Mutations Are Associated with Resistance to Non-Genotoxic MDM2 Inhibition in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is a genetically and clinically heterogeneous malignancy affecting older individuals. There are a number of current treatment options for CLL, including monoclonal antibodies, targeted drugs, chemotherapy, and different combinations of these. However, for those patients who are intrinsically treatment resistant, or relapse following initial responses, novel targeted therapies are still needed. Targeting the mouse double-minute-2 human homolog (MDM2), a primary negative regulator of p53, is an appealing therapeutic strategy for non-genotoxic reactivation of p53, since the gene is in its wild-type state at diagnosis in approximately 90% of patients. Mutated and are both associated with more aggressive disease, resistance to therapies and poorer overall survival for CLL. In this study, we performed a screen for and mutations and tested RG7388 (idasanutlin), a second-generation MDM2 inhibitor, in a cohort of CLL primary patient samples. mutations were detected in 24 of 195 cases (12.3%) and found associated with poor overall survival (hazard ratio [HR] 2.12, = 0.032) and high CD38 expression (median CD38 (%) 32 vs. 5; = 0.0087). The novel striking finding of this study was an independent link between mutational status and poor response to RG7388. Overall, mutations in CLL patient samples were associated with resistance to treatment with RG7388 ex vivo, and patients with the wild type for both and are more likely to benefit from treatment with MDM2 inhibitors.