Health-related quality of life outcomes in patients with myelodysplastic syndromes with ring sideroblasts treated with luspatercept in the MEDALIST phase 3 trial

Patients with myelodysplastic syndromes (MDS) often experience chronic anemia and long-term red blood cell transfusion dependence associated with significant burden on clinical and health-related quality of life (HRQoL) outcomes. In the MEDALIST trial (NCT02631070), luspatercept significantly reduced transfusion burden in patients with lower-risk MDS who had ring sideroblasts and were refractory to, intolerant to, or ineligible for prior treatment with erythropoiesis-stimulating agents. We evaluated the effect of luspatercept on HRQoL in patients enrolled in MEDALIST using the EORTC QLQ-C30 and the QOL-E questionnaire. Change in HRQoL was assessed every 6 weeks in patients receiving luspatercept with best supportive care (+ BSC) and placebo + BSC from baseline through week 25. No clinically meaningful within-group changes and between-group differences across all domains of the EORTC QLQ-C30 and QOL-E were observed. On one item of the QOL-E MDS-specific disturbances domain, patients treated with luspatercept reported marked improvements in their daily life owing to the reduced transfusion burden, relative to placebo. Taken together with previous reports of luspatercept + BSC reducing transfusion burden in patients from baseline through week 25 in MEDALIST, these results suggest luspatercept may offer a treatment option for patients that reduces transfusion burden while providing stability in HRQoL

Health-Related Quality of Life Outcomes in Patients with Myelodysplastic Syndromes with Ring Sideroblasts Treated with Luspatercept in the Medalist Study

Introduction: Patients with myelodysplastic syndromes (MDS) experience severe anemia, which is commonly managed with frequent red blood cell transfusions (RBCT) in patients refractory to erythropoiesis-stimulating agents. At diagnosis, 85% of patients have anemia and 30-50% depend on RBCT. The administration of RBCT itself provides transient relief in anemia-related symptoms. Per protocol, MEDALIST investigators were advised to transfuse for symptoms related to anemia at the investigators' discretion. Hence, cessation or reduction of RBCT may increase anemia-related symptoms and negatively impact health-related quality of life (HRQoL). Luspatercept is a first-in-class erythroid maturation agent providing clinically meaningful reduction in transfusion burden in patients with transfusion-dependent anemia due to Revised International Prognostic Scoring System (IPSS-R)-defined Very low-, Low-, or Intermediate-risk MDS with ring sideroblasts in the phase 3 MEDALIST trial (NCT02631070). However, the impact of luspatercept on patients' HRQoL has not been evaluated. This analysis aimed to evaluate the effect of luspatercept versus placebo on HRQoL of patients treated for MDS from baseline through Week 25 of the MEDALIST study. Methods: Patients received luspatercept or placebo every 3 weeks for 24 weeks, plus best supportive care (BSC), including tailored amounts of RBCT. Effects of luspatercept versus placebo on HRQoL were evaluated as secondary and exploratory endpoints in the MEDALIST study. In the primary analysis, mean change from baseline to Week 25 (clinical assessment visit) in the European Organisation for Research and Treatment of Cancer's core quality of life questionnaire, version 3.0 (EORTC QLQ-C30) and in the QoL assessment in MDS questionnaire (QOL-E) was determined using mixed-effects repeated measures analysis. Clinically meaningful change within each treatment arm was defined as a ≥ 10-point change in patient-reported outcome (PRO) score from baseline for all EORTC QLQ-C30 domains, and ≥ 0.5 standard deviation of the baseline domain score for all QOL-E domains. Differences between luspatercept and placebo were considered clinically meaningful if the change from baseline between treatment arms exceeded the threshold for a clinically meaningful difference. In an exploratory analysis, patient-reported impact of transfusion dependence and overall side effects on their daily life was estimated using the QOL-E instrument. Results: A total of 229 patients were randomized; 153 patients to luspatercept and 76 to placebo. The HRQoL-evaluable population, consisting of patients with ≥ 1 post-baseline HRQoL score, was 149 patients in the luspatercept arm and 76 patients in the placebo arm. Questionnaire compliance rates among patients remaining on treatment were similar between luspatercept and placebo treatment groups at Week 25 (EORTC QLQ-C30, 88.2% vs 79.4% and QOL-E, 72.5% vs 69.7%). At baseline, MEDALIST patients had a clinically meaningfully worse HRQoL compared with the general population in 5 of 15 EORTC QLQ-C30 domains: physical functioning, role functioning, social functioning, fatigue, and dyspnea. Through Week 25, there was no clinically meaningful difference in change from baseline between and within the luspatercept and placebo arms across all EORTC QLQ-C30 (Global health status shown in Figure A) and QOL-E domains. A greater proportion of patients in the luspatercept arm relative to placebo reported improvements in daily life from the impact of transfusion burden (Figure B). Relative to baseline, the proportion of patients reporting a lower impact of transfusion dependence on their daily life was 39% versus 22% in luspatercept versus placebo at Week 25; in contrast, the proportion of patients reporting a higher impact of transfusion dependence on their daily life was 12% versus 22% in luspatercept versus placebo. Impact of treatment side effects on patients was comparable between luspatercept and placebo. Conclusions: Luspatercept with BSC reduced RBCT burden and patient-reported transfusion impact on their daily life, while maintaining other aspects of HRQoL from baseline through Week 25 in the MEDALIST study. Disclosures Oliva: Alexion: Consultancy; BMS: Consultancy, Honoraria, Patents & Royalties, Speakers Bureau; Novartis: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Apellis: Consultancy. Platzbecker:Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria. Garcia-Manero:Bristol-Myers Squibb: Consultancy, Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; Novartis: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; H3 Biomedicine: Research Funding. Mufti:BMS, Novartis: Research Funding; Abbvie, Novartis: Consultancy. Santini:Takeda, Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Acceleron, BMS, Menarini, Novartis: Consultancy; BMS, J&J, Novartis: Honoraria. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Komrokji:BMS: Honoraria, Speakers Bureau; Acceleron: Honoraria; Geron: Honoraria; Agios: Honoraria, Speakers Bureau; AbbVie: Honoraria; JAZZ: Honoraria, Speakers Bureau; Incyte: Honoraria; Novartis: Honoraria. Shetty:BMS: Current Employment, Current equity holder in publicly-traded company. Tang:BMS: Current Employment, Current equity holder in publicly-traded company. Guo:BMS: Consultancy. Zhang:BMS: Current Employment. Ha:Bristol Myers Squibb: Current Employment. Ito:BMS: Current Employment, Current equity holder in publicly-traded company. Lord-Bessen:Bristol Myers Squibb: 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. Fenaux:Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding

