Results of a randomized, double‐blind study of romiplostim versus placebo in patients with low/intermediate‐1–risk myelodysplastic syndrome and thrombocytopenia

Abstract

BACKGROUNDThrombocytopenia in patients with myelodysplastic syndrome (MDS) is associated with shortened survival and an increased risk of evolution to acute myeloid leukemia (AML). In this study, the authors evaluated the efficacy of romiplostim in patients who had thrombocytopenia with low-risk/intermediate-1–risk MDS.METHODSPatients who had thrombocytopenia with low-risk/intermediate-1–risk MDS (N = 250) were randomized 2:1 to receive romiplostim or placebo weekly for 58 weeks.RESULTSThe primary endpoint— the number of clinically significant bleeding events (CSBEs) per patient—had a hazard ratio for romiplostim:placebo of 0.83 (95% confidence interval, 0.66-1.05; P = .13). CSBEs were reduced significantly in the romiplostim group for patients who had baseline platelet counts ≥20 × 109/L (P < .0001). For patients who had baseline platelet counts <20 × 109/L, there was no difference in the number of CSBEs, but the platelet transfusion rates were higher in the placebo group (P < .0001), which may have affected the overall CSBE results in this group with severe thrombocytopenia. The incidence of bleeding events was reduced significantly in the romiplostim group (relative risk, 0.92), as were protocol-defined platelet transfusions (relative risk, 0.77). Platelet response rates according to 2006 International Working Group criteria were higher for the group that received romiplostim (odds ratio, 15.6). On the basis of interim data, an independent data monitoring committee advised halting study drug because of concerns regarding excess blasts and AML rates with romiplostim (interim hazard ratio, 2.51). At 58 weeks, the AML rates were 6% in the romiplostim group and 4.9% in the placebo group (hazard ratio, 1.20; 95% confidence interval, 0.38-3.84), and the overall survival rates were similar.CONCLUSIONSRomiplostim treatment in patients with low-risk/intermediate-1–risk MDS increased platelet counts and decreased the number of bleeding events and platelet transfusions. Although study drug was discontinued because of an initial concern of AML risk, survival and AML rates were similar with romiplostim and placebo.

How we manage immune thrombocytopenia in the elderly

“…Conflicting results have been reported concerning the risk of leukaemia with TPO-RAs in MDS, and currently, no firm conclusions can be drawn (Kantarjian et al, 2010;Giagounidis et al, 2014;Khan et al, 2015).…”

Myelodysplastic syndromes: Contemporary review and how we treat

“…Romiplostim has been studied in a randomized doubleblinded trial involving 250 patients with low/intermediate-1 risk MDS patients and thrombocytopenia [80]. It decreased the number of clinically significant bleeding events compared to placebo (hazard ratio of 0.83 for romiplostim compared to placebo) in patients with a baseline platelet count < 20 3 10 9 /L.…”

Treatment of low-risk myelodysplastic syndromes

“…61 Although the study was stopped because of an increase of blasts, at 58 weeks, the AML rates and the OS rates were not significantly different between PBO and romiplostim. 62 Endogenous levels of TPO, similar to what was observed for EPO, could serve to select patients sensitive to thrombomimetic drugs. Eltrombopag, an orally bioavailable, synthetic nonpeptide TPO-receptor agonist, differs substantially from romiplostim in structure and mechanism of action, and binds to the transmembrane and juxtamembrane /L) IPSS lower-risk MDS patients in an ongoing phase 2, multicenter, prospective, PBO-controlled, single-blind study at escalating doses from 50 to 300 mg per day.…”

“…The availability of agents actively promoting megakaryocytopoiesis and PLT function could therefore represent an important possible therapeutic option for MDS (Table 2). [61][62][63][64][65][66] Several agents (interleukin-11, recombinant human thrombopoietin [TPO], pegylated recombinant human megakaryocyte growth and development factor, and interleukin-6) have been investigated in MDS, but only 2 have demonstrated safe activity. AMG-531, now known as romiplostim, is a peptide TPO mimetic, synthesized as a dimer resulting from the fusion of a novel peptide and antibody or "peptibody" that can stimulate PLT production via the TPO receptor without competing with TPO.…”