Effects of rapamycin in combination with fludarabine on primary chronic lymphocytic leukemia cells

CARLOS BUSSI; VIVIANA HELLER; PABLO IRIBARREN; DANIELA ARROYO; CARMEN STANGANELLI; CECILIA RODRÍGUEZ; DARÍO SASTRE; IRMA SLAVUTSKY

LEUKEMIA AND LYMPHOMA

TAYLOR & FRANCIS LTD

Lugar: Londres; Año: 2019 vol. 60 p. 1299 - 1303

1042-8194

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults, characterized by the expansion of a population of monoclonal CD5+ B-lymphocytes that accumulate in the blood, bone marrow, and secondary lymphoid tissues. CLL continues to be an incurable disease and can arise in two forms, aggressive and indolent, both characterized by a typical defect in apoptosis. Despite the new therapeutic options, the gold standard for the first-line treatment of fit patients with CLL is the combination of purine analogs (such as, fludarabine) in combination with cyclophosphamide and the monoclonal antibody rituximab. However, new and more efficient therapeutic strategies are currently under investigation. Among them, rapamycin (R), an inhibitor of the mammalian target of rapamycin (mTOR) complex, has been shown to synergize when combined with cytotoxic agents in leukemic cells in vitro. In this report, we analyzed the synergistic effect in inducing cell death of R in combination with fludarabine (Fd) treatment in peripheral blood mononuclear cells (PBMC) from CLL patients. In addition, we evaluated the correlation of the response to the combined treatment with several prognostic markers. We showed that R and Fd synergistically increased cell death in CLL cells and it correlated with Bcl-2 basal levels. Considering the new treatment paradigms based on this molecule, we anticipate that evaluating Bcl-2 expression in CLL patients would be relevant when using purine analogs, such as Fd, in combination with other pharmacological agents for CLL therapy.