Luspatercept for the treatment of anaemia in non-transfusion-dependent β-thalassaemia (BEYOND): a phase 2, randomised, double-blind, multicentre, placebo-controlled trial

Background In patients with non-transfusion-dependent beta-thalassaemia, haemoglobin concentrations lower than 10 g/dL are associated with a higher risk of morbidity, mortality, and impaired quality of life. No drugs are specifically approved for anaemia management in patients with non-transfusion-dependent beta-thalassaemia, other than transfusion therapy administered infrequently in accordance with patients' needs. We assessed the efficacy and safety of luspatercept versus placebo in patients with non-transfusion-dependent beta-thalassaemia.Methods We did a phase 2, randomised, double-blind, multicentre, placebo-controlled trial in 12 centres in six countries (Thailand [n=1], Lebanon [n=1], Greece [n=2], Italy [n=5], the UK [n=1], and the USA [n=2]). Eligible patients were aged 18 years or older, had confirmed diagnosis of beta-thalassaemia or haemoglobin E/beta-thalassaemia (concomitant a-globin deletion, mutation, or duplication were allowed), and a baseline haemoglobin concentration of 10.0 g/dL or lower. All patients were non-transfusion-dependent. Patients were randomly assigned (2:1) to luspatercept or placebo using an interactive response technology system and stratified by baseline haemoglobin concentration (>= 8.5 g/dL vs <8.5 g/dL) and baseline Non-Transfusion-Dependent beta-thalassaemia-Patient-Reported Outcome Tiredness/Weakness domain score (>= 3 vs <3). All patients, study site staff, and sponsor representatives (who reviewed the data), except for designated individuals, were masked to drug assignment until the time the study was unblinded. Luspatercept or placebo was given once subcutaneously every 3 weeks for 48 weeks in the double-blind treatment period. Luspatercept was started at 1.0 mg/kg with titration up to 1.25 mg/kg, or reduction in the event of toxicity or excessive haemoglobin concentration increase. The primary endpoint was achievement of an increase from baseline of 1.0 g/dL or higher in mean haemoglobin concentration over a continuous 12-week interval during weeks 13-24, in the absence of transfusions. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT03342404, and is ongoing.Findings Between Feb 5, 2018, and Oct 14, 2019, 160 patients were screened for eligiblity, of whom 145 were randomly assigned to luspatercept (n=96) or placebo (n=49). 82 (57%) patients were female and 63 (43%) were male. 44 (30%) patients were Asian, 87 (60%) were White, and 14 (10%) identified as another race. The study met its primary endpoint: 74 (77%) of 96 patients in the luspatercept group and none in the placebo group had an increase of at least 1.0 g/dL in haemoglobin concentration (common risk difference 77.1 [95% CI 68.7-85.5]; p<0.0001). The proportion of patients with serious adverse events was lower in the luspatercept group than in the placebo group (11 [12%] vs 12 [25%]). Treatment-emergent adverse events most commonly reported with luspatercept were bone pain (35 [37%]), headache (29 [30%]), and arthralgia (28 [29%]). No thromboembolic events or deaths were reported during the study.Interpretation Luspatercept represents a potential treatment for adult patients with non-transfusion-dependent beta-thalassaemia, for whom effective approved treatment options are scarce. Copyright (C) 2022 Published by Elsevier Ltd. All rights reserved

