Belimumab, a Neutralizing BAFF (B Cell Activating Factor) Antibody, Enhances the Susceptibility of Chronic Lymphoid Leukemia (CLL) Cells to Abt-199 Treatment

Abt-199 is a small molecule BCL-2 inhibitor which has recently been approved for treatment of CLL and mediates its effects by induction of apoptosis in the leukemic cells. The TNF family member B cell activating factor (BAFF) contributes to disease pathophysiology in mature B cell malignancies including CLL by sustaining survival and preventing apoptosis of the malignant B cells. BAFF also plays a prominent role in autoimmune diseases, and accordingly a BAFF-neutralizing antibody termed Belimumab (Benlysta ® ) has been developed and is approved for treatment of systemic lupus erythematosus. Notably, elevated levels of BAFF have also been detected in sera of B cell lymphoma patients. We demonstrated recently that BAFF protects CLL cells from NK cell cytotoxicity including Rituximab-induced antibody-dependent cellular cytotoxicity (ADCC), the major mechanism by which this CD20-antibody mediates its therapeutic effects. In turn, susceptibility of CLL cells to both direct and Rituximab-induced NK cell killing could be restored by BAFF neutralization with Belimumab (Wild et al , Leukemia 2015). Here we studied whether Belimumab could also serve to increase the susceptibility of CLL cells to Abt-199 treatment. As no information on Abt-199 plasma peak levels in CLL patients is available, we first exposed primary CLL cells of leukemia patients to varying concentrations of Abt-199 and identified 5 nMas in vitro LC 50 concentration in analyses of leukemia cell metabolic activity. Next we studied how BAFF influenced the therapeutic efficacy of Abt-199. Analyses of CLL cell metabolic activity and apoptosis/cell death revealed that BAFF concentration-dependently protected primary CLL cells from the therapeutic effects of Abt-199. Notably, CLL cell susceptibility to Abt-199 could be restored by neutralization of BAFF by Belimumab. Together, our findings demonstrate that BAFF contributes to CLL cell resistance to Abt-199 treatment. BAFF neutralization by Belimumab may in turn constitute a promising strategy to increase/restore the therapeutic efficacy of Abt-199, which warrants future clinical studies of combinatorial approaches to improve CLL treatment. Disclosures No relevant conflicts of interest to declare.