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.
Highlights
Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in Western countries [1]
We reported recently that BAFF protects primary chronic lymphocytic leukemia (CLL) cells from rituximab-induced natural killer (NK) cell killing, and sensitivity of CLL cells to NK cell cytotoxicity could be restored by belimumab [24]
We determined suitable concentrations of the small molecule inhibitors idelalisib, ibrutinib and venetoclax for our in vitro studies based on plasma peak levels achieved in leukemia patients [29,30,31]
Summary
Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in Western countries [1]. The increasing understanding of disease pathophysiology in CLL recently enabled the development of small molecule inhibitors targeting molecular structures of central importance for prolonged survival of B cells. Three such compounds, the B cell receptor inhibitors ibrutinib and idelalisib as well as the Bcl-2 antagonist venetoclax have been approved for CLL treatment and all profoundly improved long term survival of patients [4,5,6]. Disease progression after initial response is mainly caused by occurrence of resistance over the course of therapy [9,10,11,12]
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