Longer-term benefit of luspatercept in transfusion-dependent lower-risk myelodysplastic syndromes with ring sideroblasts

Luspatercept is an approved therapy for selected patients with lower risk myelodysplasia requiring transfusion despite erythropoiesis-stimulating agents, based on the early results of a randomized trial against placebo. Zeidan and colleagues report that after a median of 26 months follow-up, 27% of patients commencing luspatercept were continuing therapy. Their updated analyses confirm that a significant minority (45%) of eligible patients can achieve transfusion independence, with a median durability of 30 weeks. These longer follow-up data better quantify the incremental benefit of luspatercept over placebo

Efficacy and Safety of Luspatercept Treatment in Patients with Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T): A Retrospective Analysis from the Medalist Study

Introduction: Patients (pts) with MDS/MPN-RS-T have limited treatment options for anemia due to ineffective erythropoiesis. Luspatercept, the first-in-class erythroid maturation agent that enhances late-stage erythropoiesis, is approved by the FDA for treatment of anemia in adult pts with lower-risk (LR) MDS with ring sideroblasts (RS) or MDS/MPN-RS-T after erythroid-stimulating agent (ESA) failure. In the randomized, double-blind, phase 3 MEDALIST study, luspatercept significantly reduced transfusion burden vs placebo in pts with LR-MDS (NCT02631070; Fenaux P, et al. N Engl J Med 2020;382:140-51). Here, we assess the efficacy and safety of luspatercept in pts with MDS/MPN-RS-T enrolled in the MEDALIST study. Methods: Eligible pts were ≥ 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS; 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, titration to 1.75 mg/kg) or placebo administered subcutaneously every 3 wks. The primary endpoint was achievement of RBC transfusion independence (RBC-TI) ≥ 8 wks during Wks 1-24. Results: A retrospective analysis identified 23/229 (10.0%) pts enrolled in the MEDALIST trial who had MDS/MPN-RS-T, per WHO 2016 criteria (Arber DA, et al. Blood 2016;127:2391-405); 14 received luspatercept and 9 received placebo. Pts in this subgroup received a median of 4.0 RBC units/8 wks (range 2.0-11.5) during the 16 wks prior to treatment. At baseline, pts had a median hemoglobin (Hb) level of 7.7 g/dL (range 7.0-9.0), a median leukocyte count of 5.1 × 109/L, a median platelet count of 447.0 × 109/L, and 18 (78.3%) pts had serum erythropoietin levels < 200 U/L (Table). In the luspatercept arm, 9/14 (64.3%) pts with MDS/MPN-RS-T achieved the primary endpoint of RBC-TI for ≥ 8 wks during Wks 1-24, compared with 2/9 pts (22.2%) receiving placebo (odds ratio 11.3; 95% confidence interval [CI] 1.19, 106.12; P = 0.028). Pts receiving luspatercept were significantly more likely to achieve clinical benefit (achieving RBC-TI ≥ 8 wks and/or modified hematologic improvement-erythroid [mHI-E] per IWG 2006 criteria [≥ 4 units/8 wks reduction in RBC transfusion in pts with ≥ 4 units/8 wks baseline RBC transfusion burden; Hb increase by ≥ 1.5 g/dL] during Wks 1-24 in pts with < 4 units/8 wks baseline RBC transfusion burden), compared with pts receiving placebo (78.6% vs 33.3%; P = 0.034). Median time from the start of clinical benefit response to end of treatment was 94.6 wks (range 8.0-150.0) in the luspatercept arm and 23.9 wks (range 23.7-57.9) in the placebo arm. During Wks 1-24, mHI-E was achieved by 10 luspatercept pts (6 were high transfusion burden [HTB; defined as baseline transfusion burden ≥ 4 units/8 wks] and 4 were low transfusion burden [LTB; defined as baseline transfusion burden < 4 units/8 wks]) and 1 placebo pt (1/5 HTB). RBC-TI ≥ 8 wks was achieved by 4/8 HTB pts receiving luspatercept (vs 0/5 placebo) and 5/6 LTB pts (vs 2/4 placebo). After 24 wks, pts in the luspatercept arm had a mean Hb increase of +1.7 g/dL compared with an increase of +0.9 g/dL in pts in the placebo arm (least squares [LS] mean difference +0.85 g/dL; 95% CI −1.13, +2.82). Greater reductions from baseline in mean serum ferritin levels were seen with luspatercept (−121.8 μg/L) compared with placebo (−91.9 μg/L) over Wks 9-24 (LS mean difference −90.1; 95% CI −758.4, 578.2). Pts in the luspatercept arm had median platelet counts of 467.5 × 109/L and median leukocyte counts of 6.5 × 109/L post 24 wks of treatment, compared with pts in the placebo arm with 514.0 × 109/L and 6.2 × 109/L, respectively. The incidence of specific TEAEs (occurring in ≥ 1 patient) are as follows: fatigue (1/14 [7.1%] luspatercept vs 1/9 [11.1%] placebo), dizziness (7/14 [50.0%] vs 0/9), dyspnea (3/14 [21.4%] vs 0/9), nausea (6/14 [42.9%] vs 2/9 [22.2%]), arthralgia (1/14 [7.1%] vs 0/9), diarrhea (6/14 [42.9%] vs 1/9 [11.1%]), and hypertension (3/14 [21.4%] vs 0/9). In the luspatercept arm, 1/14 (7.1%) pts experienced ≥ 1 thromboembolic event (transient ischemic attack) and 1/9 (11.1%) pts in the placebo arm progressed to AML (as of July 1, 2019). Conclusions: Luspatercept demonstrated clinical efficacy in pts with MDS/MPN-RS-T with a generally well-tolerated safety profile. These data support the clinical benefits of luspatercept in this patient population with otherwise limited treatment options. Disclosures Komrokji: Geron: Honoraria; Novartis: Honoraria; Incyte: Honoraria; JAZZ: Honoraria, Speakers Bureau; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau; Acceleron: Honoraria; BMS: Honoraria, Speakers Bureau. Platzbecker:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Fenaux:BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Garcia-Manero:Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; H3 Biomedicine: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Merck: Research Funding. Mufti:Abbvie, Novartis: Consultancy; BMS, Novartis: Research Funding. Santini:Janssen: Research Funding; BMS, J&J, Novartis: Honoraria; Acceleron, BMS, Menarini, Novartis: Consultancy; Takeda, Pfizer: Membership on an entity's Board of Directors or advisory committees. Diez-Campelo:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Finelli:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: 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. Jurcic:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Daiichi-Sankyo: 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; Arog Pharmaceuticals: Research Funding; Astellas: Research Funding; Forma Therapeutics: Research Funding; Genentech: Research Funding; Kura Oncology: Research Funding; PTC Therapeutics: Research Funding. Greenberg:BMS: Research Funding; Aprea: Research Funding; Notable Labs: Research Funding; H3 Biotech: Research Funding. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zeidan:Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Trovagene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Leukemia and Lymphoma Society: Other; CCITLA: Other; Astex: Research Funding; MedImmune/Astrazeneca: Research Funding; Ionis: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding; Taiho: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Cardiff Oncology: Consultancy, Honoraria, Other; Agios: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. DeZern:Astex: Research Funding; Celgene: Consultancy, Honoraria; MEI: Consultancy; Abbvie: Consultancy. Savona:Incyte: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; Karyopharm: Consultancy, Current equity holder in publicly-traded company; Ryvu: Consultancy; Boehringer Ingelheim: Patents & Royalties; Astex: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Shetty:BMS: Current Employment, Current equity holder in publicly-traded company. Ito:BMS: Current Employment, Current equity holder in publicly-traded company. Zhang:BMS: Current Employment. Ha:BMS: Current Employment. Sinsimer: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. Verma:BMS: Consultancy, Research Funding; acceleron: Consultancy, Honoraria; Jans