Thrombopoietin receptor agonists for chemotherapy-induced thrombocytopenia: a new solution for an old problem

Abstract

Chemotherapy-induced thrombocytopenia (CIT) is common, resulting in increased bleeding risk and chemotherapy delays, dose reduction, and treatment discontinuation, which can negatively affect oncologic outcomes. The only agent approved by the US Food and Drug Administration to manage CIT (oprelvekin) was voluntarily withdrawn from the market by the manufacturer, leaving few options for patients. Therefore, patients experiencing CIT present a significant clinical challenge in daily practice. The availability of thrombopoietin receptor agonists has led to formal clinical trials describing efficacy in CIT as well as a rather extensive body of published observational data from off-label use in this setting but no formal regulatory indications for CIT to date. The accumulated data, however, have affected National Comprehensive Cancer Network guidelines, which now recommend consideration of TPO-RA clinical trials as well as off-label use of romiplostim. This review article details the evidence to date for the management of CIT with thrombopoietin receptor agonists (TPO-RAs), discussing the efficacy data, the specific circumstances when treatment is warranted (and when it is generally unnecessary), and safety considerations. Specific recommendations regarding patient selection, initiation, dosing, titration, and discontinuation for TPO-RA therapy in CIT are given, based on published data and expert opinion where evidence is lacking.

Graphical abstract

Figure 1.

Weekly vs intracycle dosing of romiplostim for CIT. (A) A graphical representation comparing weekly and intracycle dosing over multiple different types of chemotherapy regimens. (B) Median weekly platelet counts in a cohort of patients with solid tumors receiving standard weekly romiplostim dosing (n = 65, dark blue) vs intracycle romiplostim dosing (n = 57, light blue). Error bars represent interquartile ranges. Adapted with permission from Al-Samkari et al.

Figure 2.

Platelet count course for Clinical Case 1. Representative of a typical case in which TPO-RA support is necessary for adequate platelet count recovery to support many remaining chemotherapy cycles at full dose and on schedule after development of persistent CIT. Green zone represents goal platelet count on romiplostim, yellow zone represents CIT platelet count range resulting in dose reduction and/or treatment delay of chemotherapy, and red zone represents profound thrombocytopenia resulting in increased risk for bleeding.

Figure 3.

Median weekly platelet counts for various patient populations treated for CIT with romiplostim from a study of 173 patients with CIT. Solid tumor patients with no predictors of romiplostim nonresponse (n = 122, blue); solid tumor patients with predictors of romiplostim nonresponse (n = 31, gray) including bone marrow invasion by tumor, prior pelvic irradiation, or prior temozolomide treatment; patients with aggressive lymphoma (n = 13, red); and patients with myeloma (n = 7, purple). All patients with lymphoma and myeloma had known marrow involvement by tumor. PNR, predictors of nonresponse. Reproduced with permission from Al-Samkari et al.