Overcoming stroma-mediated treatment resistance in chronic lymphocytic leukemia through BCL-2 inhibition.

Despite recent advances in the treatment of chronic lymphocytic leukemia (CLL) with chemoimmunotherapy, many patients with CLL are older or frail and cannot tolerate aggressive chemotherapy. Even those who can inevitably develop resistance due to factors such as deletion of pro-apoptotic factors like TP53 or the support of pro-survival signals from the stromal microenvironment. Using BH3 profiling, we found that CLL cells co-cultured with stroma are less primed to undergo apoptosis in response to BCL-2 inhibition. Currently, several approaches to BCL-2 inhibition with well-tolerated oral agents are in development in the clinic. Dosing of navitoclax (ABT-263) was complicated by thrombocytopenia due to BCL-XL inhibition, but the BCL-2 specific inhibitor ABT-199 (GDC-0199) should avoid this issue, and may overcome stroma-mediated resistance to apoptosis. We are developing BH3 profiling as a biomarker to predict response to novel therapies such as ABT-199, and to identify resistance mechanisms to new agents being studied in CLL.