Preclinical evidence for management of thrombocytopenia associated with bromodomain extra-terminal (BET) inhibition therapy.

Abstract

e24207 Background: Thrombocytopenia is a potential dose-limiting toxicity associated with many oncology agents including BET inhibitors (BETi). Thrombocytopenia in rats closely mirrors clinical dose-limiting thrombocytopenia, enabling the use of this model to explore potential supportive care options. Methods: A pan-BETi molecule A-1550592 (1mg/kg) was administered by oral gavage for 4 days to Sprague Dawley rats and hematologic parameters measured on Day 5. Recombinant human erythropoietin (rhEPO 150 IU) was administered subcutaneously 4 days before and concomitantly with BETi. Folic Acid (FA, 3mg/kg and 30 mg/kg) was administered subcutaneously 4 days before and concomitantly with BETi. Romiplostim (30 micrograms) was administered prior to (2 doses) and concomitantly (1 dose) with BETi on days 2, 4 and 6. Results: rhEPO administration resulted in reticulocyte increases as compared to BETi alone (BETi, n = 3: 54x109; BETi + rhEPO, n = 3: 272x109; Control, n = 3: 346X109cells/mL). Interestingly, rhEPO administration was also associated with platelet increases in the rhEPO+ BETi group compared to BETi alone (BETi, n = 3: 465x109; BETi + EPO, n = 3: 808x109; Control, n = 3: 1175x109cells/mL). rhEPO was also noted to reverse the moderate decreased bone marrow cellularity seen with BETi administration. FA partially mitigated thrombocytopenia in the FA+ BETi group when compared with BETi alone (BETi, n = 3: 529x109; BETi + 3 mg FA, n = 3: 585x109; BETi + 30 mg FA, n = 3: 973x109; Control, n = 3: 1138x109). Romiplostim partially mitigated thrombocytopenia in the Romiplostim + BETi group when compared with BETi alone (BETi, n = 5: 808x109; Romiplostim, n = 5: 2678x109; BETi + Romiplostim, n = 5: 1150x109cells/mL). Conclusions: The observed hematologic responses in the rodent model to BET inhibition and various supportive care agents (rhEPO, FA, Romiplostim) suggests that these agents may be effective in mitigating clinical thrombocytopenia associated with BETi.