Abstract: Introduction: Regular red blood cell (RBC) transfusions are the main supportive treatment for chronic anemia due to β-thalassemia. Transfusion-dependent pts require ICT to prevent iron overload from RBC transfusions, and associated complications. Thus, there is a clinical need to reduce transfusions and iron burden in pts with anemia due to β-thalassemia. Luspatercept, an erythroid maturation agent, is approved by the FDA for treatment of anemia in adult pts with β-thalassemia who require regular RBC transfusions. The phase 3, double-blind, randomized, placebo (PBO)-controlled BELIEVE study is evaluating the efficacy and safety of luspatercept in adult pts with β-thalassemia requiring regular RBC transfusions (NCT02604433; Cappellini MD, et al. N Engl J Med 2020;382:1219-31). Here we assess the effect of long-term luspatercept use on iron loading and ICT use in the BELIEVE trial. Methods: Pts were ≥ 18 years with β-thalassemia or hemoglobin (Hb) E/β-thalassemia (compound β-thalassemia mutation and/or multiplication of α-globin genes was allowed) and required regular RBC transfusions (defined as 6-20 RBC units in the 24 wks prior to randomization with no transfusion-free period & gt; 35 days). Pts were randomized 2:1 to luspatercept 1.0 mg/kg (up to 1.25 mg/kg allowed) or PBO subcutaneously every 3 wks for ≥ 48 wks. Pts in both treatment arms continued to receive RBC transfusions to maintain target pretransfusion Hb levels, as well as ICT (deferasirox, deferoxamine, and deferiprone alone or in combination) per product label and physician practice prior to randomization. After study unblinding, pts randomized to PBO were eligible to cross over to luspatercept in an open-label phase. Risk for iron overload-related complications was evaluated by stratifying pts into categories based on serum ferritin (SF) level ( & lt; 1,000 μg/L, 1,000 to & lt; 2,500 μg/L, ≥ 2,500 μg/L), liver iron concentration (LIC; ≤ 3 mg/g dw, & gt; 3 mg/g dw), and myocardial iron (by T2* MRI; ≤ 20 ms, & gt; 20 ms). Long-term changes in SF and ICT use were assessed in luspatercept pts remaining on treatment up to data cutoff (July 1, 2019) or study discontinuation, whichever was earlier. Results: Of 336 pts enrolled, 224 were randomized to luspatercept and 112 to PBO. Mean baseline SF, LIC, and myocardial T2* for luspatercept vs PBO arms were 2,097 vs 1,845 μg/L, 12.0 vs 10.1 mg/g dw, and 33.5 vs 34.8 ms, respectively. Overall, 97.3% of pts received ICT at baseline. As of July 1, 2019, 67.9% of pts initially randomized to luspatercept were still receiving treatment at the end of 2 years; 92 (82.1%) PBO pts crossed over to luspatercept after study unblinding. Of 141 luspatercept-treated pts with baseline mean SF ≥ 1,000 μg/L, 24 (17.0%) pts achieved post-baseline mean SF & lt; 1,000 μg/L when assessed over Wks 1−24, vs 3 (5.0%) PBO-treated pts. During Wks 73−96, 26/56 (46.4%) luspatercept pts with baseline mean SF ≥ 1,000 μg/L achieved post-baseline mean SF & lt; 1,000 μg/L (Figure A). At Wks 24 and 48, 5/120 (4.2%) and 13/134 (9.7%) luspatercept pts, respectively, shifted from LIC & gt; 3 mg/g dw at baseline to ≤ 3 mg/g dw, vs 4/61 (6.6%) and 4/68 (5.9%) PBO pts; 15/105 (14.3%) of luspatercept pts shifted from LIC & gt; 3 mg/g dw at baseline to ≤ 3 mg/g dw at Wk 96. 6/30 (20.0%) pts receiving luspatercept shifted from myocardial iron T2* ≤ 20 ms at baseline to & gt; 20 ms at Wk 48 (vs 1/11 [9.1%] PBO pts); at Wk 96, 6/24 (25.0%) luspatercept-treated pts shifted from ≤ 20 ms to & gt; 20 ms. During Wks 1-12, mean daily deferasirox dose in luspatercept pts was 1,477.08 mg (mean change from baseline +136.27 mg) and 1,516.28 mg (mean change from baseline +131.80 mg) in PBO pts. No significant difference was seen between luspatercept and PBO arms during the first 48 weeks, however, the proportion of patients receiving ≥ 1 ICT gradually declined in both luspatercept responders (defined as pts achieving ≥ 33% reduction in transfusion burden from baseline during Wks 13−24) and non-responders over time (Figure B). Both luspatercept responders and non-responders also experienced a gradual decrease in mean daily dose of deferasirox over time (Figure C). Conclusions: Compared with PBO-treated pts, a higher proportion of luspatercept-treated pts shifted to lower SF, LIC, and myocardial iron levels during the first 48 