Beyond mechanisms: toward patient-centered choices in BTKi-venetoclax fixed-duration therapy for CLL

We read with interest the timely perspective recently published in Leukemia by Tedeschi et al. addressing fixed-duration (FD) combination therapies of venetoclax with Bruton tyrosine kinase inhibitors (BTKis) in chronic lymphocytic leukemia (CLL) [1].The authors examine the evolving landscape of time-limited regimens and present a mechanistic rationale to guide readers in preferring one BTKi over another in combination with venetoclax [1].The authors' major claims are that the support for ibrutinib-venetoclax (I+V) is based on indirect, cross-trial comparisons across heterogeneous patient populations enrolled in the GLOW, CAPTIVATE, and AMPLIFY studies [2-4].Given the relevance of the issue in clinical practice, the authors' conclusions warrant a more cautious interpretation in the absence of direct evidence before privileging one BTKi partner over another in FD treatment strategies.First, as detailed in a previous analysis, these trials differ significantly in baseline characteristics, including number of patients, median age, fitness status, comorbidity burden, and the prevalence of high-risk genomic abnormalities such as del(17p) and TP53 mutations [5].Moreover, these cross-trial comparisons are inherently constrained by differing median follow-up durations (~3.4 years for AMPLIFY, 5.3 years for GLOW, and 5.5 years for CAPTIVATE), which may bias estimates of efficacy [2][3][4].Another critical consideration is the varying applicability of trial findings to broader patient populations.The majority of evidence supporting FD venetoclax-BTKi regimens originates from clinical trials enrolling predominantly fit patients (e.g., CAPTIVATE, AMPLIFY) [3,4].The seminal CLL17 trial addresses this issue only partially.Specifically, in the I+V arm, the median age was 66 years (IQR 59-73), and the median CIRS score was 3 (IQR 1-5), suggesting limited representation of older or more comorbid individuals [6].Caution is warranted when extrapolating the results of these trials to elderly patients or those with substantial comorbidities, who constitute a significant subset of the CLL population.The GLOW trial provides valuable outcome data for older, comorbid patients treated with the I+V combination, demonstrating substantial efficacy [2].However, in this study, a higher incidence of severe cardiotoxicity and sudden deaths-presumed to be cardiac in origin-was observed [2].These safety concerns ultimately prevented FDA approval of this combination in the United States.Despite the lack of FDA approval, the 2026 NCCN guidelines for the management of CLL include fixed-duration or measurable residual disease (MRD)-guided treatment with I+V as one of the "other therapeutic approaches," as an alternative to the preferred front-line fixed-