Abstract
Romiplostim is an investigational Fc-peptide fusion protein (peptibody) that stimulates platelet production by a mechanism similar to endogenous thrombopoietin. MDS pts receiving hypomethylating agents such as azacytidine frequently develop clinically significant thrombocytopenia. This is an ongoing phase 2 multicenter, randomized, double-blind, placebo-controlled study evaluating the effect of romiplostim on the incidence of clinically significant thrombocytopenia in pts with low or intermediate risk MDS receiving azacytidine. Eligible pts were randomized (stratified by baseline [BL] platelet count [≥ or <50 × 109/L]) 1:1:1 to 3 treatment groups to receive placebo or romiplostim at 500μg or 750μg weekly, by subcutaneous (s.c.) injection. All pts received 4 cycles of azacytidine 75mg/m2/day by s.c. injection for the 1st 7 days of each 28-day treatment cycle. The primary endpoint was the incidence of clinically significant thrombocytopenic events, defined as platelet counts <50 × 109/L after Week 3 of treatment or receipt of platelet transfusions (txns) at any time during the treatment period. Secondary endpoints included the incidence of platelet txns and platelet nadir during azacytidine treatment cycles. Safety of romiplostim in combination with azacytidine was evaluated. Forty pts were randomized and treated. The 3 groups were balanced for the stratification factor, but some MDS disease characteristics were imbalanced including IPSS score >1 (54%, placebo vs 23% and 29% romiplostim 500μg and 750μg). Results presented are from a planned interim analysis after all pts had completed or withdrawn from the treatment period. Overall pt incidence of clinically significant thrombocytopenic events was 85%, 62% and 71% for the placebo, romiplostim 500μg and 750μg groups, respectively. In a summary by azacytidine treatment cycle, the pt incidence of thrombocytopenic events per cycle was higher in the placebo group (50%–85% of pts) than in the romiplostim 500μg (44%–69% of pts) and 750μg (18%–64% of pts) groups, respectively. The pt incidence of platelet txns was 69% for placebo vs 46% and 36% for romiplostim 500μg and 750μg groups. Platelet counts on the 1st day of each azacytidine cycle and at the nadir of each 28-day cycle (Table) were lower in the placebo than the romiplostim groups.
All pts (100%) had ≥1 adverse event (AE). Serious AEs (SAEs) were observed in 77%, 46%, and 71% of placebo, romiplostim 500μg and 750μg groups, respectively. Two pts in the romiplostim groups experienced ≥1 treatment-related SAE (1 arthralgia, romiplostim 500μg; 1 rash and hypersensitivity, romiplostim 750μg). Two pts in the placebo group had grade 3 or above bleeding events (1 pulmonary hemorrhage and 1 hemorrhage) vs 1 pt in the romiplostim 500μg group (epistaxis) and none in the romiplostim 750μg group. Two pts died in the placebo group (1 fungal pneumonia, 1 pulmonary hemorrhage) vs none in the romiplostim groups. One case of disease progression from MDS to AML was observed in the 500μg group. In summary, romiplostim reduced pt incidence of clinically significant thrombocytopenic events and platelet txns, and improved platelet nadir in MDS pts receiving azacytidine in this study. These findings are consistent with increased platelet counts over time. Romiplostim in combination with azacytidine appears to be well tolerated in this pt population.
Azacytidine Treatment Cycle Placebo (N=13) 500μg Romiplostim (N=13) 750μg Romiplostim (N=14) n Cycle BLa Platelet nadirb N Cycle BLa Platelet nadirb n Cycle BLa Platelet nadirb aMedian of platelet count (×109/L) on 1st day of each azacytidine treatment cycle bMedian of lowest platelet count (×109/L) during each azacytidine treatment cycle BL = baseline 1 13 25 14 13 40 33 14 37 32 2 11 48 16 10 121 63 13 115 53 3 11 54 33 10 73 43 11 222 116 4 10 88 40 9 60 53 10 315 91
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