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

Background/Objectives: Covalent Bruton’s tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib) improve outcomes in advanced chronic lymphocytic leukemia (CLL) but resistance, largely driven by BTK C481 mutations, and adverse events limit long-term benefit. Noncovalent BTK inhibitors (e.g., pirtobrutinib) reversibly inhibit the BTK ATP-binding pocket independent of C481, potentially overcoming resistance and reducing toxicity. This review summarizes clinical evidence for pirtobrutinib in CLL. Methods: A PubMed search of articles through July 2025 was conducted, focusing on clinical trials of pirtobrutinib. We extracted efficacy, safety, and resistance data, emphasizing the BRUIN CLL-321 phase 3 trial and related studies. Results: Pirtobrutinib demonstrates activity against BTK resistance mutations with a favorable safety profile, partly due to high kinase selectivity. In BRUIN CLL-321, pirtobrutinib achieved an overall response rate (ORR) of 62% and a median progression-free survival (PFS) of 20 months in heavily pretreated patients, including those with resistance mutations. Yet, resistance mechanisms—such as alternative pathway activation and additional BTK mutations—emerge in a subset. Baseline genetic features, including BTK mutation status and cytogenetics, influence response durability and outcomes. Ongoing phase 3 trials comparing pirtobrutinib with covalent BTK inhibitors will clarify its potential as a first-line option and its integration into treatment algorithms. In relapsed/refractory CLL, noncovalent BTK inhibitors may be incorporated into personalized pathways, including bridging to CAR-T therapy, to optimize long-term disease control. Conclusions: Pirtobrutinib offers a promising strategy to address resistance and potentially improve durable disease control in CLL. Definitive trials will define its role relative to covalent BTK inhibitors and its utility across treatment lines within personalized, multimodal regimens.