Luspatercept Treatment Leads to Long Term Increases in Hemoglobin and Reductions in Transfusion Burden in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS): Preliminary Results from the Phase 2 PACE-MDS Extension 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 the ineffective erythropoiesis.

Aims: This is an ongoing, phase 2, multicenter, open-label, 24-month extension study (following a 3-month base study) to evaluate the longer-term effects of luspatercept on anemia in patients (pts) with low/int-1 risk MDS (IPSS classification). Study outcomes include erythroid response of increased Hb in low transfusion burden (LTB) pts (<4 RBC units/8 weeks), reduced transfusions in high transfusion burden (HTB) patients (≥4 RBC units/8 weeks), transfusion independence, safety, PK, and PD biomarkers.

Methods: In the base study, eligibility criteria included age ≥18 yr; anemia defined as being HTB or LTB with Hb <10.0 g/dL; EPO >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; total n=27) 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 (n=31) with a starting dose level of 1.0 mg/kg was enrolled with individual pt dose titration allowed. Patients completing the 3-month base study were eligible to enroll into this extension study (with or without interruption ≥3 months) where they continue to receive luspatercept every 3 weeks for up to 24 months.

Results: Enrollment is complete for this extension study (n=32). Preliminary safety and efficacy data (as of 17-Apr-2015) were available for 22 of 32 patients (9 LTB/13 HTB) with continuous luspatercept treatment for a median of 8 cycles (range 5-12). Median age was 70.5 yr, 64% had prior ESA therapy, and 18% had prior lenalidomide. All 22 patients had ≥15% ring sideroblasts (RS+) in bone marrow.

Eight of 9 (89%) of LTB patients achieved an IWG HI-E response for hemoglobin increase (≥1.5 g/dL for ≥8 weeks). Mean change in hemoglobin in these patients exceeded 1.5 g/dL for a median duration of 17 weeks (range 5-22 weeks) as of the data cutoff date in this ongoing study.

Ten of 13 (77%) of HTB patients achieved an IWG HI-E response (reduction of ≥4 RBC units transfused over 8 weeks). Of the 14 patients who received transfusion of ≥2 RBC units over 8 weeks prior to the start of treatment, 6 (43%) patients achieved transfusion independence for at least 8 weeks (median 23 weeks, range 10-30 weeks as of the data cutoff date). All 6 patients were continuing to receive treatment as of the data cutoff date; updated data for duration of response will be presented.

Luspatercept has been generally well-tolerated in the extension study, with no grade 3 or higher related adverse events.

Conclusions: Based on preliminary data from the 24-month extension study in lower risk MDS patients, luspatercept treatment led to sustained HI-E response for increased Hb levels, decreased transfusion requirement or transfusion independence in the majority of patients, with a favorable safety profile. Phase 3 studies in patients with anemia due to lower risk MDS are planned.