wks, indicative of lower risk of iron overload complications. Long-term luspatercept treatment led to an increasing proportion of patients with SF & lt; 1,000 μg/L and decreasing trends of overall ICT use and deferasirox dosage. Figure 1 Disclosures Hermine: Celgene BMS: Consultancy, Research Funding; AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; Alexion: Research Funding; Roche: Consultancy; Novartis: Research Funding. Cappellini:CRISPR Therapeutics, Novartis, Vifor Pharma: 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; BMS: Honoraria. Taher:Novartis Pharmaceuticals: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ionis Pharmaceuticals: Consultancy; Vifor Pharma: Consultancy, Research Funding; Silence Therapeutics: Consultancy. Coates:Sangamo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios pharma: Consultancy, Honoraria; Celgene, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; apo pharma (Chiesi Pharma): Consultancy, Honoraria; Vifor Pharma: Consultancy, Honoraria. Viprakasit:BMS, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios Pharmaceuticals, Ionis Pharmaceuticals, La Jolla Pharmaceuticals, Protagonist Therapeutics, Vifor Pharma: Consultancy, Research Funding. Voskaridou:ADDMEDICA Company: Consultancy, Research Funding; NOVARTIS Company: Research Funding; GENESIS Company: Consultancy, Research Funding; PROTAGONIST Company: Research Funding; ACCELERON Company: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Lal:Chiesi USA: Consultancy; Novartis: Research Funding; Celgene, BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; La Jolla Pharmaceutical Company: Research Funding; bluebird bio, Inc.: Research Funding; Insight Magnetics: Research Funding; Terumo Corporation: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharmaceuticals: Consultancy. Perrotta:Acceleron Pharma: Research Funding; Celgene, BMS: Honoraria; Novartis: Honoraria, Research Funding. Kattamis:Genesis Pharma SA: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apopharma/Chiesi: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ionis: Membership on an entity's Board of Directors or advisory committees; Vertex: Membership on an entity's Board of Directors or advisory committees; Vifor: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy. Shetty:BMS: Current Employment, Current equity holder in publicly-traded company. Zhang:BMS: Current Employment. Tian:BMS: Current Employment. Miteva:BMS: Current Employment. Zinger:Celgene International, A Bristol-Myers Squibb Company: Current Employment. Tang:BMS: Current Employment, Current equity holder in publicly-traded company. Backstrom:BMS: Current equity holder in publicly-traded company; Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company. Porter:Agios Pharmaceuticals: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Protagonist Therapeutics: Honoraria; Silence Therapeutics: Honoraria; La Jolla Pharmaceuticals: Honoraria; Vifor Pharmaceuticals: Honoraria; bluebird bio, Inc.: Consultancy, Honoraria.

Abstract: Patients with transfusion‐dependent (TD) β‐thalassemia require long‐term red blood cell transfusions (RBCTs) that lead to iron overload, impacting health‐related quality of life (HRQoL). Methods The impact of luspatercept, a first‐in‐class erythroid maturation agent, versus placebo on HRQoL of patients with TD β‐thalassemia was evaluated in the phase 3 BELIEVE trial. HRQoL was assessed at baseline and every 12 weeks using the 36‐item Short Form Health Survey (SF‐36) and Transfusion‐dependent Quality of Life questionnaire (TranQol). Mean change in HRQoL was evaluated from baseline to week 48 for patients receiving luspatercept + best supportive care (BSC) and placebo + BSC and between luspatercept responders and non‐responders. Results Through week 48, for both groups, mean scores on SF‐36 and TranQol domains were stable over time and did not have a clinically meaningful change. At week 48, more patients who achieved clinical response (≥50% reduction in RBCT burden over 24 weeks) in the luspatercept + BSC group had improvement in SF‐36 Physical Function compared with placebo + BSC (27.1% vs. 11.5%; p  = .019). Conclusions Luspatercept + BSC reduced transfusion burden while maintaining patients' HRQoL. HRQoL domain improvements from baseline through 48 weeks were also enhanced for luspatercept responders.

