Efficacy and safety of non-covalent BTK inhibitors: A systematic review focused on indolent lymphomas.

e19081 Background: Covalent Bruton’s tyrosine kinase inhibitors (cBTKi) have transformed the treatment of B-cell malignancies; however, long-term efficacy is limited by intolerance, off-target toxicities, and acquired resistance, most commonly due to mutations at the BTK C481 binding site. Non-covalent (reversible) BTK inhibitors, including pirtobrutinib (LOXO-305), nemtabrutinib (ARQ-531) which bind BTK independently of C481. Although early-phase trials have shown activity across several B-cell malignancies, their role in indolent B-cell lymphomas remains unclear. We therefore conducted a systematic review to evaluate the efficacy and safety of non-covalent BTK inhibitors across B-cell malignancies, with a focus on indolent lymphoma subtypes. To our knowledge, this is the first systematic review evaluating efficacy and safety of non-covalent BTK inhibitors in indolent B-cell lymphomas. Methods: A systematic review was performed according to PRISMA 2020 guidelines. PubMed, Embase, and ClinicalTrials.gov were searched in November 2025 for clinical trials and observational studies evaluating non-covalent BTK inhibitors in relapsed or refractory indolent B-cell lymphomas, including follicular lymphoma (FL), marginal zone lymphoma (MZL), and Waldenström’s macroglobulinemia (WM). Studies reporting efficacy and/or safety outcomes were included. Extracted data included overall response rate (ORR), duration of response (DoR), progression-free survival (PFS), follow-up duration, and treatment-related adverse events. Risk of bias was assessed using the ROBINS-I tool. Results: Five studies involving 215 patients met inclusion criteria: FL (n=89), MZL (n=48), and WM (n=78). Median age ranged from 59–68 years. Patients were heavily pretreated (median 3–4 prior lines), including anti-CD20 antibodies, chemotherapy, and cBTKi; most cBTKi discontinuations were due to progression or intolerance. ORR ranged from 39–50% in FL (weighted mean 46%), 50–64% in MZL (weighted mean 56%), and 68% in WM. Responses were observed in patients previously exposed to cBTKi, including those with documented resistance, supporting activity independent of C481 binding. Median DoR was 5.5–5.8 months in FL and 8.5 months to not reached in MZL. In WM, the estimated 6-month DoR was 86%. Median follow-up ranged from 7–16 months. Treatment was generally well tolerated. Common adverse events included fatigue, diarrhea, contusions, and cytopenias. Grade ≥3 toxicities were mainly hematologic (neutropenia, anemia, thrombocytopenia). Treatment discontinuation due to adverse events was infrequent (2–17%). Conclusions: Non-covalent BTK inhibitors are effective, well tolerated, and capable of overcoming cBTKi resistance in relapsed or refractory indolent B-cell lymphomas (excluding CLL/SLL), supporting further prospective studies and real-world use.