 0.8 mg/kg with escalation up to 1.25 mg/kg. Results. A total of 30 TD pts enrolled in the base study and, of those, 24 enrolled in the extension study (data as of 11 March 2016). Data summarized are for the long-term extension study. Median age was 38 yr (range 22-55 yr), 67% had prior splenectomy. At baseline, median transfusion burden was 8 units/12 weeks (range 4-15 units) and mean (SD) liver iron concentration (LIC) was 5.1 (5.3) mg/g dw. A total of 20/24 (83%) and 16/24 (67%) TD pts achieved a ≥ 33% and ≥ 50% decrease in transfusion burden over any 12-week period compared to baseline, respectively. Duration of response ranged from 12 to 48+ weeks. A total of 34 NTD pts enrolled in the base study and, of those, 27 enrolled in the extension study (data as of 11 March 2016). Data summarized are for the long-term extension study. Median age was 37 yr (range 23-62 yr); 67% had prior splenectomy. At baseline, median Hgb was 8.7 g/dL (range 7.6-9.8 g/dL) and mean (SD) LIC was 4.9 (3.4) mg/g dw. A total of 21/27 (78%) and 15/27 (56%) NTD pts achieved ≥ 1.0 g/dL and ≥ 1.5 g/dL increases, respectively, in mean Hgb over any 12-week period compared to baseline. Duration of response ranged from 16 to 72+ weeks, with no trend for lower Hgb response over time. Increases in mean hemoglobin over a 12-week period correlated with increases in a pt-reported QoL questionnaire, FACIT-F (r=0.67, p=0.001). 3/5 (60%) pts with baseline LIC ≥ 5 mg/g dw had a decrease in LIC ≥ 2 mg/g dw after at least 6 months of treatment; 8/9 (89%) patients with baseline LIC < 5 mg/g dw maintained LIC < 5 mg/g dw. Luspatercept was generally well tolerated, with no related SAEs. AEs were mostly mild-moderate. The most frequent related AEs (≥ 10% in base + extension studies) in TD pts were bone pain, myalgia, arthralgia, headache, asthenia, and musculoskeletal pain. The most frequent related AEs (≥ 10% in base + extension studies) in NTD pts were bone pain, headache, musculoskeletal pain, and arthralgia. Conclusions: Luspatercept treatment in pts with beta-thalassemia had a favorable safety profile. Efficacy was clinically relevant in both NTD pts (increased Hgb levels, decreased LIC, and improved quality of life) and TD pts (decreased RBC transfusions). A Phase 3, double-blind, placebo-controlled study of luspatercept in regularly transfused adults with beta-thalassemia is ongoing (NCT02604433). Disclosures Zhang: Acceleron Pharma: Employment. Wilson:Acceleron Pharma: Employment, Equity Ownership. Leneus:Acceleron Pharma: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Attie:Acceleron Pharma: Employment, Equity Ownership.

