Pediatr Blood Cancer 2015;62:208–213
Long-Term Use of the Thrombopoietin-Mimetic Romiplostim in Children With Severe Chronic Immune Thrombocytopenia (ITP) James B. Bussel, MD,1* Loan Hsieh, MD,2 George R. Buchanan, MD,3 Kimo Stine, MD,4 Ram Kalpatthi, David J. Gnarra, MD,6 Richard H. Ho, MD,7 Kun Nie, PhD,8 and Melissa Eisen, MD8 Background. Treatment of chronic severe pediatric ITP is not well studied. In a phase 1/2 12–16-week study, 15/17 romiplostim-treated patients achieved platelet counts 50 109/L, and romiplostim treatment was well tolerated. In a subsequent open-label extension (109 weeks), 20/22 patients received romiplostim; all achieved platelet counts >50 109/L. Twelve patients continued in a second extension (127 weeks). Longitudinal data from start of romiplostim treatment through the two extensions were evaluated to investigate the safety and efficacy of long-term romiplostim treatment in chronic severe pediatric ITP. Procedure. Patients received weekly subcutaneous romiplostim, adjusted by 1 mg/kg/week to maintain platelet counts (50–200 109/L, maximum dose 10 mg/kg). Bone marrow examinations were not required. Results. At baseline, patients were median age 10.0 years; median ITP duration 2.4 years; median platelet count 13 109/L; 73% were male; and 36% had prior splenectomy. Median romiplostim treatment duration was 167 weeks
5 MD,
(Q1, Q3: 78,227 weeks), and median average weekly dose was 5.4 mg/kg (Q1, Q3: 4.3, 8.0 mg/kg). Seven patients discontinued treatment: four withdrew consent, two were noncompliant, and one received alternative therapy. None withdrew because of adverse events (AEs). After the first 12 weeks, median platelet counts remained >50 109/L. Eight (36.4%) patients received rescue medication, and 14 (63.6%) used concurrent ITP therapy. Seven patients (31.8%) reported serious AEs, and two (9.1%) reported lifethreatening AEs (both thrombocytopenia); there were no serious AEs attributed to treatment and no fatalities. Conclusions. Long-term romiplostim treatment in this small cohort increased and maintained platelet counts for over 4 years in children with ITP with good tolerability and without significant toxicity. Pediatr Blood Cancer 2015;62:208–213. # 2014. The Authors. Pediatr Blood & Cancer published by Wiley Periodicals, Inc.
Key words: autoimmunity; bleeding; platelets; thrombopoietin
INTRODUCTION Immune thrombocytopenia (ITP) during childhood is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production resulting in thrombocytopenia. The presentation of this disease varies, ranging from severe acute bleeding to mild bruising and purpura to an asymptomatic incidental diagnosis [1–4]. In contrast to adult ITP, treatment options for severe chronic ITP in children are very poorly studied; even single-arm trials are limited. Current therapeutic approaches to managing chronic pediatric ITP rely on data from adult studies further informed by small pilot studies in children and expert opinion, as there is virtually no evidence derived from randomized controlled trials [1]. Two thrombopoietin (TPO) receptor agonists, romiplostim and eltrombopag, have been approved for the treatment of chronic ITP in adults in the United States and elsewhere. Romiplostim, an Fcpeptide fusion protein that stimulates growth and maturation of megakaryocytes thus increasing platelet production, was developed to address the unmet need in the long-term treatment of adults with chronic ITP. In randomized controlled trials, romiplostim consistently demonstrated a high response rate and a good safety and tolerability profile, and reduced the need for splenectomy and use of rescue medication [5–7]. Additionally, adults with ITP who received romiplostim experienced a significant reduction in the rate of moderate and severe bleeding events and reported improved quality of life [5,8,9]. Long-term studies have shown good safety and tolerability profiles in adults over more than 5 years of continuous treatment [10]. The use of romiplostim in pediatric ITP was initially explored in a small randomized, double-blind, placebo-controlled, phase 1/2 study of patients between the ages of 1 and 18 years who had been diagnosed with ITP at least 6 months prior to enrollment [11]. The primary endpoint was the mean percentage of patients who achieved a platelet count 50 109/L for 2 consecutive weeks, which was achieved in 15 of 17 patients who received romiplostim compared with none who received placebo (P ¼ 0.0008) [11]. Likewise, the C
