A single-arm, long-term efficacy and safety study of subcutaneous romiplostim in children with immune thrombocytopenia

Abstract

Romiplostim is a thrombopoietin (TPO) receptor agonist approved for children and adults with immune thrombocytopenia (ITP) for ≥6 months, recommended as second-line treatment. This phase 3b, single-arm, multicenter study investigated long-term efficacy and safety of romiplostim in children ≥1 to <18 years old with ≥6 months' ITP duration and platelet counts ≤30 × 109/L. Children received weekly subcutaneous romiplostim (1 μg/kg titrated to 10 μg/kg) to maintain platelets within 50 to 200 × 109/L. A subset underwent bone marrow examinations. The primary end point was percentage of time with platelet response during the first 6 months' treatment (counts ≥50 × 109/L without rescue medication within the preceding 4 weeks). Overall, 203 patients (median age, 10.0 years) received ≥1 dose of romiplostim, median treatment duration was ∼3 years, and median average weekly dose was 6.9 μg/kg. Ninety-five (46.8%) discontinued (lack of efficacy, n = 43 [21.2%]). Platelet responses were achieved a median (interquartile range) of 50.0% (16.7%-83.3%) of the time during the first 6 months, increasing to 78.2% (26.7%-90.4%) during the overall 36-month treatment period. Eleven patients (5.4%) achieved sustained responses (consecutive counts ≥50 × 109/L without ITP medications for ≥24 weeks). Treatment-related adverse events (AEs) occurred in 56 patients (27.6%), with 8 (3.9%) experiencing serious treatment-related AEs; all of these led to discontinuation, including 4 cases of neutralizing antibodies (romiplostim, n = 3; TPO, n = 1). Bleeding occurred in 141 patients (69.5%), decreasing over time; grade ≥3 bleeding events occurred in 20 (9.9%). At year 2, eight of 63 evaluable patients (12.7%) had grade 2 reticulin. Long-term romiplostim resulted in sustained on-treatment platelet responses with an overall safety profile consistent with previous studies. This trial was registered at www.clinicaltrials.gov as #NCT02279173.

Conflict of interest statement

Conflict-of-interest disclosure: J.G. has received consulting fees from Novartis, Amgen Inc., Ono, Alexion, Biotest, Dova, and Octapharma; has received speakers bureau fees from Novartis and Amgen; and is an ITP Support Association medical advisor. J.B. has participated in advisory boards and received consultancy fees from Amgen Inc., Novartis, Dova, Rigel, UCB, Argenx, Momenta, Regeneron, Kezar, Principia, and CSL-Behring; has participated in speakers bureaus with Novartis and 3S Bio; and has received honoraria from UpToDate. M.T. has received funding for clinical trials from Amgen Inc., Grifols, Novo Nordisk, and Principia; has participated in advisory boards supported by Amgen Inc., Dova, Genentech, Grifols, Novo Nordisk, and Shire/Takeda; and received speakers bureau fees from Novo Nordisk and Shire/Takeda. N.C. has received honoraria for speaking engagements and participated in advisory boards with Novartis, Amgen Inc., Rigel, and Principia; and has received support for clinical trials from Amgen Inc., Novartis, Rigel, Principia, and UCB. J.D. has received research grants from Novartis and consulting fees from Dova and Novartis. A.M. has received lecturer fees from Novartis and Amgen Inc. K.W., M.E., and C.B. are employees of and may hold stock options in Amgen Inc. The remaining author declares no competing financial interests.

© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract

Figure 1.

CONSORT flow diagram. Summary of the overall population (A) and European cohort (B).

Figure 2.

Median (IQR) weekly romiplostim dose over time stabilized after 12 weeks and decreased slightly after 100 weeks during the treatment period.

Figure 3.

Median (IQR) platelet count increased over time. Only platelet counts for which rescue medication was not administered <28 days before evaluation were included.

Figure 4.

Platelet counts over the course of treatment for those who developed neutralizing antibodies. Horizontal dashed line indicates threshold for platelet response (50 × 109/L). Arrows indicate visits at which the patient tested positive for neutralizing antibodies. For patients who had transient neutralizing antibodies (ie, patients 1, 2, 5, and 6), the gray boxes denote indicative periods for which the patients were positive for neutralizing antibodies, and vertical dashed lines indicate visits when the patient no longer tested positive. ∗Patient 5 had multiple positive-to-negative and negative-to-positive visits; only the duration of the first positive-to-negative result is shown.