Background: Management of anemia is a common therapeutic challenge in patients with myelodysplastic syndromes (MDS). Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia in lower-risk MDS. Luspatercept binds GDF11 and other TGF-β superfamily ligands to promote late-stage erythroid differentiation and increase hemoglobin (Hgb) levels (Suragani R, Nat Med, 2014 and Attie K, Am J Hematol, 2014). Aims: This is an ongoing, phase 2, multicenter, open-label study to evaluate the effects of luspatercept in patient (pts) with low-intermediate risk MDS. Endpoints included erythroid response (IWG HI-E), RBC transfusion independence (RBC-TI, ≥ 8 weeks), duration of HI-E, pharmacodynamic and iron metabolism biomarkers, safety, and pt-reported QoL. Methods: Inclusion criteria included age ≥ 18 yr, Hgb < 10 g/dL (if < 4U RBC/8 weeks), no prior HMA, and no current lenalidomide or erythropoiesis-stimulating agent (ESA). An expansion cohort of up to 56 patients was added to this phase 2 study to evaluate response to luspatercept in pts who do not qualify for the phase 3 MEDALIST trial (for RS+ positive patients with baseline EPO ≥ 200 U/L and ≥ 2U RBC/8 weeks). These include pts with low transfusion burden (< 4U RBC/8 weeks) who are either 1) ring sideroblast (RS)+ (≥ 15% RS in bone marrow) with baseline EPO ≤ 200 U/L and no prior ESA use, or 2) RS- with any baseline EPO level and any prior ESA use. Patients are treated with 1.0 mg/kg of luspatercept every 3 weeks for up to 5 doses, with titration up to 1.75 mg/kg. Patients may rollover to an open-label extension study for up to an additional 2 years of treatment. Results: Results for the initial patient cohorts have demonstrated a high proportion of HI-E and RBC-TI responses in RS+ patients. Data for the additional ESA-naïve RS+ patients with low EPO levels and RS- patients with 3 months of treatment will be presented at the meeting. Conclusions: Erythroid response to luspatercept has been demonstrated in RS+ patients with lower-risk MDS and is being explored in ESA-naïve RS+ patients with low EPO levels and RS- patients. A Phase 3 study of luspatercept in regularly-transfused RS+ patients with lower-risk MDS according to IPSS-R is ongoing (MEDALIST study; NCT02631070). Disclosures Donovan: Acceleron Pharma: Employment. Wilson:Acceleron Pharma: Employment, Equity Ownership. Zhang:Acceleron Pharma: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Attie:Acceleron Pharma: Employment, Equity Ownership. Giagounidis:Celgene Corporation: Consultancy.

Background: In β-thalassemia, imbalanced production of α and β globin chains in erythroid precursors inhibits late-stage erythroid differentiation, leading to ineffective erythropoiesis and anemia. Luspatercept is a modifiedactivin receptor type IIB-IgG Fc fusion protein that promotes terminal erythroid differentiation and mitigates ineffective erythropoiesis in murine β-thalassemia. In phase 2 studies, luspatercept led to long-term increases in hemoglobin (Hb) levels and reduction in transfusion burden in patients (pts) with β-thalassemia. Aims: To characterize the pharmacokinetics (PK) of luspatercept, and to explore the exposure-response relationship for efficacy and safety in pts with β-thalassemia, thereby informing selection of the starting dose for phase 3 studies of luspatercept in β-thalassemia. Methods : PK, safety, and efficacy data were collected from two phase 2 studies (base and extension). In the base study, luspatercept was administered once every 3 weeks by subcutaneous injection to sequential cohorts for up to 5 doses. The base study included a dose-finding phase (at fixed doses ranging from 0.2 mg/kg to 1.25 mg/kg) and an expansion cohort (at a starting dose of 0.8 mg/kg followed by individual dose titration up to 1.25 mg/kg). Pts completing the base study were eligible to enroll in an extension study, where they continued to receive luspatercept every 3 weeks for up to 24 months. Pts who had treatment interruption for ≥ 3 months before enrolling in the extension study received