Treatment strategies for a rapidly evolving landscape in chronic lymphocytic leukemia management

Abstract With the advent of targeted therapies for chronic lymphocytic leukemia (CLL), treatment choice has expanded and patients are living longer. Careful consideration is needed regarding treatment duration and sequence, how best to meet patients' needs, balancing toxicities while improving long‐term survival and maximizing depth of response. This review addresses these considerations and discusses current targeted treatment dilemmas. Targeted therapies have dramatically transformed the CLL treatment landscape. Two treatment paradigms have emerged using B‐cell lymphoma 2 inhibitors (BCL2i) and Bruton's tyrosine kinase (BTK): (i) fixed duration and (ii) continuous treatment. The BCL2i venetoclax can attain deep remissions with a fixed‐duration approach, resulting in high rates of undetectable minimal residual disease (uMRD) in treatment‐naïve and relapsed/refractory (R/R) patients with CLL. BTKis such as ibrutinib and acalabrutinib achieve high objective response rates and long‐term disease control, although they rarely attain complete response or uMRD status as monotherapy. Numerous studies are evaluating the clinical utility of BTKi and BCL2i as combination therapies, where deep remissions have been found to occur. MRD status may also be a useful marker for deciding when to stop continuous therapy, and randomized trials on MRD‐guided treatment strategies are currently ongoing. The current treatment choice between continuous or fixed‐duration therapy should be based on comorbidities, risks, preferences, and treatment goals, whilst areas of emerging clinical interest include the potential utility of BTKi‐BCL2i combination therapies, as well as an MRD‐guided treatment strategies in the future.