THE BTK INHIBITOR IBRUTINIB (IBRU) IMPAIRS MACROPHAGE-MEDIATED PHAGOCYTOSIS OF LEUKEMIC B CELLS FROM CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS

BORGE M; PODAZA E.; COLADO A; ALMEJUN B; FERNANDEZ GRECCO H.; CABREJO M.; BEZARES RF; GIORDANO M; GAMBERALE R

Mar del Plata

Congreso; LXII Reunión Anual de la Sociedad Argentina de Inmunología; 2014

Malignant B cell expansion is promoted by the permissive microenvironment present in lymphoid organs of CLL patients. There, BCR stimulation of leukemic cells and the array of signals provided by T lymphocytes, stroma and myeloid cells favor leukemic clone proliferation and prevent both spontaneous and drug-induced apoptosis. Ibrutinib (Ibru) is an orally available BTK inhibitor which, administered once daily continuously, has shown impressive results in clinical trials and has recently been approved as a single agent for CLL treatment. Combined therapies with Ibru and monoclonal antibodies (mAb) are being tested in clinical trials. The standard first-line treatment of fit CLL patients includes the anti-CD20 mAb Rituximab (Rx) while the anti-CD52 mAb Campath (Cpth) was employed for relapsed or refractory patients. They both mediate anti-tumor effects by a variety of mechanisms including the ingestion of opsonized target cells by macrophages. The objective of this study was to determinate the effect of Ibru on macrophage phagocytosis of CLL cells opsonized with Rx or Cpth. To this aim macrophages were differentiated from monocytes from healthy donors in the presence of GM-CSF. Then, CFSE-labeled CLL cells were coated with Rx or Cpth and used as target cells. The phagocytosis assay was performed in the presence or absence of Ibru and was analyzed by flow cytometry after 2hs. We found that Ibru diminishes macrophage-phagocytosis of Rx-coated CLL cells (p˂0.05 for Ibru 0.5 µM and 5 µM) and Cpth-coated CLL cells (p˂0.05 for Ibru 5 µM). This impairment was not due to a reduced binding of opsonized cells by Ibru-treated macrophages (p˃0.05). Importantly, Ibru did not affect macrophage viability during the phagocytosis assay (p˃0.05). Our results suggest that Ibru may impair mAbs anti-tumor effects. Thus, alternative Ibru dosing schedules, sequential vs concurrent, might be consider in clinical trials testing the combination of Ibru and mAb to preserve the efficacy of both.