Clinical implications of cancer gene mutations in patients with chronic lymphocytic leukemia treated with lenalidomide

Lenalidomideis clinically active in chronic lymphocytic leukemia (CLL), but its effectiveness in the context of the CLL mutationallandscape is unknown. We performed targeted capture sequencing of 295 cancer genes in specimens from 102 CLL patients with treatment-naive disease (TN patients) and 186 CLL patients with relapsed/refractory disease (R/R patients) who received lenalidomide-based therapy at our institution. The most frequently mutatedgene was SF3B1 (15%), followed by NOTCH1 (14%) and TP53 (14%), with R/R patients having significantly more TP53 mutationsthan TN patients. Mutated IGHVwas associated with an increased prevalence of MYD88 mutations(p=0.005) and del(13q) (p=0.028), whereas unmutated IGHVwas associated with an increased prevalence of NOTCH1 (p=0.035) and XPO1(p=0.047). Among all lenalidomide-treated patients, del(17p) (p≤0.001), del(11q) (p=0.032), and complex karyotype (p=0.022), along with mutationsin TP53 (p≤0.001), KRAS (p=0.034), and DDX3X(p≤0.001), were associated with worse overall response (OR). R/R patients with SF3B1 and MGA mutationshad significantly worse OR (p=0.025 and 0.035, respectively). TN and R/R patients with del(17p) and TP53 mutationshad worse overall survival (OS) and progression-free survival (PFS). In R/R patients, complex karyotype and SF3B1 mutationswere associated with worse OS and PFS; DDX3X mutationswere associated with worse PFS only. Weibull regression multivariate analysis revealed that TP53 aberrations—del(17p) and/or TP53 mutation—along with complex karyotype and SF3B1 mutations, were associated with worse OS in the R/R cohort. Taken together, cancer gene mutationsin CLL contribute to the already comprehensive risk stratification and add to prognosis and response to treatment. The related trials were registered to https://clinicaltrials.gov as NCT00267059, NCT00535873, NCT00759603, NCT01446133, and NCT01002755.