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Ferrata Storti Foundation
Haematologica 2022 Volume 107(1):134-142
The impact of early discontinuation/dose modification of venetoclax on outcomes
in patients with relapsed/refractory chronic lymphocytic leukemia: post-hoc analyses from the phase III MURANO study
Anthony R. Mato,1 Jeff P. Sharman,2 Juliana M.L. Biondo,3 Mei Wu,3 Yong Mun,3 Su Y. Kim,4 Kathryn Humphrey,5 Michelle Boyer,5 Qian Zhu3 and John F. Seymour6
1Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2Willamette Valley Cancer Institute and Research Center, Eugene, OR, USA/US Oncology Research, US Oncology Network, The Woodlands, TX, USA; 3Genentech, Inc., South San Francisco, CA, USA; 4AbbVie, North Chicago, IL, USA; 5Roche Products Limited, Welwyn Garden City, UK and 6Peter MacCallum Cancer Centre, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Victoria, Australia
ABSTRACT
Fixed-duration venetoclax plus rituximab (VenR) has a manageable safety profile and improves survival in patients with relapsed/refrac- tory (R/R) chronic lymphocytic leukemia (CLL). We present data from the phase III MURANO study on the impact of venetoclax modification or premature discontinuation on outcomes in patients with R/R CLL. Time- dependent Cox proportional hazards regression models, stratified by 17p deletion and risk status, evaluated the impact of venetoclax discontinua- tion/modification on investigator-assessed progression-free survival (PFS) and overall survival (OS). Analyses were performed retrospectively (with- out type-1 error control) in intention-to-treat patients from the VenR arm of MURANO. Overall, 140 of 194 (72%) patients in the VenR arm com- pleted 2 years of therapy; 54 of 194 (28%) patients prematurely discontin- ued treatment. Inferior PFS was observed in patients prematurely discon- tinuing venetoclax for any reason (disease progression excluded; P<0.0001) and specifically in patients discontinuing due to adverse event (AE) (P<0.0001), versus those who did not discontinue early. Risk of a PFS/OS event was significantly reduced by each extra month (exposure cycle) of venetoclax therapy (P=0.0263 for PFS; P<0.0001 for OS). Treatment interruption for AE occurred in 134 of 194 (69%) patients, most commonly due to neutropenia (84 of 194; 43%), per protocol require- ments. Treatment interruption had no impact on PFS or OS, regardless of duration. Dose reductions were required by 45 of 194 (23%) patients, but had no significant impact on outcomes. In MURANO, premature discon- tinuation was associated with suboptimal outcomes; venetoclax treatment modification was not. These data highlight the importance of effective toxicity control to realize the full benefit of venetoclax treatment (clinical- trials gov. Identifier: NCT02005471).
Introduction
Chronic lymphocytic leukemia (CLL), the most common adult leukemia in Western countries, accounts for approximately one-third of new adult leukemia diagnoses in the United States.1,2 Although no curative treatment for CLL exists (apart from allogeneic stem cell transplantation, which is unsuitable for most patients),3 chemoimmunotherapy achieves disease control and prolongs survival, and has historically been the standard treatment. More recently, novel targeted therapies have improved outcomes over chemoimmunotherapy in first-line (1L) and relapsed/refractory (R/R) CLL.4 These comprise selective kinase inhibitors tar- geting the B-cell receptor and its downstream proteins (including the Bruton tyro-
Chronic Lymphocytic Leukemia
Correspondence:
ANTHONY R. MATO
matoa@mskcc.org
Received: July 10, 2020.
Accepted: November 27, 2020. Pre-published: December 17, 2020.
https://doi.org/10.3324/haematol.2020.266486 ©2022 Ferrata Storti Foundation
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