Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study

• Published in: Journal of clinical oncology Vol. 37; no. 4; pp. 269 - 277
• Main Authors: Kater, Arnon P., Seymour, John F., Hillmen, Peter, Eichhorst, Barbara, Langerak, Anton W., Owen, Carolyn, Verdugo, Maria, Wu, Jenny, Punnoose, Elizabeth A., Jiang, Yanwen, Wang, Jue, Boyer, Michelle, Humphrey, Kathryn, Mobasher, Mehrdad, Kipps, Thomas J.
• Format: Journal Article
• Language: English
• Published: United States 01.02.2019
• Subjects: Aged; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bendamustine Hydrochloride - administration & dosage; Bendamustine Hydrochloride - adverse effects; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - adverse effects; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - mortality; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Male; Middle Aged; Neoplasm, Residual; Progression-Free Survival; Recurrence; Rituximab - administration & dosage; Rituximab - adverse effects; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Time Factors
• ISSN: 0732-183X; 1527-7755; 1527-7755
• DOI: 10.1200/JCO.18.01580

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. 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. 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 ) 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 to less than 10 ) predicted improved PFS compared with high-level MRD (10 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. 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.