RBC Transfusion Burden, Median
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Abstract Number Assessment of dose-dependent response to luspatercept in patients with lower-risk myelodysplastic EP812 Scientific Content on Demand syndromes with ring sideroblasts in the phase 3 MEDALIST trial To request a copy of this poster: Uwe Platzbecker,1 Pierre Fenaux,2 Ghulam J. Mufti,3 Guillermo Garcia-Manero,4 Rami S. Komrokji,5 Rena Buckstein,6 María Diez-Campelo,7 Carlo Finelli,8 Mikkael A. Sekeres,9 Dominik Selleslag,10 Amy E. DeZern,11 Bruno Quesnel,12 Odile Beyne-Rauzy,13 Maria Teresa Voso,14 Peter L. Greenberg,15 Amer M. Zeidan,16 Lionel Adès,2 Amit Verma,17 Michael R. Savona,18 Abderrahmane Laadem,19 Rodrigo Ito,19 Jennie Zhang,19 Anita Rampersad,19 Jessica Morison,19 Chrystal U. Louis,19 Peter G. Linde,20 Valeria Santini21 1Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany; 2Service d’Hématologie Séniors, Hôpital Saint-Louis, Université Paris 7, Paris, France; 3Department of Haemato-Oncology, King's College London, London, UK; 4Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 5Moffitt Cancer Center, Tampa, FL, USA; 6Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 7Hematology Department, Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, Salamanca, Spain; 8Department of Oncology and Hematology, S. Orsola-Malpighi University Hospital, Bologna, Italy; 9Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA; 10Department of Haematology, AZ Sint-Jan, Bruges, Belgium; 11The Sidney 12 13 14 15 Scan QR code Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA; Service des Maladies du Sang, Hôpital Huriez, Centre Hospitalier Universitaire de Lille, Lille, France; Médicine Interne, Institute Universitaire du Cancer de Toulouse Oncopole, Toulouse, France; Dipartimento di Biopatologia e Diagnostica per Immagini, University of Rome Tor Vergata, Rome, Italy; Stanford University Cancer Center, Stanford, CA, USA; via a barcode reader application. 16Department of Internal Medicine, Yale School of Medicine and Yale Cancer Center, Yale University, New Haven, CT, USA; 17Department of Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA; 18Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA; 19Bristol Myers Squibb, Princeton, NJ, USA; 20Acceleron Pharma, Cambridge, MA, USA; 21MDS Unit, Azienda This QR code will take you to an external site. Ospedaliero Universitaria (AOU) Careggi, University of Florence, Florence, Italy QR codes are valid for 120 days after the congress presentation date. Introduction • Baseline RBC transfusion burden subgroups for these analyses include: Figure 2. Achievement of RBC-TI ≥ 8 weeks (A and B) and HI-E (C and D) Table 2. Dose escalations and time to dose escalation by RBC-TI response Table 3. Dose delays and reductions — ≤ 6 RBC units/8 weeks during Weeks 1–48 • Patients with lower-risk myelodysplastic syndromes (LR MDS) develop anemia due to Luspatercept Luspatercept Luspatercept Parameter, n (%) Luspatercept (N = 153) a a 1,2 — > 6 RBC units/8 weeks Parameter responders non-responders overall ineffective erythropoiesis, leading to red blood cell (RBC) transfusion dependence A B ≥ 1 dose delay 74 (48.4) 100 (n = 69) (n = 84) (N = 153) • Luspatercept is a first-in-class erythroid maturation agent that binds to select Safety analysis Breakdown of the 69 luspatercept RBC-TI Due to pre-dose Hb levels ≥ 11.5 g/dL 13 (8.5) respondersa by baseline RBC transfusion burden 90 transforming growth factor-β superfamily ligands to diminish Smad2/3 signaling and • Data cutoff for incidence of dose reductions, dose delays, and TEAEs was July 1, 2019 No dose escalation, n (%) 24 (34.8) 11 (13.1) 35 (22.9) ≥ 1 dose reduction 9 (5.9) 3 enhance late-stage erythropoiesis 80 8.7% Dose escalation to 1.33 mg/kg, n (%) 45 (65.2) 73 (86.9) 118 (77.1) Due to Hb increase ≥ 2 g/dL vs pre-dose Hb level 3 (2.0) (n = 6) • MEDALIST is an ongoing phase 3, randomized, double-blind, placebo-controlled trial Due to any suspected related grade ≥ 3 AE 5 (3.3) Results 70 Time to dose escalation to 1.33 mg/kg, 105 (40–419) 43 (39–258) 63 (39–419) evaluating the efficacy and safety of luspatercept in patients with LR MDS with ring 60 median (range), days Data cutoff: July 1, 2019. sideroblasts (RS) who require RBC transfusions Patients 45.1% AE, adverse event; Hb, hemoglobin. 