Efficacy and Safety of Romiplostim in Patients with Low or Intermediate-Risk Myelodysplastic Syndrome (MDS) Receiving Decitabine.

MDS patients receiving hypomethylating agents commonly develop clinically significant thrombocytopenia, for which platelet transfusions are often the only treatment. Romiplostim is a peptibody protein that increases platelet production by a mechanism similar to thrombopoietin. This report describes a phase 2, multicenter, randomized, double-blind, placebo-controlled study of romiplostim in combination with hypomethylating agents in patients with MDS. Results from patients receiving azacitidine have previously been reported (Kantarjian et al, ASH 2008, #224); we report results from the combination of romiplostim with decitabine.

Eligible patients had low, intermediate-1, or intermediate-2 risk MDS per IPSS. Patients were randomized (1:1) to receive placebo or 750μg romiplostim by weekly subcutaneous injection and were stratified by baseline platelet count (≥ or <50×10⁹/L). Patients received decitabine according to the FDA-approved dose and schedule, or using a modified dosing regimen (20 mg/m² IV over 1 hour for 5 days every 4 weeks). The primary endpoint was the incidence of clinically significant thrombocytopenic events, defined as platelet counts <50×10⁹/L starting at week 3 of treatment, or receipt of platelet transfusions at any time during the treatment period. Other endpoints included the safety of romiplostim in combination with decitabine and the incidence of platelet transfusions, bleeding events, and platelet nadir during decitabine treatment cycles. Results from 4 decitabine treatment cycles are presented.

Twenty-nine patients were randomized and treated. Nine of 14 (64%) placebo-treated and 10/15 (67%) romiplostim-treated patients completed 4 cycles of decitabine. Baseline characteristics were generally well balanced between the 2 groups, except that more patients in the placebo group had an IPSS score >1 (8/14, 57%) than those in the romiplostim group (5/15, 33%). The primary endpoint was reached in 11/14 (79%) placebo patients and 12/15 (80%) romiplostim patients: After the first cycle, median platelet counts at the beginning of each decitabine cycle were lower in placebo-treated than in romiplostim-treated patients (Table). Platelet transfusions were administered to 57% of placebo patients and 47% of romiplostim patients. The overall incidence of bleeding events was higher in the placebo group (43%) than the romiplostim group (27%). An MDS treatment response (complete or partial response) was achieved by 5/14 (36%) placebo patients and 7/15 (47%) romiplostim patients. All patients experienced at least 1 adverse event. Serious adverse events occurred in 57% of placebo- and 53% of romiplostim-treated patients. One patient in the romiplostim group experienced a treatment-related serious adverse event (pulmonary artery thrombosis leading to study withdrawal). Bone marrow blasts were increased in 2 patients, both from the placebo group. Disease progression to AML (23% bone marrow blasts and 21% peripheral blasts) occurred in one patient from each treatment group. Four patients died: 2 in the placebo group (neutropenic sepsis and intracranial hemorrhage) and 2 in the romiplostim group (sepsis and acute cholecystitis). None of the deaths were considered investigational product-related.

Romiplostim in combination with decitabine appeared to be well tolerated in lower-risk MDS patients. A clinical benefit of adding romiplostim to decitabine treatment was indicated by numerically increased platelet counts at the beginning of each treatment cycle, decreased platelet transfusion rates and decreased bleeding events in romiplostim-treated patients compared with the placebo group. Conclusions are limited by the small sample size of this exploratory phase 2 study, and further investigation of the safety and efficacy of romiplostim in treatment-related thrombocytopenia in MDS is warranted.

Greenberg:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding. Off Label Use: Use of romiplostim, a thrombopoietin mimetic, to treat Thrombocytopenia in MDS. Damon:Celgene: Speakers Bureau; Genentech: Equity Ownership; Eisai: Speakers Bureau. Wei:Amgen Inc.: Employment, Equity Ownership. Kantarjian:Amgen Inc.: Research Funding. Franklin:Amgen Inc.: Employment, Equity Ownership.