Fixed-duration venetoclax plus rituximab (VenR) has a manageable safety profile and improves survival in patients with relapsed/refractory (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 discontinuation/modification on investigator-assessed progression-free survival (PFS) and overall survival (OS). Analyses were performed retrospectively (without type-1 error control) in intention-to-treat patients from the VenR arm of MURANO. Overall, 140/194 (72%) patients in the VenR arm completed 2 years of therapy; 54/194 (28%) patients prematurely discontinued treatment. Inferior PFS was observed in patients prematurely discontinuing 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 AEs occurred in 134/194 (69%) patients, most commonly due to neutropenia (84/194; 43%), per protocol requirements. Treatment interruption had no impact on PFS or OS, regardless of duration. Dose reductions were required by 45/194 (23%) patients, but had no significant impact on outcomes. In MURANO, premature discontinuation 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.
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