Pirtobrutinib in Chronic Lymphocytic Leukemia: Navigating Resistance and the Personalisation of BTK-Targeted Therapy

The advent of the covalent Bruton’s tyrosine kinase (BTK) inhibitors ibrutinib, acalabrutinib, and zanubrutinib has markedly improved outcomes for patients with advanced chronic lymphocytic leukaemia (CLL), yielding high response rates and durable remissions. However, resistance—predominantly driven by Cys481 mutations—and adverse events, including cardiac arrhythmias and infections, limit their long-term benefit. To address these challenges, noncovalent BTK inhibitors such as pirtobrutinib have been developed. These agents reversibly inhibit the ATP-binding pocket of BTK independently of cysteine residue 481 (Cys481). Noncovalent BTK inhibitors demonstrate activity against resistance mutations and exhibit a favourable safety profile, in part owing to high kinase selectivity. In the BRUIN CLL-321 phase 3 study, pirtobrutinib showed meaningful activity in heavily pretreated populations, including patients with resistance mutations, with an overall response rate of approximately 62% and a median progression-free survival (PFS) of around 20 months. Nevertheless, resistance mechanisms—including alternative pathway activation and additional BTK mutations—emerge in a subset of patients. Molecular and genomic analyses indicate that baseline genetic features, including BTK mutation status and other cytogenetic abnormalities, substantially influence response durability and treatment outcomes. Ongoing phase 3 trials directly comparing pirtobrutinib with established covalent BTK inhibitors will likely clarify its role as a first-line option and may support its integration into standard treatment algorithms. In the relapsed/refractory setting, the strategic incorporation of noncovalent BTK inhibitors like pirtobrutinib into personalised treatment pathways—including as bridging therapy to cellular approaches such as chimeric antigen receptor T-cell (CAR-T) therapy—holds promise for optimising long-term disease control. This evolving therapeutic landscape aims to enhance response durability, curb resistance, and, ultimately, improve prospects for durable disease control and potential curative interventions in CLL.