Abstract: Introduction: Patients (pts) with transfusion-dependent (TD) β-thalassemia may require long-term red blood cell transfusions (RBCT) that can lead to iron overload and associated complications, which impact negatively on health-related quality of life (HRQoL). Administration of RBCT provides transient relief from anemia-related symptoms associated with β-thalassemia; reduction of RBCT may increase anemia-related symptoms and thereby worsen HRQoL. The phase 3 BELIEVE study (NCT02604433) showed that the first-in-class erythroid maturation agent luspatercept provided clinically meaningful reduction in RBCT burden, but the impact of luspatercept on HRQoL is not well understood. This analysis assessed the effect of luspatercept plus best supportive care (BSC, including RBCT, iron chelation therapy) vs placebo (PBO) plus BSC on HRQoL in pts with TD β-thalassemia. Methods: Pts received luspatercept (starting dose 1.0 mg/kg with titration up to 1.25 mg/kg every 3 weeks) or PBO, subcutaneously for ≥ 48 weeks plus BSC. HRQoL was assessed using the generic 36-item Short Form Health Survey (SF-36) and the thalassemia-specific Transfusion-dependent Quality of Life questionnaire (TranQol), at screening (≤ 4 weeks prior to first study dose) and every 12 weeks up to 48 weeks of treatment. The HRQoL evaluable population included all pts who completed the HRQoL assessment at screening and ≥ 1 post-screening assessment visit. The TranQol and SF-36 were considered complete if ≥ 75% and ≥ 50% of items, respectively, were answered at a given time point. The primary analysis assessed changes from baseline between groups up to Week 48. The primary domains of interest were: TranQol total score and Physical Health (PH); and the SF-36 Physical Component Summary (PCS), Physical Functioning (PF), and General Health (GH). Other domains were considered exploratory domains. Changes from baseline were compared using ANCOVA models adjusting for baseline domain scores and geographic region. In exploratory analyses, the proportion of pts achieving a clinically meaningful improvement in domain scores were compared between pts on luspatercept achieving a clinical response (≥ 50% reduction in RBCT burden over 12 weeks; ≥ 33% reduction in RBCT burden over 12 weeks; transfusion independence [TI] any 8 weeks; or TI any 12 weeks), and PBO. Results: 336 pts were randomized to treatment; 224 to luspatercept and 112 to PBO. The HRQoL evaluable population was 212 (94.6%) in the luspatercept arm and 104 (92.9%) in the PBO arm. HRQoL questionnaire compliance rates among pts still on treatment were & gt; 87.5% for both questionnaires at Week 48. Baseline HRQoL scores were similar to the US general population for most SF-36 domains, although GH, Role-Emotional, and Role-Physical domain scores were impaired in the BELIEVE population. Mean scores on all primary and exploratory domains were stable over time in both treatment groups and did not differ between treatment groups at Week 24 and 48. When considering responders to luspatercept, pts receiving luspatercept and achieving a ≥ 50% reduction in RBCT burden over 12 weeks were significantly more likely than pts receiving PBO to have a clinically meaningful improvement in PCS (31.1% vs 16.5%; P = 0.024), and PF (30.0% vs 13.2%; P = 0.007) at Week 48 (Table). Statistically significant differences between luspatercept and PBO were also seen among pts achieving TI for any 8 or any 12 weeks for some SF-36 domains, but no statistical difference was seen in pts achieving a ≥ 33% reduction in RBCT burden for either SF-36 or TranQol domains although the proportion of pts with improved scores was higher with luspatercept, especially at Week 48. Conclusions: Overall, the addition of luspatercept to BSC reduced transfusion burden while sustaining TranQol and SF-36 HRQoL scores over time through Week 48 compared with those receiving PBO. Pts with TD β-thalassemia responding to luspatercept were more likely to achieve clinically meaningful improvements in HRQoL compared with PBO. Disclosures Cappellini: Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics, Novartis, Vifor Pharma: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Taher:Silence Therapeutics: Consultancy; Vifor Pharma: Consultancy, Research Funding; Ionis Pharmaceuticals: Consultancy; BMS: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding. Piga:BMS: Research Funding; Novartis: Research Funding. Shah:Novartis, BMS: