TY - JOUR
T1 - 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
AU - Kater, Arnon P.
AU - Wu, Jenny Qun
AU - Kipps, Thomas
AU - Eichhorst, Barbara
AU - Hillmen, Peter
AU - D'Rozario, James
AU - Assouline, Sarit
AU - Owen, Carolyn
AU - Robak, Tadeusz
AU - de la Serna, Javier
AU - Jaeger, Ulrich
AU - Cartron, Guillaume
AU - Montillo, Marco
AU - Dubois, Julie
AU - Eldering, Eric
AU - Mellink, Clemens
AU - van der Kevie-Kersemaekers, Anne-Marie
AU - Kim, Su Young
AU - Chyla, Brenda
AU - Punnoose, Elizabeth
AU - Bolen, Christopher R.
AU - Assaf, Zoe June
AU - Jiang, Yanwen
AU - Wang, Jue
AU - Lefebure, Marcus
AU - Boyer, Michelle
AU - Humphrey, Kathryn
AU - Seymour, John F.
N1 - Funding Information: Supported by Genentech and AbbVie. Third-party medical writing assistance under the direction of A.P.K. and J.F.S. was provided by Stephanie Cumberworth and Kate Rijnen of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche. Publisher Copyright: © 2020 by American Society of Clinical Oncology Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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 5 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n 5 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 5.042); 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.
AB - 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 5 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n 5 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 5.042); 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.
UR - http://www.scopus.com/inward/record.url?scp=85096888582&partnerID=8YFLogxK
U2 - https://doi.org/10.1200/JCO.20.00948
DO - https://doi.org/10.1200/JCO.20.00948
M3 - Article
C2 - 32986498
SN - 0732-183X
VL - 38
SP - 4042
EP - 4054
JO - Journal of clinical oncology
JF - Journal of clinical oncology
IS - 34
ER -