a starting dose of 0.8 mg/kg (followed by dose titration) and were treated as "new" pts in the exposure-response analysis. The main exposure endpoint was area under the luspatercept serum concentration-time curve (AUC). Clinical endpoints included Hb increase, transfusion reduction, and drug-related adverse events (AEs) in weeks 1-15. Responders were defined as non-transfusion-dependent (NTD) pts with a mean Hb increase ≥ 1.0 g/dL/15 weeks, and transfusion-dependent (TD) pts with a transfusion reduction ≥ 33%/15 weeks. Results : As of July 20, 2016, preliminary data were available for 89 pts, including 49 NTD pts (baselineHb 6.5-9.8 g/dL) and 40 TD pts (baseline transfusion burden 4-18 units/12 weeks). Median age was 37 years (range 20-62), and 47% were female. A total of 49 pts were eligible for individual dose titration, with ~71% having at least 1 dose escalation (to 1 mg/kg) and 27% having 2 dose escalations (up to 1.25 mg/kg) within the first 5 cycles. Luspatercept PK was adequately described by a 1-compartment PK model with linear absorption and elimination. The half-life of luspatercept in serum was~10 days across doses. Body weight positively correlated with luspatercept clearance and its volume of distribution. TD pts had~23% lower volume of distribution than NTD pts. In NTD pts, higher luspatercept serum AUC correlated with a greater increase in Hblevels (P < 0.01). Most TD pts had a reduction in transfusion burden; however, an exposure-dependent trend was not apparent for relative or absolute reduction in units transfused, possibly due to the narrow exposure range tested. The median AUC was similar for NTD responders and TD responders (~100d·μg/mL vs ~120d·μg/mL). As AUC increased, the frequency of responders increased for NTD pts, TD pts, and the 2 groups combined (Figure). Population PK simulation predicted that a starting dose of 1.0 mg/kg luspatercept would result in > 90% of NTD pts and ~50% of TD pts achieving the median AUC concentration observed in responders. By contrast, < 50% pts (NTD or TD) were predicted to achieve the target AUC at the 0.8 mg/kg dose. Grade 2-3 drug-related AEs (all types) were more frequent with higher AUC (P < 0.05). In both NTD and TD pts, bone and muscle pain were the most common AEs; however, these AES did not have a significant relationship with luspatercept serum exposure. Conclusions: Higher luspatercept serum exposure correlated with greater erythroid hematopoietic response as well as more frequent grade 2-3 related AEs. Exposure-response modeling and PK simulation support a phase 3 starting dose of 1.0 mg/kg and intra-patient dose escalation up to 1.25 mg/kg according to pts' response. A phase 3 study of luspatercept in regularly transfused adults with β-thalassemia is ongoing (BELIEVE study; ClinicalTrials.gov NCT02604433). Disclosures Chen: Celgene Corporation: Employment, Equity Ownership. Laadem:Celgene Corporation: Employment, Equity Ownership. Wilson:Acceleron Pharma: Employment, Equity Ownership. Zhang:Acceleron Pharma: Employment. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Ritland:Celgene Corporation: Employment, Equity Ownership. Attie:Acceleron Pharma: Employment, Equity Ownership.

Background: Luspatercept is a modified ActRIIB-IgG Fc fusion protein that corrects ineffective erythropoiesis. In phase 2 studies, luspatercept treatment led to long-term increases in hemoglobin (Hb) levels and reduction in transfusion burden in patients (pts) with IPSS Low- or Intermediate-1-risk MDS. Aims: To characterize the pharmacokinetics (PK) of luspatercept and explore the exposure-response relationship for efficacy and safety in pts with MDS, thereby informing selection of the starting dose for phase 3 studies of luspatercept in MDS. Methods : PK, safety, and efficacy data were collected from two phase 2 studies (base and extension). In the base study, luspatercept was administered once every 3 weeks by subcutaneous injection to sequential cohorts for up to 5 doses. The base study included a dose-finding phase (at