Efficacy and Safety of Non-Covalent Bruton Tyrosine Kinase Inhibitors in Relapsed and Refractory Chronic Lymphocytic Leukemia
Materials and Methods/Case Presentation/Objective:
A systematic search of MEDLINE, Embase, Cochrane Library, Web of Science, and major hematology conference proceedings was conducted from database inception through May 2026. Prospective clinical trials, observational studies, and real-world cohorts evaluating non-covalent Bruton tyrosine kinase inhibitors in adults with relapsed and refractory chronic lymphocytic leukemia were included. Outcomes of interest included overall response rate, progression-free survival, overall survival, treatment discontinuation, adverse events, grade 3 or higher toxicities, atrial fibrillation, bleeding events, infections, and treatment-related mortality. Data were extracted and synthesized qualitatively because of heterogeneity in study design, follow-up duration, and outcome reporting.
Results/Description/Main Outcome Measure(s): The available evidence was dominated by studies of pirtobrutinib, with limited emerging data for other non-covalent Bruton tyrosine kinase inhibitors. In heavily pretreated relapsed and refractory chronic lymphocytic leukemia, pirtobrutinib demonstrated clinically meaningful activity, with an overall response rate of 62% and median progression-free survival of 20 months. In the phase III BRUIN CLL-321 trial, pirtobrutinib demonstrated superior efficacy and favorable tolerability compared with investigator's choice of idelalisib plus rituximab or bendamustine plus rituximab. Early rocbrutinib data in 42 Bruton tyrosine kinase inhibitor-exposed patients demonstrated an overall response rate of 78% at doses of 200 mg or higher. Responses were observed across high-risk subgroups, including patients with TP53 aberrations and Bruton tyrosine kinase mutation-associated resistance. Treatment discontinuation rates were generally low. The safety profile was favorable, with lower rates of atrial fibrillation and major bleeding than historically reported with first-generation covalent Bruton tyrosine kinase inhibitors. Common adverse events included infections, cytopenias, fatigue, and diarrhea, while treatment-related mortality was uncommon.
Conclusion(s).: Non-covalent Bruton tyrosine kinase inhibitors demonstrate substantial clinical activity and a favorable safety profile in relapsed and refractory chronic lymphocytic leukemia, including patients previously exposed to covalent Bruton tyrosine kinase inhibitors and those with high-risk disease features. These agents provide an effective treatment option for patients with resistance or intolerance to prior Bruton tyrosine kinase-directed therapy and may help address an important unmet clinical need. Additional long-term follow-up and comparative studies are needed to define their optimal sequencing within the evolving chronic lymphocytic leukemia treatment landscape.
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