Clinical characteristics and outcome of a cohort of CLL patients with BTK T474 gatekeeper mutation

BTK T474 gatekeeper mutations confer resistance to both commercially approved covalent and non-covalent BTK inhibitors (BTKis) in chronic lymphocytic leukemia (CLL), yet their clinical implications remain poorly characterized. While pirtobrutinib was developed to overcome resistance mediated by BTK C481 mutations, its use has been increasingly associated with the emergence of BTK T474, which is associated with resistance to this and commercially available BTKis. We retrospectively analyzed 17 relapsed/refractory CLL patients from two academic centers who acquired BTK T474 mutations on BTKi therapy, integrating paired next-generation sequencing (NGS), cytogenetics, and clinical outcomes. Results showed that this was a heavily pretreated, high-risk cohort; 42% had del(17p) and/or TP53 mutations. T474I was the most common substitution (82%). At first T474 detection, patients were receiving ibrutinib (6/17), acalabrutinib (5/17), pirtobrutinib (5/17), or nemtabrutinib (1/17); median time on the current BTKi at time of mutation detection was 28 months (range, 4-69). Concurrent BTK C481 mutations were present in 14/17 (82%). Median T474 VAF at progression was 13%, and all patients progressed after T474 detection with a median time to progression of 4 months. Non-BTK mutations were frequent (82%), most commonly TP53 and SF3B1. After progression, venetoclax-based therapy produced the longest median progression-free survival (18 months). Median overall survival was 44 months from first documentation of T474 mutation (95% CI, 20-62) and PFS after T474 detection was 6 months. This analysis showed that BTK T474 emergence identifies a high-risk CLL population with rapid progression after detection, underscoring the need for effective post-BTKi strategies.