Novel Combination of Erythropoietin and Romiplostim to Treat Chemotherapy-Induced Anemia and Thrombocytopenia via Pharmacodynamic Interaction on Hematopoietic Stem and Progenitor Cells

Chemotherapy-induced anemia and thrombocytopenia (CIAT) in cancer patients are often caused by the damage of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. We have previously shown that romiplostim, a thrombopoietin receptor agonist that could stimulate the expansion of HSPCs, could synergize with recombinant human erythropoietin (rHuEPO) to promote erythropoiesis in addition to stimulating platelet production, whereas rHuEPO could influence the platelet count through stem cell competition. Therefore, we hypothesize that a combination of romiplostim with rHuEPO can alleviate CIAT simultaneously, while minimizing the risk of thrombosis. In this study, we demonstrated that rHuEPO and romiplostim exhibit no stimulatory effects on the growth and invasion of LA-7 cancer cells both in vitro and in vivo. Using a rat model with carboplatin-induced anemia and thrombocytopenia, we showed that the red blood cells and hemoglobin concentration recovered faster, and the secondary thrombocytopenia was alleviated in the rHuEPO and romiplostim combination therapy groups compared with the corresponding rHuEPO monotherapy groups. The rebound phenomenon of platelets was inhibited compared with the romiplostim monotherapy group. In vitro study further demonstrated that romiplostim expands HSPCs and synergizes with rHuEPO to promote erythropoiesis, while rHuEPO inhibited megakaryopoiesis. Furthermore, we developed a mechanism-based pharmacokinetic-pharmacodynamic model to quantify the effects of the two drugs. This study suggests that rHuEPO and romiplostim combination therapy can treat CIAT simultaneously in rats while minimizing the risk of thrombosis, indicating that combination therapy might be superior to monotherapy in the supportive therapy of cancer patients undergoing chemotherapy.