Biomarkers of ineffective erythropoiesis predict response to Luspatercept in patients with low or intermediate-1 risk Myelodysplastic Syndromes (MDS): final results from the phase 2 PACE-MDS study

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.