Neutralization of B-Cell Activating Factor (BAFF) by Belimumab Reinforces Small Molecule Inhibitor Treatment in Chronic Lymphocytic Leukemia

SIMPLE SUMMARY: Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in Western countries. Despite the substantial progress achieved by the recent introduction of the novel small molecule inhibitors idelalisib, ibrutinib and venetoclax in CLL treatment, therapy resistance occurs frequently and the disease so far remains incurable. In the present study we report that BAFF, a member of the TNF protein family, protects CLL cells from treatment-induced cell death. In turn, the therapeutic effects of idelalisib, ibrutinib and venetoclax can be reinforced by neutralizing BAFF with belimumab, an antibody which presently is clinically approved for treatment of systemic lupus erythematosus. Based on the data presented in this study, a clinical study to evaluate whether drug repurposing of belimumab for BAFF neutralization can serve to improve response to small molecule inhibitor treatment in CLL is in preparation. ABSTRACT: The introduction of idelalisib, ibrutinib and venetoclax for treatment of chronic lymphocytic leukemia (CLL) has greatly improved long term survival of patients. However, many patients do not achieve complete remission and suffer from development of resistance upon treatment with these small molecule inhibitors. Here we report that the TNF family member B-cell activating factor (BAFF) mediates resistance of CLL cells to idelalisib, ibrutinib and venetoclax by sustaining survival and preventing apoptosis of the malignant B cells as revealed by analysis of cellular ATP levels and mitochondrial membrane integrity as well as caspase activation, respectively. As BAFF also plays a prominent role in autoimmune diseases, the BAFF-neutralizing antibody belimumab was developed and approved for treatment of systemic lupus erythematosus (SLE). When we employed belimumab in the context of CLL treatment with idelalisib, ibrutinib and venetoclax, BAFF neutralization was found to significantly increase the sensitivity of the leukemic cells to all three small molecule inhibitors. Notably, BAFF neutralization proved to be beneficial independently of clinical stage according to Binet and Rai or IgVH mutational status. Our results identify drug repurposing of belimumab for neutralization of BAFF to complement small molecule inhibitor treatment as a promising therapeutic approach in CLL that is presently undergoing clinical evaluation.