Eltrombopag Decreases Proliferation of Human Leukemia and Lymphoma Cell Lines In Vitro.

Eltrombopag is a novel, oral platelet growth factor that interacts with the thrombopoietin receptor on bone marrow progenitors to stimulate megakaryocyte and platelet production. Clinical trials have demonstrated that eltrombopag increases platelet counts in healthy volunteers and in patients with idiopathic thrombocytopenic purpura (ITP) and hepatitis C. Because thrombopoietin (TPO) receptors are expressed on lymphoma and leukemia cell lines and recombinant human TPO (rhTPO) has been shown to stimulate their proliferation in vitro, experiments were conducted to evaluate the effects of eltrombopag on the proliferation of leukemia and lymphoma cells in vitro. Five leukemia and lymphoma cell lines (ie, CCRF-CEM, K562, MOLT-4, RPMI-8226 and SR) representing lymphoblastic T cell leukemia, chronic myelogenous leukemia, acute lymphoblastic T cell leukemia, plasmacytoma and immunoblastic large cell lymphoma, were exposed to eltrombopag (0.1–40 ug/mL), rhTPO (100 ng/mL) or both for 3 days. Proliferation was measured by 18-hour incubation with tritiated thymidine incorporation. As expected, rhTPO alone led to a small, statistically significant increase in the proliferation of CCRF-CEM and RPMI-8226 cells, while it had no effect on the other cell lines. However, the addition of eltrombopag to rhTPO negated the increased proliferation seen with rhTPO alone. Even more remarkable, treatment with eltrombopag alone inhibited the proliferation of all five leukemia and lymphoma cell lines with an IC₅₀ range of 0.56 to 5.9 ug/mL and 100% inhibition (IC₁₀₀) of thymidine incorporation at 10 ug/mL (Table). Previous studies have shown that eltrombopag induces proliferation and differentiation of bone marrow progenitor cells in vitro and increases platelet counts in vivo. While eltrombopag and rhTPO interact with the TPO receptor to stimulate the production of platelets, there are differences in the site of receptor interaction and their signaling pathways. The findings of the current study suggest that eltrombopag may inhibit the proliferation of leukemia and lymphoma cell lines unlike the effect that has been demonstrated with rhTPO. Interestingly, eltrombopag may also serve to mitigate rhTPO-mediated proliferation of malignant hematologic cell lines. These findings merit further evaluation of the effects of eltrombopag on leukemia, lymphoma, and solid tumor cell proliferation.