Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study

Abstract

Purpose: In previous analyses of the MURANO study, fixed-duration venetoclax plus rituximab (VenR) resulted in improved progression-free survival (PFS) compared with bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics.

Patients and methods: Patients with CLL were randomly assigned to 2 years of venetoclax (VenR for the first six cycles) or six cycles of BR. PFS, overall survival (OS), peripheral-blood minimal residual disease (MRD) status, genomic complexity (GC), and gene mutations were assessed.

Results: Of 389 patients, 194 were assigned to VenR and 195 to BR. Four-year PFS and OS rates were higher with VenR than BR, at 57.3% and 4.6% (hazard ratio [HR], 0.19; 95% CI, 0.14 to 0.25), and 85.3% and 66.8% (HR, 0.41; 95% CI, 0.26 to 0.65), respectively. Undetectable MRD (uMRD) at end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15). Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with GC than in those without GC (P = .042); higher GC was associated with shorter PFS. Higher MRD positivity rates were seen with BIRC3 and BRAF mutations at EOCT and with TP53, NOTCH1, XPO1, and BRAF mutations at EOT.

Conclusion: Efficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS.

Trial registration: ClinicalTrials.gov NCT02005471.

FIG 1.

Kaplan-Meier assessments of (A) progression-free survival (PFS) and (B) overall survival (OS). BR, bendamustine plus rituximab; EOCT, end of combination therapy; EOT, end of treatment; HR, hazard ratio; ITT, intent-to-treat; VenR, venetoclax plus rituximab.

FIG 2.

Landmark Kaplan-Meier analyses. (A) Progression-free survival (PFS) from end of combination therapy (EOCT) in both study arms based on minimal residual disease (MRD) status at EOCT. (B) PFS from end of treatment (EOT) in patients in the venetoclax plus rituximab (VenR) arm who completed 2 years of venetoclax, based on MRD status at EOT (excludes two patients who completed venetoclax but experienced disease progression before MRD measurement). (C) PFS from EOCT in the VenR arm based on MRD status at EOCT and involvement of lymph nodes. BR, bendamustine plus rituximab; CR, complete response; CRi, complete response with incomplete marrow recovery; nPR, nodular partial response; PR, partial response; uMRD, undetectable minimal residual disease.

FIG 3.

Impact of genomic alterations on minimal residual disease (MRD) response in patients treated with venetoclax plus rituximab (VenR; biomarker-evaluable population [BEP]). MRD status at (A) end of combination therapy and (B) end of treatment (EOT) according to major cytogenetic alterations, using Döhner hierarchical classification. Missing values resulted from disease progression (n = 12), death (n = 11), missing visit (n = 8), or MRD technical issues (n = 2). Other group includes all patients not harboring one of the four named abnormalities; del13q14 group includes both mono- and biallelic deletions. P values were calculated using Fisher’s exact test. (C) MRD status at EOT according to genomic complexity (GC) status; samples with missing MRD values were not included in the BEP for this analysis. CLL, chronic lymphocytic leukemia.

FIG 4.

(A) Oncoprint of most frequently mutated genes (≥ 5%) in the venetoclax plus rituximab (VenR) arm. Progression-free survival (PFS) in patients with cytogenetic alterations, using Döhner hierarchical classification, in the (B) VenR arm and (C) bendamustine plus rituximab (BR) arm. HR, hazard ratio.

FIG 5.

Multivariable analysis of progression-free survival (PFS) according to (A) genomic complexity (GC) status and (B) driver mutation burden (number of recurrently mutated genes with mutations). Covariates were IGHV status, Rai stage at baseline, TP53 mutation status and/or del(17p) by array comparative genomic hybridization, fludarabine resistance status, and maximum nodal size > 10 cm. BR, bendamustine plus rituximab; HR, hazard ratio; VenR, venetoclax plus rituximab.