fixed doses from 0.125 to 1.75 mg/kg), and an expansion cohort (at a starting dose of 1.0 mg/kg followed by individual dose titration up to 1.75 mg/kg). Pts completing the base study were eligible to enroll in an extension study, where they continued to receive luspatercept every 3 weeks for up to 24 months. Pts who had treatment interruption for ≥ 3 months before enrolling in the extension study received a starting dose of 1.0 mg/kg (followed by dose titration) and were treated as "new" pts in the exposure-response analysis. The main exposure endpoint was area under the luspatercept serum concentration−time curve (AUC). Clinical endpoints included Hb increase, transfusion reduction, and drug-related adverse events (AEs) in weeks 1-15. Responders were defined as pts achieving erythroid hematologic improvement (HI-E) per IWG criteria, i.e. Hb increase ≥ 1.5 g/dL for 8 weeks in low transfusion burden (LTB) pts, and transfusion reduction ≥ 4 RBC units/8 weeks in high transfusion burden (HTB) pts. Results : As of July 20, 2016, preliminary data were available for 66 pts: 22 LTB pts (baseline Hb 6.4-10.1 g/dL) and 44 HTB pts (baseline transfusion burden 4-18 units/8 weeks). Median age was 72 years (range 27-90); 41% were female. A total of 39 pts were eligible for individual dose titration; of these, ~49% had ≥ 1 dose escalation (to 1.33 mg/kg) and ~15% had 2 dose escalations (to 1.75 mg/kg) in the first 3 months. Luspatercept PK was adequately described by a 1-compartment PK model with linear absorption and elimination. Half-life of luspatercept in serum was ~10-14 days across doses. Body weight positively correlated with luspatercept clearance and its volume of distribution. Baseline transfusion burden (LTB vs HTB) and erythropoietin (EPO) level (10-4,752 U/L) had no significant effect on luspatercept PK. In LTB pts who were transfusion-free on treatment, higher luspatercept AUC correlated with greater Hb increase (P < 0.01). In HTB pts, AUC correlated with reduced transfusion units in pts with baseline EPO ≤ 500 U/L (P< 0.01) but not in pts with baseline EPO > 500 U/L. Median AUC was 148 d·µg/mL in LTB responders and 185 d·µg/mL in HTB responders. Luspatercept AUC also correlated with frequency of IWG HI-E responders for LTB pts, HTB pts (baseline EPO ≤ 500 U/L), and the 2 groups combined. In pts requiring transfusion (≥ 2 units/8 weeks) with baseline EPO ≤ 500 U/L, baseline transfusion burden was a significant predictor of achieving transfusion independence (TI) ≥ 8 weeks, and higher luspatercept AUC was associated with greater TI rate after accounting for baseline transfusion burden. Thus, individualized dosing based on baseline transfusion burden may increase the likelihood of achieving TI in HTB pts. Population PK simulation predicted that the starting dose resulting in 90% of LTB pts and 50% of HTB pts achieving efficacious AUC for HI-E would be 1 mg/kg and 1.1 mg/kg, respectively; higher doses would result in a higher proportion of pts achieving efficacious AUC. There was no significant relationship between severity and frequency of drug-related AEs and luspatercept serum exposure. Conclusions: Higher luspatercept serum exposure correlated with greater erythroid hematopoietic response for both LTB and HTB pts. Exposure-response modeling and PK simulation support a phase 3 starting dose of 1.0 mg/kg and intra-patient dose escalation up to 1.75 mg/kg according to erythroid hematopoietic response. A phase 3 study of luspatercept in regularly transfused ring sideroblast positive patients with lower-risk MDS according to IPSS-R criteria is ongoing (MEDALIST study; ClinicalTrials.gov NCT02631070). Disclosures Chen: Celgene Corporation: Employment, Equity Ownership. Laadem:Celgene Corporation: Employment, Equity Ownership. Wilson:Acceleron Pharma: Employment, Equity Ownership. Zhang:Acceleron Pharma: Employment. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Ritland:Celgene Corporation: Employment, Equity Ownership. Attie:Acceleron Pharma: Employment, Equity Ownership.

