Activating Mapk Pathway Mutations Mediate Primary Resistance To Pi3k Inhibitors In Chronic Lymphocytic Leukemia (Cll)

Resistance to PI3K inhibitors including idelalisib remains poorly understood. The present study was designed to identify mechanisms underlying PI3K inhibitor resistance in CLL through WES, RNAseq and biochemical confirmation. We performed WES on matched tumor and germline samples from 28 relapsed CLL patients treated with PI3K inhibitors (idelalisib, 79% (22/28), pilaralisib 10.7% (3/28), voxtalisib 10.7% (3/28)). The median number of prior therapies was 4.5 and the adverse cytogenetic aberrations del(17p) and del(11q) were seen in 21% and 32% respectively. A median of two longitudinal tumor samples were sequenced per patient (Nsamples= 68). An average of 23 ± 12 (range = 4-58) non-silent somatic mutations were identified in the initial sample. The non-silent mutation rate was 0.64 ± 0.32 per MB (range = 0.11-1.61) and typical of CLL. Significantly mutated genes (based on MutSig2CV …