Optimal management of chemotherapy-induced thrombocytopenia with thrombopoietin receptor agonists

Abstract

Chemotherapy-induced thrombocytopenia (CIT) is a common complication of antineoplastic therapy, resulting in antineoplastic therapy dose reductions, treatment delays, treatment discontinuation, and morbid bleeding events. Despite several decades of research into thrombopoietic growth factors in CIT, there are presently no available U.S. FDA- or EMA-approved agents to treat CIT. However, a respectable body of evidence has been published evaluating the thrombopoietin receptor agonists (TPO-RAs) for the management and prevention of CIT in patients with solid tumors, and critical studies are ongoing with the TPO-RAs romiplostim and avatrombopag. When employed in the appropriate patient population and used properly, TPO-RAs can successfully and safely manage CIT for extended periods of time with minimal apparent risks. This comprehensive review discusses the evidence for TPO-RAs in CIT in patients with solid tumors, provides detailed guidance for their use in the clinic, and discusses ongoing essential clinical trials in management of CIT.

Keywords: Avatrombopag; Bleeding; Chemotherapy; Chemotherapy-induced thrombocytopenia; Nadir CIT; Persistent CIT; Romiplostim; Supportive care; Thrombocytopenia; Thrombopoietin; Thrombopoietin receptor agonist.

Figure 1.. Mean platelet counts over time in a randomized, controlled phase 3 clinical trial evaluating avatrombopag versus placebo for the treatment of nadir CIT.

(A) Mean platelet count over time. Note that nadir during qualifying cycle (baseline) is much lower than nadir for either avatrombopag arm (as expected) or placebo arm (unexpected, signifying “spontaneous recovery”, or lack of nadir CIT reoccurrence, in a majority of patients). (B) Mean change from baseline in platelet count over time. Note the numerical outperformance of the avatrombopag arm over the placebo arm at all time points. Error bars show SDs. Cycle X is the qualifying cycle. IC=interventional cycle (cycle X + 1). OC=observational cycle (cycle X + 2). Reproduced with permission from Al-Samkari et al., 2022 [17].

Figure 2.. Graphical summary of nadir CIT and persistent CIT along with the author’s recommended treatment algorithm when TPO-RA therapy is considered.

Adapted with permission from Al-Samkari 2022 [8].

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 non-response (N=122, blue); solid tumor patients with predictors of romiplostim non-response (N=31, gray) including bone marrow invasion by tumor, prior pelvic irradiation, or prior temozolomide treatment; aggressive lymphoma patients (N=13, red); and myeloma patients (N=7, purple). All lymphoma and myeloma patients had known marrow involvement by tumor. PNR, predictors of non-response. Reproduced with permission from Al-Samkari et al., 2021 [16].