Background: Management of anemia is a common therapeutic challenge in patients with MDS. Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia in lower-risk MDS. Luspatercept binds GDF11 and other TGF-β superfamily ligands to promote late-stage erythroid differentiation and increase hemoglobin (Hgb) levels (Suragani R, Nat Med, 2014 and Attie K, Am J Hematol, 2014). Aims: This is an ongoing, phase 2, multicenter, open-label, long-term extension study to evaluate the effects of luspatercept in patients (pts) with low-intermediate risk MDS. Endpoints include long-term safety and tolerability, erythroid response (IWG HI-E), RBC transfusion independence (RBC-TI, ≥ 8 weeks), duration of HI-E, pharmacodynamic and iron metabolism biomarkers, and pt-reported QoL. Methods: Inclusion criteria included age ≥ 18 yr, Hgb < 10 g/dL (if < 4U RBC/8 weeks), ESA refractory or EPO > 500 U/L, no prior HMA, and no current lenalidomide or ESA. Luspatercept was administered SC every 3 wks for up to 5 doses in the base study (NCT01749514), including 7 dose escalation cohorts (n=27 total, 0.125 to 1.75 mg/kg) and an expansion cohort (n=31, starting dose 1.0 mg/kg, max 1.75 mg/kg). A 2-year extension study (n=32) is ongoing (NCT02268383). Results: Data (as of 4 Mar 2016) were available for the 32 extension study pts. Of these, 13 pts received < 4U RBC/8 weeks pretreatment (low transfusion burden, LTB) and 19 pts received ≥ 4U RBC/8 weeks (high transfusion burden, HTB). Median age was 72 yr (range 29-90 yr), 59% had prior ESA. Median Hgb for LTB pts was 8.5 g/dL (range 6.4-10.1 g/dL) and median RBC transfusion burden for HTB pts was 6 U/8 weeks (range 4-14 units). 91% pts were RS+ (≥ 15% RS in bone marrow). IWG HI-E was achieved in 11/13 (85%) LTB pts and 15/19 (79%) HTB pts. 11/22 (50%) pts with at least 2 units transfused in 8 weeks prior to dosing with luspatercept achieved RBC transfusion independence for at least 8 weeks. The range of transfusion independence was 9 to 80+ weeks, with most responders still receiving treatment. IWG HI-E response rates were 83% for RS+ pts, 90% for EPO < 200 U/L, 86% for EPO 200-500 U/L, and 50% for EPO > 500 U/L; 85% for ESA-naïve and 79% for those who had prior ESA treatment. RBC transfusion independence was achieved in 58% for EPO < 200 U/L, 50% for EPO 200-500 U/L, and 33% for EPO > 500 U/L. Luspatercept was well tolerated, with 3 related grade 3 adverse events of myalgia, worsening of general condition, and blast cell count increase. The most common related AEs (≥ 2 pts in both base and extension studies) were fatigue, bone pain, diarrhea, myalgia, headache, hypertension, and injection site erythema. Conclusions: Long-term treatment with luspatercept was well tolerated and led to erythroid response in 81% of low-intermediate risk MDS pts who enrolled into the extension study. A Phase 3 study of luspatercept in regularly-transfused RS+ patients with lower-risk MDS according to IPSS-R is ongoing (MEDALIST study; NCT02631070). Disclosures Platzbecker: Onconova, Teva, Celgene, Janssen, Novartis, Amgen: Honoraria, Research Funding. Donovan:Acceleron Pharma: Employment. Wilson:Acceleron Pharma: Employment, Equity Ownership. Zhang:Acceleron Pharma: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Attie:Acceleron Pharma: Employment, Equity Ownership. Giagounidis:Celgene Corporation: Consultancy.

