Arnon P Kater1, John F Seymour2, Peter Hillmen3, Barbara Eichhorst4, Anton W Langerak5, Carolyn Owen6, Maria Verdugo7, Jenny Wu8, Elizabeth A Punnoose8, Yanwen Jiang8, Jue Wang8, Michelle Boyer9, Kathryn Humphrey9, Mehrdad Mobasher8, Thomas J Kipps10. 1. 1 Amsterdam Universitair Medische Centra, University of Amsterdam, Amsterdam, the Netherlands. 2. 2 Royal Melbourne Hospital and University of Melbourne, Melbourne, Victoria, Australia. 3. 3 St James's University Hospital, Leeds, United Kingdom. 4. 4 University of Cologne, Cologne, Germany. 5. 5 Erasmus MC University Medical Center, Rotterdam, the Netherlands. 6. 6 University of Calgary, Calgary, Alberta, Canada. 7. 7 AbbVie, North Chicago, IL. 8. 8 Genentech, South San Francisco, CA. 9. 9 Roche Products Limited, Welwyn Garden City, United Kingdom. 10. 10 University of California School of Medicine, San Diego, CA.
Abstract
PURPOSE: The MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. With all patients off treatment, we report minimal residual disease (MRD) kinetics and updated outcomes. METHODS: Patients were randomly assigned to 2 years of venetoclax plus rituximab during the first six cycles, or six cycles of bendamustine-rituximab. Primary end point was PFS. Safety and peripheral blood (PB) MRD status-at cycle 4, 2 to 3 months after end of combination therapy (EOCT), and every 3 to 6 months thereafter-were secondary end points. RESULTS:Of 194 patients, 174 (90%) completed the venetoclax-rituximab phase and 130 (67%) completed 2 years of venetoclax. With a median follow-up of 36 months, PFS and overall survival remain superior to bendamustine-rituximab (hazard ratio, 0.16 [95% CI, 0.12 to 0.23]; and hazard ratio, 0.50 [95% CI, 0.30 to 0.85], respectively). Patients who received venetoclax-rituximab achieved a higher rate of PB undetectable MRD (uMRD; less than 10-4) at EOCT (62% v 13%) with superiority sustained through month 24 (end of therapy). Overall, uMRD status at EOCT predicted longer PFS. Among those with detectable MRD, low-level MRD (10-4 to less than 10-2) predicted improved PFS compared with high-level MRD (10-2 or greater). At a median of 9.9 months (range, 1.4 to 22.5 months) after completing fixed-duration venetoclax-rituximab, overall only 12% (16 of 130) of patients developed disease progression (11 high-level MRD, three low-level MRD). At the end of therapy, 70% and 98% of patients with uMRD remained in uMRD and without disease progression, respectively. CONCLUSION: With all patients having finished treatment, continued benefit was observed for venetoclax-rituximab compared with bendamustine-rituximab. uMRD rates were durable and predicted longer PFS, which establishes the impact of PB MRD on the benefit of fixed-duration, venetoclax-containing treatment. Low conversion to detectable MRD and sustained PFS after completion of 2 years of venetoclax-rituximab demonstrate the feasibility of this regimen.
RCT Entities:
PURPOSE: The MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. With all patients off treatment, we report minimal residual disease (MRD) kinetics and updated outcomes. METHODS:Patients were randomly assigned to 2 years of venetoclax plus rituximab during the first six cycles, or six cycles of bendamustine-rituximab. Primary end point was PFS. Safety and peripheral blood (PB) MRD status-at cycle 4, 2 to 3 months after end of combination therapy (EOCT), and every 3 to 6 months thereafter-were secondary end points. RESULTS: Of 194 patients, 174 (90%) completed the venetoclax-rituximab phase and 130 (67%) completed 2 years of venetoclax. With a median follow-up of 36 months, PFS and overall survival remain superior to bendamustine-rituximab (hazard ratio, 0.16 [95% CI, 0.12 to 0.23]; and hazard ratio, 0.50 [95% CI, 0.30 to 0.85], respectively). Patients who received venetoclax-rituximab achieved a higher rate of PB undetectable MRD (uMRD; less than 10-4) at EOCT (62% v 13%) with superiority sustained through month 24 (end of therapy). Overall, uMRD status at EOCT predicted longer PFS. Among those with detectable MRD, low-level MRD (10-4 to less than 10-2) predicted improved PFS compared with high-level MRD (10-2 or greater). At a median of 9.9 months (range, 1.4 to 22.5 months) after completing fixed-duration venetoclax-rituximab, overall only 12% (16 of 130) of patients developed disease progression (11 high-level MRD, three low-level MRD). At the end of therapy, 70% and 98% of patients with uMRD remained in uMRD and without disease progression, respectively. CONCLUSION: With all patients having finished treatment, continued benefit was observed for venetoclax-rituximab compared with bendamustine-rituximab. uMRD rates were durable and predicted longer PFS, which establishes the impact of PB MRD on the benefit of fixed-duration, venetoclax-containing treatment. Low conversion to detectable MRD and sustained PFS after completion of 2 years of venetoclax-rituximab demonstrate the feasibility of this regimen.
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Authors: Andrew D Zelenetz; Gilles Salles; Kylie D Mason; Carla Casulo; Steven Le Gouill; Laurie H Sehn; Herve Tilly; Guillaume Cartron; Martine E D Chamuleau; Andre Goy; Constantine S Tam; Pieternella J Lugtenburg; Adam M Petrich; Arijit Sinha; Divya Samineni; Sylvia Herter; Ellen Ingalla; Edith Szafer-Glusman; Christian Klein; Deepak Sampath; Martin Kornacker; Mehrdad Mobasher; Franck Morschhauser Journal: Blood Date: 2019-03-08 Impact factor: 22.113
Authors: Victor S Lin; Thomas E Lew; Sasanka M Handunnetti; Piers Blombery; Tamia Nguyen; David A Westerman; Bryone J Kuss; Constantine S Tam; Andrew W Roberts; John F Seymour; Mary Ann Anderson Journal: Blood Date: 2020-06-18 Impact factor: 22.113