Consultancy, Honoraria, Speakers Bureau; Bluebird Bio: Consultancy, Honoraria; IQVIA: Consultancy, Membership on an entity's Board of Directors or advisory committees. Voskaridou:ADDMEDICA Company: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ACCELERON Company: Consultancy, Research Funding; PROTAGONIST Company: Research Funding; GENESIS Company: Consultancy, Research Funding; NOVARTIS Company: Research Funding. Viprakasit:Agios Pharmaceuticals, Ionis Pharmaceuticals, La Jolla Pharmaceuticals, Protagonist Therapeutics, Vifor Pharma: Consultancy, Research Funding; BMS, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Porter:Silence Therapeutics: Honoraria; La Jolla Pharmaceuticals: Honoraria; Vifor Pharmaceuticals: Honoraria; Protagonist Therapeutics: Honoraria; BMS: Consultancy, Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria. Hermine:AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; BMS, Alexion, Novartis, Inatherys: Research Funding. Neufeld:Takeda: Consultancy; Octapharma: Consultancy; Novo Nordsik: Consultancy; genetech: Consultancy; Bayer: Other: DSMB; Imara Pharma: Other: DSMB service; ApoPharma/Chiezi: Other: DSMB service; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Acceleron Pharma: Consultancy, Other: DSMB. Thompson:BMS: Consultancy, Research Funding; Baxalta: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CRISPR/Vertex: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Biomarin: Research Funding. Tang:BMS: Current Employment, Current equity holder in publicly-traded company. Yu:Evidera: Current Employment. Guo:BMS: Consultancy. Shetty:BMS: Current Employment, Current equity holder in publicly-traded company. Miteva:BMS: Current Employment. Zinger:Celgene, a Bristol Myers Squibb company: Current Employment. Backstrom:Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company; BMS: Current equity holder in publicly-traded company. Oliva:Abbvie: Consultancy; Amgen: Consultancy; Novartis: Consultancy; BMS: Consultancy, Honoraria, Patents & Royalties, Speakers Bureau; Alexion: Consultancy; Apellis: Consultancy.

Abstract: 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.

Abstract: Introduction: Patients (pts) with non-transfusion-dependent β-thalassemia (NTDT) suffer from chronic anemia due to ineffective erythropoiesis. Low hemoglobin (Hb) levels in pts with anemia are associated with development of clinical complications and poor quality of life (QoL). There are no approved treatments for NTDT-associated anemia. Luspatercept has been shown to increase Hb levels in pts with NTDT in the BEYOND study (Taher AT, et al. HemaSphere 2021;5[Suppl 2];Abstract S101). This Hb increase was correlated with improvement in the NTDT Patient-Reported Outcomes (NTDT-PRO) Tiredness/Weakness (T/W) domain. Here we report the effect of luspatercept on red blood cell transfusion (RBCT) burden and QoL outcomes in pts with NTDT in the BEYOND study. Methods: Eligible pts with Hb ≤ 10 g/dL were randomized to luspatercept (1.0-1.25 mg/kg) or placebo (PBO) subcutaneously for ≥ 48 weeks (wk). The disease-specific instrument NTDT-PRO, measuring chronic anemia symptoms in pts with NTDT, was administered to pts as a daily diary starting on the 7 days prior to Dose 1, Day 1, until wk 24, and thereafter over the 7 days prior to dosing at every other dosing visit. The 36-item Short Form Health Survey Version 2 (SF-36 v2) and Functional Assessment of Chronic Illness Therapy-Fatigue, Fatigue subscale (FACIT-F FS) were completed by the pts at screening and at every other dosing visit thereafter starting with day 1, dose 1. Mean change from baseline in NTDT-PRO T/W and Shortness of Breath (SoB) domain scores and in FACIT-F FS score over a continuous 12-wk interval during wk 13 to 24 and wk 37 to 48 was assessed using analysis of covariance (ANCOVA) with treatment group and other relevant covariates in the model. The SF-36 v2 physical component summary (PCS) and mental component summary (MCS) mean change from baseline at wk 24 and wk 48 were analyzed using a mixed-effect repeated measures model with intercept and time as the random effect. The model included change from baseline scores up to wk 48 as the outcome, treatment group assignment, time, baseline scores, randomization stratification factor(s), time-by-baseline score, and time-by-treatment group assignment terms. Descriptive statistics were used to ascertain the number of RBC units, RBCT events, reason for RBCT, and