Background: Luspatercept is a fusion protein (modified activin receptor IIB-IgG Fc) being investigated for the treatment of anemias with ineffective erythropoiesis. MDS patients have increased Smad2/3 signaling in the bone marrow, leading to ineffective erythropoiesis. Luspatercept inhibits Smad2/3 signaling and promotes late-stage erythroid differentiation, thereby correcting ineffective erythropoiesis. Aims: This completed, 3-month, phase 2, multicenter, open-label study evaluated the effects of luspatercept on anemia in patients with low/int-1 risk MDS (IPSS classification). Study outcomes include erythroid response of increased hemoglobin (Hb) in low transfusion burden (LTB) patients ( Methods: Inclusion criteria include age ≥ 18 yr, anemia defined as being HTB or LTB with Hb 500 U/L or nonresponsive/refractory to ESAs, no prior azacitidine or decitabine, and no current treatment with ESA, G-CSF, GM-CSF, or lenalidomide. Luspatercept was administered once every 3 weeks by SC injection in sequential cohorts (n=3-6 each) at dose levels ranging from 0.125 to 1.75 mg/kg for up to 5 doses with a 3-month follow-up. An expansion cohort with a starting dose level of 1.0 mg/kg was enrolled with individual patient dose titration allowed. Patients completing this study were eligible to enroll into the PACE-MDS extension study. Results: Enrollment is complete for 27 patients in the dose escalation cohorts and 31 patients in the expansion cohort (total n=58). Preliminary safety and efficacy data (as of 17-Apr-2015) were available for 49 patients (22 female/27 male, 17 LTB/32 HTB). Final 3-month data for all 58 patients will be presented. Median age was 71 years, 61% had prior ESA therapy, and 18% had prior lenalidomide. Forty (83%) patients had ≥15% ring sideroblasts (RS+) in the bone marrow. The median baseline Hb for LTB patients was 8.7 g/dL (range 6.8-10.1 g/dL). The median number of RBC units transfused over 8 weeks prior to treatment for HTB patients was 6 units (range 4-14 units). Luspatercept was generally well-tolerated. In patients (n=40) receiving 0.75-1.75 mg/kg, 48% of patients responded per IWG HI-E (Hb increase ≥1.5 g/dL for LTB patients or reduction of ≥ 4 RBC units/8 weeks for HTB patients). Higher response rates were observed in RS+ patients, including patients with EPO ≥ 200 U/L; patients with splicing factor (SF) mutations present (primarily SF3B1) had 60% response rate (see Table). Of the patients who received RBC transfusions prior to luspatercept treatment (range 2-14 units/8 weeks), 11 of 30 (37%) patients were transfusion-free for ≥8 weeks during the 12 week treatment period. Neutrophil responses (IWG HI-N) were seen in 4 of 8 (50%) patients with baseline neutrophil count The relationship of erythroid response to bone marrow erythroid cellularity, morphology and characteristics, comprehensive gene mutation profile, GDF15, and other biomarkers of ineffective erythropoiesis will be presented. Conclusions: Based on these data, treatment with luspatercept in lower risk MDS patients at therapeutic dose levels for 3 months led to a high response rate for increased Hb levels or decreased transfusion burden, including transfusion independence, with a favorable safety profile. Ring sideroblasts, splicing factor gene mutations and other biomarkers of ineffective erythropoiesis may help define a MDS population most likely to respond to luspatercept treatment. Phase 3 studies in patients with anemia due to lower risk MDS are planned. Disclosures Platzbecker: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Boehringer: Research Funding. Ottmann:BMS: Honoraria, Research Funding; Novartis: Consultancy. Hankin:Acceleron: Employment. Wilson:Acceleron: Employment. Zhang:Acceleron: Employment. Laadem:Celgene Corporation: Employment. Sherman:Acceleron Pharma: Employment. Attie:Acceleron: Employment.