percentage of patients who received rescue medication during the treatment period was lower in the romiplostim-treated group than in the placebo-treated group [11]. Overall, the response of pediatric patients to romiplostim was similar to that of adults observed in two phase 3 studies of romiplostim in patients with ITP [5,11]. In addition, romiplostim was well tolerated and there were no safety issues. Another small study had similar findings, although with a slightly lower response rate [12]. However no data on long-term use of romiplostim in children exist. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 1
Department of Pediatrics, Division of Hematology, Weill Medical College of Cornell University, New York, New York; 2Children’s Hospital of Orange County/University of California, Irvine, California; 3 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas; 4Arkansas Children’s Hospital, Little Rock, Arkansas; 5Children’s Mercy Hospital, Kansas City, Missouri; 6Children’s Hospital and Medical Center, University of Nebraska Medical Center, Omaha, Nebraska; 7Department of Pediatrics, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tennessee; 8Amgen Inc., Thousand Oaks, California Conflicts of interest: Dr. Bussel has received research funding from Amgen, Cangene, GlaxoSmithKline (GSK), Genzyme, IgG of America, Immunomedics, Ligand, Eisai, Shionogi and Sysmex; his family owns stock in Amgen and GSK; he has served on advisory boards for Amgen, GSK, Ligand, Shionogi, and Eisai; and he has consulted for Portola. Dr. Stine has served on advisory boards for Kedrion, Octapharma, and Biogen Idec. Dr. Nie and Dr. Eisen are employees and stockholders of Amgen. The other authors do not have any disclosures.
Correspondence to: James B. Bussel, Weill Medical College of Cornell University, 525 East 68th Street, Payson Pavilion–695, New York, NY 10065. E-mail:
[email protected] Received 29 October 2013; Accepted 14 May 2014
2014 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals, Inc. DOI 10.1002/pbc.25136 Published online 24 October 2014 in Wiley Online Library (wileyonlinelibrary.com).
Romiplostim in Pediatric ITP After completing the initial first-in-children phase 1/2 study [11], patients were offered the option of entering an extension study. At the end of this first extension study, patients who were still aged 50 109/L. Twelve patients continued in a second extension study (127 weeks). This report presents the results of up to 4.7 years of romiplostim treatment of pediatric patients with ITP who received romiplostim or placebo in the randomized study [11] through the first or the first and second extension studies. The objective of these post hoc analyses was to describe the safety and efficacy of longterm use of romiplostim in children with severe, chronic ITP.
METHODS Study Design and Treatment Study design for the initial 12–16 week phase 1/2 study [11] and first open-label extension study [13,14] has been described elsewhere. Briefly, children aged 1–18 years who had been diagnosed with ITP per American Society of Hematology guidelines [15] 6 or more months before screening were eligible to enter the initial study if the mean of two platelet counts taken within 3 weeks before enrollment was 30 109/L, with no individual platelet count exceeding 35 109/L. Exclusion criteria included having undergone splenectomy within 8 weeks of screening, ongoing stable treatment for ITP besides corticosteroids, and receiving rituximab within 14 weeks before the screening visit. Patients with a history of a bone marrow stem cell disorder, venous or arterial thrombotic or thromboembolic event, systemic lupus erythematosus, or Evans syndrome or other known secondary causes of thrombocytopenia were also excluded. Patients who completed the initial phase 1/2 study were eligible to enter the first open-label extension study; the second open-label extension study was restricted so that only patients aged