time to first RBCT event. Results: Of 145 pts, 96 were randomized to luspatercept and 49 to PBO. NTDT-PRO analyses were conducted in the intention-to-treat population. The QoL-evaluable populations for FACIT-F FS and SF-36 v2 analyses (luspatercept vs PBO) were: 94 vs 47 and 92 vs 46 pts, respectively. Baseline domain scores of the QoL measures were comparable between the 2 treatment arms. Mean change from baseline (least squares mean [LSM]) in NTDT-PRO T/W domain score (wk 13-24) was −0.68 vs −0.20 for luspatercept vs PBO, respectively (LSM difference [LSMD] −0.48; 95% confidence interval [CI] −1.03 to 0.08; P = 0.0924). Improvement was more pronounced in the luspatercept arm during wk 37-48 (Table). Within the NTDT-PRO SoB domain, mean change from baseline (wk 13-24) was −0.46 vs 0.02 for luspatercept vs PBO, respectively (LSMD −0.49; 95% CI −1.02 to 0.04; P = 0.0721) and during wk 37-48 was −0.59 vs 0.47 for luspatercept vs PBO, respectively (LSMD −1.07; 95% CI −1.80 to −0.33; P = 0.0047) (Table). Favorable QoL improvements were also observed in the luspatercept arm vs PBO and increased over time for both FACIT-F FS and SF-36 v2 assessments (Table). During wk 1-48, 79/96 (82.3%) luspatercept vs 22/49 (44.9%) PBO pts were RBCT-free (P & lt; 0.0001); 5/13 (38.5%) and 1/7 (14.3%) pts treated with luspatercept and PBO, respectively, who received RBCTs at baseline, became RBCT-free during wk 1-48. Among all pts who received RBCTs during wk 1-48, pts receiving luspatercept required fewer RBCTs compared with pts receiving PBO (median 1.0 RBCTs [range 1.0-6.0] vs 2.0 [1.0-7.0] , respectively), and fewer RBC units (median 2.0 units [range 1.0-8.0] vs 2.5 [1.0-13.0] , respectively). Time to first RBCT (median [range] days) was longer for pts receiving luspatercept vs PBO (336 [2.0-336.0] vs 260.0 [9.0-336.0], respectively) and, in both arms, the main reasons for receiving RBCTs were anemia and surgery. Conclusions: In pts with NTDT, luspatercept improved RBCT burden and QoL compared with PBO. The improvement was more pronounced over time and consistent across 3 QoL-measuring instruments. Most pts receiving luspatercept remained RBCT-free during wk 1-48 of treatment. Figure 1 Figure 1. Disclosures Kattamis: Novartis: Consultancy, Honoraria, Research Funding; Chiesi: Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; CRISPR/Vertex: Consultancy, Honoraria; VIFOR: Consultancy; IONIS: Consultancy; Agios Pharmaceuticals: Consultancy; Amgen: Consultancy. Viprakasit: Ionis Pharmaceuticals,: Consultancy, Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; La Jolla Pharmaceuticals: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Vifor Pharma: Consultancy, Research Funding. Cappellini: IONIS Pharmaceuticals: Consultancy; Protagonist Therapeutics: Research Funding; La Jolla: Research Funding; Vifor: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CRISPR Therapeutics: Research Funding. Voskaridou: NOVARTIS: Research Funding; IMARA: Research Funding; BMS: Consultancy, Research Funding; GENESIS: Consultancy, Research Funding; PROTAGONIST: Research Funding; ADDMEDICA: Consultancy, Research Funding. Piga: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron: Research Funding. Porter: Celgene (BMS): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria; Protagonism: Honoraria; La Jolla Pharmaceuticals: Honoraria. Coates: UpToDate: Patents & Royalties; Sangamo: Consultancy; Forma Pharma: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Apo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chiesi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vifor Pharma: Consultancy. Forni: Bluebirdbio: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Shetty: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Miteva: BMS: Current Employment. Esposito: Bristol Myers Squibb: Current Employment. Kuo: Bristol Myers Squibb: Current Employment. Guo: Gilead: Consultancy; Janssen: Consultancy; UCB: Consultancy; Daiichi Sankyo: Consultancy; EMD Serono: Consultancy; Bristol Myers Squibb: Consultancy; Evidera: Current Employment. Pelligra: Evidera: Current Employment; Bristol Myers Squibb: Research Funding. Lord-Bessen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Yucel: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Taher: Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Vifor Pharma: Consultancy, Research Funding; Agios Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy, Research Funding.

