Romiplostim Treatment of Chemotherapy-Induced Thrombocytopenia

Gerald A. Soff, MD; Yimei Miao, BS; Gemma Bendheim, BS; Jeanette Batista, MSN; Jodi V. Mones, MD; Rekha Parameswaran, MD; Cy R. Wilkins, MD; Sean M. Devlin, PhD; Ghassan K. Abou-Alfa, MD; Andrea Cercek, MD; Nancy E. Kemeny, MD; Debra M. Sarasohn, MD; Simon Mantha, MD, MPH

Disclosures

J Clin Oncol. 2019;37(31):2892-2898. 

In This Article

Abstract and Introduction

Abstract

Purpose: Chemotherapy-induced thrombocytopenia (CIT) leads to delay or reduction in cancer treatment. There is no approved treatment.

Methods: We conducted a phase II randomized trial of romiplostim versus untreated observation in patients with solid tumors with CIT. Before enrollment, patients had platelets less than 100,000/μL for at least 4 weeks, despite delay or dose reduction of chemotherapy. Patients received weekly titrated romiplostim with a target platelet count of 100,000/μL or more, or were monitored with usual care. The primary end point was correction of platelet count within 3 weeks. Twenty-three patients were treated in a randomization phase, and an additional 37 patients were treated in a single-arm, romiplostim phase. Resumption of chemotherapy without recurrent CIT was a secondary end point.

Results: The mean platelet count at enrollment was 62,000/μL. In the randomization phase, 14 of 15 romiplostim-treated patients (93%) experienced correction of their platelet count within 3 weeks, compared with one of eight control patients (12.5%; P < .001). Including all romiplostim-treated patients (N = 52), the mean platelet count at 2 weeks of treatment was 141,000/μL. The mean platelet count in the eight observation patients at 3 weeks was 57,000/μL. Forty-four patients who achieved platelet correction with romiplostim resumed chemotherapy with weekly romiplostim. Only three patients (6.8%) experienced recurrent reduction or delay of chemotherapy because of isolated CIT.

Conclusion: This prospective trial evaluated treatment of CIT with romiplostim. Romiplostim is effective in correcting CIT, and maintenance allows for resumption of chemotherapy without recurrence of CIT in most patients.

Introduction

Suppression of hematopoiesis is a common adverse effect of chemotherapy, resulting in delay or dose reduction of cancer treatment. Although there are multiple reasons for delay or dose reduction of chemotherapy, marrow suppression remains a major cause.[1] In one report, 22.7% of patients experienced chemotherapy dose delay because of inadequate blood counts.[2] Neutropenia can be effectively treated with filgrastim;[3] however, there is no available treatment of chemotherapy-induced thrombocytopenia (CIT). Retrospective cohort studies have reported treatment-related thrombocytopenia (≤ 100,000/μL) rates of 16.5% and 21.8%,[2,4] and more than 30% for platinum- or gemcitabine-based regimens.[2] The major consequence of CIT is reduction in relative dose intensity (RDI). Reduced RDI may result from a number of factors besides CIT, but thrombocytopenia is an important contributor.[1,5,6] Reduction in RDI affects progression-free or overall survival in studies of colorectal, ovarian, and breast cancers.[7–10]

Platelet transfusions provide only transient and unpredictable improvement in platelet counts and are not practical to maintain platelet counts through cycles of chemotherapy nadir.[11] Thrombopoietin (TPO) is the primary growth factor that stimulates megakaryocytes and platelet production.[12] Recombinant TPO and a polyethylene glycol–modified variant were both found to raise platelet counts in test patients.[12] However, therapeutic development was halted after the development of antidrug antibodies that cross-reacted with endogenous TPO, causing thrombocytopenia.[12,13] There are no approved treatments for CIT, and this remains an important unmet need.

More recently, TPO receptor agonists have been developed. Romiplostim is a subcutaneously administered Fc-peptide fusion protein, which contains two 14 amino-acid peptides, stabilized by linkage to the immunoglobulin G Fc domain, that binds to and activates the TPO receptor.[12] Romiplostim does not contain the peptide sequence of endogenous TPO, and cross-reactive antibodies have not been reported. Romiplostim is approved and widely used to treat immune thrombocytopenia.[12] Several oral, small-molecule TPO receptor agonists have also been developed, but none are approved for treatment of CIT.[12,14,15]

Several small studies, presented only as abstracts, demonstrated that administration of romiplostim both before and after chemotherapy was effective in improving platelet counts, but did not lead to an impact on ongoing cancer therapy or ongoing RDI.[16,17] We previously published a case series of 20 patients with solid tumors with CIT (< 100,000/μL) treated with weekly romiplostim, suggesting romiplostim may treat CIT and allow for resumption of chemotherapy.[18] A more recent retrospective case series showed similar findings.[19] We report the results of a prospective, phase II clinical trial of romiplostim for CIT in patients with solid tumors.

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