Introduction Anemia and bone disease are hallmarks of multiple myeloma (MM). Sotatercept (ACE-011) is a novel, first-in-class activin type IIA receptor fusion protein that binds with high affinity to activin A and GDF11, and it acts during late-stage erythropoiesis to increase the production of mature erythrocytes through a mechanism independent of erythropoietin. Sotatercept has shown promising activity in clinical trials for anemia in myelodysplastic syndromes (Komrokji et al., ASH 2014) and in thalassemia (Cappellini et al., EHA 2015). Additionally, we have shown that targeting activin A through an analog of sotatercept reverses osteoblast inhibition and improves MM bone disease in a mouse model (Vallet et al., PNAS 2010). Lenalidomide increases activin A secretion with consequent inhibition of osteoblastogeneis, and this can be abrogated by treatment with an activin A neutralizing antibody (Scullen et al., Leukemia 2013). Sotatercept has been previously studied with melphalan, prednisolone, and thalidomide in MM (Abdulkadyrov et al., Br J Haematol 2014). Based on these findings, we evaluated sotatercept in combination with lenalidomide and dexamethasone in MM (NCT01562405). Methods Patient with relapsed and/or refractory MM with at least one prior line of therapy, anemia with hemoglobin Results Thirteen patients with a median age of 62 years (range 49-77) and a median of 2 prior lines (range 1-5) of therapy have been enrolled to date (July 31, 2015). Median duration of treatment is 8.1 months (range 0.5, 27 months); five patients continue on study. The MTD has not been reached, and the current dosing level is sotatercept 45 mg with lenalidomide 25 mg. Grade 3-4 adverse events included anemia (38%), diarrhea (15%), fatigue (15%), hypophosphatemia (15%), and thrombocytopenia (38%). Grade 3 hypertension occurred in one patient receiving sotatercept 15 mg (hemoglobin at the time, 11.5 g/dL). There was one death on study that was unrelated to treatment. In patients who completed at least two cycles of treatment, there was a significant mean increase in hemoglobin on study of 0.94 g/dL (N = 10, p = 0.0048) from a mean starting hemoglobin 10.27 g/dL (range 8.6, 12.2). Mean maximal increase in hemoglobin was 2.11 g/dL (range 1.1, 4). Bone density by DEXA was assessed after four cycles. In patients who received a cumulative dose of sotatercept over 45 mg (N = 6), total lumbar spine BMD increased by a mean of 2.0% after four cycles; 83% had increase in BMD. ORR for this combination was 60% (CR = 1, VGPR = 1, PR = 4, SD = 4) in patients evaluable for response. Conclusion Sotatercept in combination with lenalidomide and dexamethasone is well tolerated with expected toxicities related to lenalidomide in MM. Preliminary data from this ongoing study suggest that sotatercept leads to early increases in both hemoglobin and bone mineral density, and it is the first agent that may address both of these significant causes of morbidity in MM. Disclosures Laubach: Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Nooka:Onyx Pharmaceuticals: Consultancy; Spectrum Pharmaceuticals: Consultancy. O'Donnell:Millennium: Consultancy. Puccio-Pick:Celgene Corp.: Employment. Laadem:Celgene Corporation: Employment. Sherman:Acceleron Pharma: Employment. Raje:Acetylon: Research Funding; AstraZeneca: Research Funding; Onyx: Consultancy; Takeda: Consultancy; Eli Lilly: Research Funding; Millenium: Consultancy; Novartis: Consultancy; Amgen: Consultancy; BMS: Consultancy; Celgene Corporation: Consultancy.

Introduction: Anemia, a hallmark of MDS, is challenging to treat, particularly after failure of erythropoiesis-stimulating agents (ESAs). Sotatercept (ACE-011) is a novel and first-in-class activin type IIA receptor fusion protein that acts on late-stage erythropoiesis to increase mature erythrocyte release into the circulation (Carrancio et al. Br J Haematol 2014;165:870-82). Treatment with sotatercept stimulated erythropoiesis and significantly increased hemoglobin (Hb) levels in healthy volunteers (Sherman et al. J Clin Pharmacol 2013;53:1121-30), supporting its clinical development for the treatment of anemia in patients (pts) with lower-risk MDS. Methods: The primary objective of this phase 2, open-label, dose-finding study is to determine a safe, tolerable, and effective dose of sotatercept resulting in