Abstract: 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.

Abstract: 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 & gt; 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 & gt; 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.

Abstract: Introduction: β-thalassemia is a genetic blood disorder characterized by ineffective erythropoiesis and anemia. Although RBC transfusions are a key supportive treatment for patients (pts) with anemia due to β-thalassemia, they may be associated with life-threatening complications including iron overload. Luspatercept, a first-in-class erythroid maturation agent, is approved by the FDA for the treatment of anemia in adult pts with β-thalassemia requiring regular RBC transfusions. Here we present a longitudinal analysis of the benefits of luspatercept on RBC transfusion burden (TB) in the BELIEVE trial, a phase 3, double-blind, randomized, placebo (PBO)-controlled study evaluating the efficacy and safety of luspatercept in adult pts with β-thalassemia requiring regular RBC transfusions (NCT02604433; Cappellini MD, et al. N Engl J Med 2020;382:1219-31). Methods: Pts were aged ≥ 18 y with β-thalassemia or hemoglobin (Hb) E/β-thalassemia (compound β-thalassemia mutation and/or multiplication of α-globin genes was allowed) and required regular RBC transfusions (6-20 RBC units in the 24 wks prior to randomization, no transfusion-free period & gt; 35 days). Pts were randomized 2:1 to luspatercept 1.0 mg/kg (up to 1.25 mg/kg allowed) or PBO subcutaneously every 3 wks for ≥ 48 wks. Pts in both treatment arms continued to receive best supportive care, including RBC transfusions to maintain target pretransfusion Hb levels and iron chelation therapy. After study unblinding, pts randomized to PBO were eligible to cross over to receive luspatercept in an open-label phase. Mean RBC units transfused and mean change in RBC TB and number of visits were assessed in luspatercept (by primary endpoint responders and non-responders) and PBO arms during the first 48 wks. Long-term changes in RBC TB and visits in luspatercept pts remaining on treatment were assessed every 24 wks from treatment initiation to data cutoff (July 1, 2019). Results: Of 336 pts enrolled, 224 were randomized to the luspatercept arm and 112 to PBO. During the 24 wks prior to randomization, median RBC TB was 14.3 RBC units (range 6.0-26.0) and median pretransfusion Hb level was 9.27 g/dL (range 4.5-11.7). As of July 1, 2019, median treatment duration for pts in the luspatercept and PBO (prior to crossover) arms was 119.1 and 74.7 wks, respectively. 68.2% of pts initially randomized to the luspatercept arm were still receiving treatment at the end of 2 y. Pts in the luspatercept arm experienced a mean change of −2.20 RBC units/24 wks transfused vs +0.72 RBC units/24 wks in PBO-treated pts during Wks 1-24 compared to baseline (least squares [LS] mean difference −2.95; 95% confidence interval [CI] −3.59, −2.32; P & lt; 0.001) (Table A). In Wks 25-48, mean changes of −2.53 and +0.21 RBC units/24 wks transfused were reported in luspatercept- and PBO-treated pts, respectively (LS mean difference −2.76; 95% CI −3.46, −2.06; P & lt; 0.001). During Wks 1-24 and 25-48, luspatercept responders (defined as pts achieving ≥ 33% reduction in RBC TB during Wks 13-24, with a reduction of ≥ 2 RBC units, vs baseline) experienced mean transfusion reductions of −5.32 and −4.83 RBC units/24 wks, respectively, and luspatercept non-responders experienced mean changes of −1.30 and −1.85 RBC units/24 wks. Luspatercept-treated pts continued to experience durable, sustained reductions in RBC units up to 144 wks of