Romiplostim Therapy of Immune Thrombocytopenia

Source: Tarantino MD, Bussel JB, Blanchette VS, et al. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. The Lancet. 2016; 388(10039): 45; doi: 10.1016/S0140-6736(16)00279-8Investigators from multiple institutions conducted a randomized, controlled trial to assess the safety and efficacy of romiplostim, a thrombopoietin receptor agonist that stimulates platelet production, in treating children with immune thrombocytopenia (ITP). Study participants were children aged 1–17 years with primary ITP of at least 6 months’ duration and platelet counts <30,000/mL who were recruited from 27 sites in the United States, Canada, and Australia between 2012 and 2014. For the study, the children were randomly assigned (2:1) to receive either weekly romiplostim or placebo for 24 weeks; weekly doses were increased from 1 μg/kg to 10 μg/kg with a target platelet count of 50,000/mL to 200,000/mL. The primary outcome was durable platelet response, defined as achievement of weekly platelet counts ≥50,0000/mL in 6 or more of the last 8 weeks of the study. Secondary outcomes included adverse events and serious adverse events. Outcomes were compared among participants in the 2 treatment groups.Data were analyzed on 62 children, including 42 randomized to receive romiplostim and 20 in the placebo group. Baseline characteristics in the 2 treatment groups were comparable. Overall, 52% of participants in the romiplostim group and 10% of those in the placebo group achieved a durable platelet response (P=.002). By age range, durable platelet response rates were 38% and 25% for those in the romiplostim and placebo groups, respectively, among study patients 1–5 years old; 56% and 11%, respectively, for those 6–11 years old; and 56% and 0%, respectively, for those 12–17 years old. The most commonly reported adverse events were contusion, epistaxis, headache, and upper respiratory tract infections. Serious adverse events were reported in 24% (10 patients) of those in the romiplostim group, compared with 5% (1 patient) in the placebo group, although most of these were not treatment related. One participant in the romiplostim group had a serious adverse event that was considered treatment related. This participant had headache and a platelet count of 1,462,000/mL, which resolved. There were no cases of thrombotic or thromboembolic events, and no patients withdrew due to adverse events.The authors conclude that romiplostim induced a high rate of platelet response in children with chronic ITP without significant safety issues.Dr. Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.ITP is an acquired, immune-mediated destruction of normal platelets in the absence of other causes, resulting in a platelet count <100 × 103/uL.1,2 Approximately 1 in 20,000 children per year in the United States are diagnosed with acute ITP, which is self-resolving by 6 months in 75%–80% of children without significant complications. 1,2 Intracranial hemorrhage has been reported in up to 0.5% of children and severe epistaxis or gastrointestinal bleeding in 3%, commonly when platelet count is <10 to 20 × 103/uL.2In 2011, the American Society of Hematology established evidence-based guidelines recommending watchful waiting in children with no bleeding or mild symptoms (petechiae or bruising) even with platelet counts <10 × 103/uL.2 For children with bleeding, first-line pharmacotherapy (corticosteroid, intravenous immunoglobulin, and/or anti-D immunoglobulin) may temporarily increase the platelet count but does not appear to impact time to resolution of ITP nor risk of significant bleeding.2,3 Side effects of these medications, IV access, and hospitalization must be compared to their efficacy: a 50%–70% response rate defined as a platelet count ≥30 × 103/uL.2,3 Potential second-line therapies for persistent ITP (6–12 months’ duration) or chronic ITP (>12 months’ duration) with rituximab or splenectomy may have severe adverse effects, with 20%–60% response rates of varying duration.4 Spontaneous remission rates (without treatment) for chronic ITP range between 30%–40% up to 5 years from diagnosis.5In this phase III clinical trial, children diagnosed with persistent or chronic ITP and mean platelet counts <30 × 103/uL were randomized to treatment with romiplostim or placebo. Compared to 5 prior placebo-controlled studies with smaller pediatric cohorts, this treatment period was longer (6 months vs 2–3 months) and did not include randomization to another thrombopoietin receptor agonist, eltrombopag.6 Limitations of the study include no observations after 6 months of treatment5,6 and recall bias from self-report of baseline bleeding and other adverse effects. Possible confounding variables are inclusion of children with persistent ITP5 and the use of different concomitant baseline and rescue medications for platelets counts <20 × 103/uL.1,4In children with persistent or chronic ITP, weekly romiplostim seems well tolerated with a significant rise in platelet counts (≥50 × 103/uL for at least 6 weeks).

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