erythroid hematological improvement (HI-E; modified IWG 2006 criteria) in pts with anemia and IPSS-defined Low or Int-1-risk MDS or non-proliferative CMML (white blood cells < 13,000/µL). Secondary objectives include rate of RBC-transfusion independence (RBC-TI) ≥ 8 weeks. Eligible pts had anemia (≥ 2 RBC units transfusion requirement in the 12 weeks prior to enrollment for Hb ≤ 9.0 g/dL) with no response, loss of response, or low chance of response to ESAs (serum erythropoietin [EPO] > 500 mIU/mL). Pts received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks. ClinicalTrials.gov identifier: NCT01736683. Results: As of May 22, 2014, a total of 54 MDS pts were enrolled: 7, 6, 21, and 20 in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Median age was 71 years (range 56–86) and median time from diagnosis was 4 years (range 0–31); most pts were male (70%). Pts received a median of 6 RBC units (range 0–18) in the 8 weeks prior to treatment start. Forty-five pts (83%) received ≥ 4 RBC units in the 8 weeks prior to treatment start (high transfusion burden; HTB), and 9 pts (17%) received < 4 units in the 8 weeks prior to treatment start (low transfusion burden; LTB). Nineteen pts (35%) had IPSS Low and 34 pts (63%) had IPSS Int-1-risk MDS; IPSS risk data were missing for 1 pt. Fifty-one pts (94%) had prior treatment with ESAs, 30 (56%) with hypomethylating agents, 26 (48%) with lenalidomide, and 26 (48%) with other MDS treatments; 15 pts (28%) had serum EPO > 500 mIU/mL. Of the 53 pts evaluable for efficacy, HI-E was observed in 21 pts (40%) overall: 0, 4 (67%), 8 (40%), and 9 pts (45%) in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Nineteen of 44 HTB pts responded with a ≥ 4 RBC units/8 weeks transfusion burden reduction; duration of transfusion response appeared to be dose-dependent. Five HTB pts achieved RBC-TI ≥ 8 weeks, with RBC-TI duration ranging from 59–345+ days. Eight of 9 LTB pts showed Hb increases, not influenced by transfusion, ranging from 1.3–3.8 g/dL. Of these, 2 pts had a Hb increase ≥ 1.5 g/dL sustained for ≥ 8 weeks. Pts with Hb > 11.0 g/dL were subject to dose delay per protocol, which may have impacted Hb increase sustainability. RBC-TI ≥ 8 weeks was achieved in 6 LTB pts. Increases in platelet and neutrophil levels were seen in pts with baseline thrombocytopenia and pts with baseline neutropenia, respectively. Sotatercept was generally well tolerated. Twenty pts (37%) reported ≥ 1 suspected treatment-related adverse event (AE); fatigue (11%), headache (9.3%), decreased appetite (7.4%), and nausea (7.4%) were the most common. Of 35 pts (65%) who discontinued treatment, 28 discontinued due to lack of therapeutic effect and 4 due to AEs. Of those AEs leading to discontinuation, 3 were suspected to be treatment-related: 1 pt with grade 2 hemolytic anemia, 1 pt with grade 3 hypertension, and 1 pt with grade 2 muscular weakness in the sotatercept 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Other reasons for discontinuation were withdrawal of consent (n = 2; 4%) and pt decision (n = 1; 2%). Conclusions: Sotatercept was well tolerated in lower-risk MDS pts at the dose levels tested, with promising evidence of clinical activity in this largely HTB cohort of ESA-refractory, anemic, lower-risk MDS pts. Further exploration of higher sotatercept dose levels and longer-term treatment is planned. PF and AFL contributed equally to this abstract as senior co-authors. Disclosures Komrokji: Celgene Corporation: Consultancy, Research Funding. Off Label Use: Sotatercept (ACE-011) is an investigational agent that is being assessed for efficacy and safety in myelodysplastic syndromes.. Garcia-Manero:Celgene Corporation: Research Funding. Ades:Novartis: Research Funding; Celgene Corporation: Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Vo:Celgene Corporation: Employment. Prebet:Celgene Corporation: Honoraria. Boyd:US Oncology: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corporation: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corporation: Membership on an entity's Board of Directors or advisory committees. Beyne-Rauzy:Novartis: Research Funding; Celgene: Research Funding. Zou:Celgene: Employment. Attie:Acceleron Pharma: Employment. Sherman:Acceleron Pharma: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding. List:Celgene: Consultancy.