Dr Woyach on the Prevalence of Mutations in Previously Treated Patients With CLL

Jennifer A Woyach, MD, hematologist-oncologist, professor, the Division of Hematology, the Ohio State University Comprehensive Cancer Center– James, discusses the prevalence of recurrent genomic alterations in apoptotic machinery in patients with previously treated chronic lymphocytic leukemia (CLL) who were refractory to B-cell receptor pathway (BCR) inhibitors.

Woyach and colleagues presented findings from a phase 2 multicenter study (NCT02141282) at the 2023 iwCLL Annual Meeting. The study evaluated treatment with venetoclax (Venclexta) monotherapy in patients who had received prior ibrutinib (Imbruvica; arm A; n = 91) or idelalisib (Zydelig; arm B; n = 36). Along with evaluating efficacy end points such as objective response rate (ORR), progression-free survival (PFS), minimal residual disease, and overall survival (OS), a genetic analysis served as an exploratory end point.

Data from the clinical follow-up of the trial looked similar to what had been previously published, Woyach begins. The ORR for all patients was 66%, including 65% for arm A and 69% for arm B. Venetoclax elicited a median PFS of 33.7 months (95% CI, 21.8-46.2) for all patients, 24.7 months (95% CI, 19.2-40.9) for patients in arm A, and 43.4 months (95% CI, 20.1–not evaluable) for patients in arm B. There were no new safety signals with this long-term analysis, she notes.

Furthermore, differences in PFS were not observed for patients harboring pre-existing BTKmutations, she continues. However, longer OS was seen in patients who did not harbor pre-existing BTK mutations, which may be indicative of the fact that those patients weren't on ibrutinib or were intolerant to the BTK inhibitor, rather than resistant to it, Woyach states.

In the patients with the pre- and post-treatment samples available for the genetic analysis, 5 of 33 evaluable patients lost BTK mutations during treatment with venetoclax, and Woyach notes that this points to a possible avenue to re-sensitize select patients to a covalent BTK inhibitor. TP53 mutations were acquired by 4 patients during treatment. Additionally, 9 of 30 patients who experienced disease progression had a detectable BCL-2 mutation, compared with 4 of 38 38 patients who did not progress.