IBRUTINIB THERAPY DOWNREGULATES ACTIVATION-INDUCED CYTIDINE DEAMINASE AND PROLIFERATIVE FRACTIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA

SEIJA NOÉ; OPPEZZO PABLO; MORANDE PABLO; DI NOIA, JAVIER M.; SIVINA, MARIELA; BURGER, JAN A.

Ciudad Autónoma de Buenos Aires

Encuentro; 3er IBAM CLL; 2018

SAH - CLL Iberoamerican Group

Activation-induced cytidine deaminase (AID) initiates somatic hypermutation and class switch recombinationof the immunoglobulin genes. As a trade-off for its physiological function, AID can contribute to tumor developmentand progression through its mutagenic activity. In Chronic Lymphocytic Leukemia (CLL), AID isover-expressed in the peripheral blood of patients with poor prognosis, primarily in the proliferative fractions(PFs) of the tumor clone. Recent preclinical data suggested that kinase inhibitors targeting B cell receptor signalingincrease AID expression and genomic instability. To determine whether these findings translate into theclinical situation, we analyzed AID expression and PFs in serial CLL samples from patients before and duringtreatment with the BTK inhibitor ibrutinib. We found that Ibrutinib administration reduced AID expression intreated-CLL cases after 1 and 4 weeks of continuous therapy. In addition, flow cytometry analyses of the fourpreviously described PFs showed that the proportion of CD38+; CD86+; IgM+/IgG+ and CXCR4lowCD5highleukemic cells was also significantly decreased at 4 weeks after Ibrutinib treatment. Possible reasons for thediscrepancy between preclinical and clinical findings, and their impact for treatment safety are discussed.