Fixed Duration Ibrutinib‐Venetoclax, a Redefinition of the CLL Treatment Landscape

ABSTRACT The fixed‐duration combination of ibrutinib and venetoclax (IV) has emerged as a highly effective therapeutic strategy for treating chronic lymphocytic leukemia (CLL), marking a significant shift in the treatment paradigm for this disease. Preclinical studies have demonstrated the synergistic anti‐leukemic effects of the elements of this regimen and therefore provide a strong rationale for their combined use in the clinical setting. Clinical trial data of IV has demonstrated substantial improvements in progression‐free survival (PFS) rates across both treatment‐naïve and relapsed/refractory CLL. Notably, a considerable proportion of patients have achieved undetectable measurable residual disease (uMRD), a key marker of deep remission. However, several critical questions remain unanswered, including the optimal duration of IV and the prognostic significance of uMRD, particularly in high‐risk CLL subsets. Whilst uMRD is widely considered a surrogate for deep remission, the precise correlation of this parameter with long‐term survival outcomes in IV‐treated patients requires further clarification. Moreover, emergent evidence suggests that a prolonged duration of IV therapy, beyond that currently employed, may enhance MRD clearance. Future research should focus on the optimization of BTKi/venetoclax fixed‐duration regimens, particularly for elderly and medically unfit patients. In this context, the development of more selective BTKis that minimize adverse events whilst maintaining effective disease control will be crucial.