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

Abstract

Lenalidomide is clinically active in chronic lymphocytic leukemia (CLL), but its effectiveness in the context of the CLL mutational landscape is unknown. We performed targeted capture sequencing of 295 cancer genes in specimens from 102 CLL patients with treatment-naïve 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 mutated gene was <i>SF3B1</i> (15%), followed by <i>NOTCH1</i> (14%) and <i>TP53</i> (14%), with R/R patients having significantly more <i>TP53</i> mutations than did TN patients. Among all lenalidomide-treated patients, del(17p) (<i>P</i> ≤ .001), del(11q) (<i>P</i> = .032), and complex karyotype (<i>P</i> = .022), along with mutations in <i>TP53</i> (<i>P</i> ≤ .001), <i>KRAS</i> (<i>P</i> = .034), and <i>DDX3X</i> (<i>P</i> ≤ .001), were associated with worse overall response (OR). R/R patients with <i>SF3B1</i> and <i>MGA</i> mutations had significantly worse OR (<i>P</i> = .025 and .035, respectively). TN and R/R patients with del(17p) and <i>TP53</i> mutations had worse overall survival (OS) and progression-free survival (PFS). In R/R patients, complex karyotype and <i>SF3B1</i> mutations were associated with worse OS and PFS; <i>DDX3X</i> mutations were associated with worse PFS only. Weibull regression multivariate analysis revealed that <i>TP53</i> aberrations (del(17p), <i>TP53</i> mutation, or both), along with complex karyotype and <i>SF3B1</i> mutations, were associated with worse OS in the R/R cohort. Taken together, cancer gene mutations in CLL contribute to the already comprehensive risk stratification and add to prognosis and response to treatment. The related trials were registered at www.clinicaltrials.gov as #NCT00267059, #NCT00535873, #NCT00759603, #NCT01446133, and #NCT01002755.