50 (n = 69) Duration of treatment at 1.33 mg/kg, — The primary results of the MEDALIST trial demonstrated that a significant proportion of • 229 patients were randomized and received luspatercept (N = 153) or placebo (N = 76) 3.5 (1.2–17.5) 1.4 (0.7–8.3) 1.4 (0.7–17.5) median (range), months Figure 5. New onset of TEAEs at each dose level in patients receiving luspatercept-treated patients achieved RBC transfusion independence (TI) ≥ 8 weeks (Table 1) 40 4 30 In patients with baseline transfusion luspatercept during the first 24 weeks of the study — Baseline RBC transfusion burden was ≤ 6 RBC units/8 weeks in 108 of 153 (70.6%) 15.8% 91.3% 3.5 (1.2–17.5) 1.4 (0.7–8.3) 1.6 (0.7–17.5) (n = 63) burden ≤ 6 RBC units/8 weeks • Luspatercept has been approved by the US Food and Drug Administration for the luspatercept patients and in 50 of 76 (65.8%) placebo patients 20 (n = 12) 30 1.0 mg/kg 1.33 mg/kg 1.75 mg/kg treatment of anemia in adult patients failing an erythropoiesis-stimulating agent and Proportion of patients achieving In patients with baseline transfusion — Baseline RBC transfusion burden was > 6 RBC units/8 weeks in 45 of 153 (29.4%) RBC-TI ≥ 8 weeks (Weeks 1–48) (%) 10 Baseline transfusion (N = 153) (N = 128) (N = 103) 2.9 (1.3–9.5) 1.4 (0.7–5.1) 1.4 (0.7–9.5) 25 requiring ≥ 2 RBC units over 8 weeks with Very low- to Intermediate-risk MDS with RS or luspatercept patients and in 26 of 76 (34.2%) placebo patients burden ≤ 6 RBC units/8 weeks burden > 6 RBC units/8 weeks 5 0 with myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis Placebo Baseline transfusion Luspatercept Dose escalation to 1.75 mg/kg, n (%) 29 (42.0) 61 (72.6) 90 (58.8) 20 (N = 76) burden > 6 RBC units/8 weeks Table 1. Baseline patient characteristics (N = 153) 17.0% Time to dose escalation to 1.75 mg/kg, C D 14.4% Objective 171 (81–359) 91 (81–344) 106 (81–359) 15 13.6% 13.7% 13.7% Characteristic Luspatercept (N = 153) Placebo (N = 76) 100 Breakdown of the 90 luspatercept HI-E median (range), days 12.6% 13.1% 13.1% b responders by baseline RBC transfusion burden 10.9% 10.9% • To evaluate the effect of luspatercept dose on efficacy and treatment-emergent adverse Age, median (range), years 71 (40–95) 72 (26–91) 90 10.7% 10.5% 10.7% Duration of treatment at 1.75 mg/kg, 10 8.7% 9.2% 7.8% 7.8% 7.8% events (TEAEs) 8.5 (0.7–17.5) 2.9 (0.7–19.5) 5.9 (0.7–19.5) patients Luspatercept 80 median (range), months 6.3% 6.3% Male, n (%) 94 (61.4) 50 (65.8) 5.5% 4.9% 4.9% 5 3.9% Methods RBC transfusion burden, median 70 58.8% 25.6% In patients with baseline transfusion TEAE (%) with new onset of indicated a 5 (1–15) 5 (2–20) 7.7 (0.7–17.2) 2.8 (0.7–19.5) 6.2 (0.7–19.5) (range), units/8 weeks (n = 90) (n = 23) burden ≤ 6 RBC units/8 weeks 60 0 Study design ≤ 6 units/8 weeks, n (%) 108 (70.6) 50 (65.8) In patients with baseline transfusion Fatigue Diarrhea Asthenia Dizziness Nausea Back pain Headache Dyspnea 50 13.8 (4.1–17.5) 4.2 (0.7–15.2) 4.3 (0.7–17.5) • MEDALIST is an ongoing phase 3, randomized, double-blind, placebo-controlled trial > 6 units/8 weeks, n (%) 45 (29.4) 26 (34.2) burden > 6 RBC units/8 weeks Data cutoff: July 1, 2019. 40 74.4% TEAEs include adverse events that started on or after the date of first dose and on or before 42 days after the date of last dose of study b (NCT02631070); patients in the luspatercept arm who have not discontinued from IPSS-R, n (%) (n = 67) Data cutoff: May 8, 2018. treatment. If a patient experienced multiple events under the same SOC and PT, then the patient is counted only once for that SOC and 30 17.1% a treatment continue to receive the study drug (Weeks 1–48) (%) Response was defined as achieving RBC-TI ≥ 8 weeks during Weeks 1–48. PT level. All TEAEs regardless of severity are counted. Very low 18 (11.8) 6 (7.9) (n = 13) SOC, System Organ Class; PT, Preferred Term; TEAE, treatment-emergent adverse event. 20 RBC, red blood cell; TI, transfusion independence. • Patients were randomized at 65 sites between March 2016 and June 2017 Low 109 (71.2) 57 (75.0) 10 Baseline transfusion • The MEDALIST study design is shown in Figure 1 Intermediate 25 (16.3) 13 (17.1) Proportion of patients achieving HI-E burden ≤ 6 RBC units/8 weeks Figure 4. First RBC-TI ≥ 8 weeks (A) and HI-E response (B) during Weeks 1–48 — Patients were randomized 2:1 to receive luspatercept (starting dose 1.0 mg/kg) or c 0 SF3B1 mutation, n (%) 138 (93.2) 64 (86.5) Luspatercept Placebo Baseline transfusion by dose level in patients receiving luspatercept Conclusions placebo subcutaneously every 21 days for ≥ 24 weeks Serum EPO, n (%)d (N = 153) (N = 76) burden > 6 RBC units/8 weeks — Dose titration was allowed up to 1.33 mg/kg and then up to 1.75 mg/kg in the A • The majority of luspatercept patients with baseline transfusion burden 6 RBC < 200 U/L 88 (57.5) 50 (65.8) Data cutoff: May 8, 2018.