follow-up (Table B). During Wks 1-24, luspatercept-treated pts experienced a mean change of −0.49 in transfusion event frequency vs +0.32 for PBO-treated pts (LS mean difference −0.78; 95% CI −1.16, −0.40; P & lt; 0.001) (Table A). Mean changes in transfusion visits of −0.54 and +0.14 were experienced by pts in the luspatercept and PBO arms, respectively, during Wks 25-48 (LS mean difference −0.65; 95% CI −1.03, −0.26; P = 0.001). Luspatercept responders and non-responders reported mean reductions in transfusion visits during Wks 1-24 (−1.38, P & lt; 0.001 and −0.23, P = 0.006, respectively) and Wks 25-48 (−1.09, P & lt; 0.001 and −0.38, P = 0.010, respectively) vs baseline. Sustained reductions in transfusion visits persisted for over 2 y; as the BELIEVE trial is still ongoing, only a small number of pts could be evaluated at later time points (Table B). Conclusions: Luspatercept was associated with sustained reductions in RBC transfusion units and visits in responders and non-responders during the first 48 wks vs PBO. Pts on luspatercept continued to experience reductions in RBC TB and events over 2 y. Figure 1 Disclosures Taher: BMS: Consultancy, Research Funding; Ionis Pharmaceuticals: Consultancy; Vifor Pharma: Consultancy, Research Funding; Silence Therapeutics: Consultancy; Novartis Pharmaceuticals: Consultancy, Research Funding. Viprakasit:Agios Pharmaceuticals, Ionis Pharmaceuticals, La Jolla Pharmaceuticals, Protagonist Therapeutics, Vifor Pharma: Consultancy, Research Funding; BMS, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hermine:Roche: Consultancy; Celgene BMS: Consultancy, Research Funding; AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; Alexion: Research Funding; Novartis: Research Funding. Porter:Protagonist Therapeutics: Honoraria; Vifor Pharmaceuticals: Honoraria; Silence Therapeutics: Honoraria; La Jolla Pharmaceuticals: Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria; BMS: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria. Piga:BMS: Research Funding; Novartis: Research Funding. Kuo:Pfizer: Consultancy, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Apellis: Consultancy; Bluebird Bio: Consultancy. Coates:Celgene, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sangamo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios pharma: Consultancy, Honoraria; apo pharma (Chiesi Pharma): Consultancy, Honoraria; Vifor Pharma: Consultancy, Honoraria. Voskaridou:ACCELERON Company: Consultancy, Research Funding; BMS: Consultancy, Research Funding; PROTAGONIST Company: Research Funding; ADDMEDICA Company: Consultancy, Research Funding; NOVARTIS Company: Research Funding; GENESIS Company: Consultancy, Research Funding. Kattamis:Agios: Consultancy; Ionis: Membership on an entity's Board of Directors or advisory committees; Vertex: Membership on an entity's Board of Directors or advisory committees; Vifor: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apopharma/Chiesi: Honoraria, Speakers Bureau; Genesis Pharma SA: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Shetty:BMS: Current Employment, Current equity holder in publicly-traded company. Zhang:BMS: Current Employment. Tian:BMS: Current Employment. Miteva:BMS: Current Employment. Zinger:Celgene International, A Bristol-Myers Squibb Company: Current Employment. Tang:BMS: Current Employment, Current equity holder in publicly-traded company. Backstrom:Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company; BMS: Current equity holder in publicly-traded company. Cappellini:BMS: Honoraria; CRISPR Therapeutics, Novartis, Vifor Pharma: 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.