MRD-guided ibrutinib and venetoclax in patients with chronic lymphocytic leukemia and complex karyotype

Complex karyotype (CK) is a strong predictor of early progression and poor survival in chronic lymphocytic leukemia (CLL), including during targeted therapy. Minimal residual disease (MRD)–guided therapy may improve outcomes by enabling deeper remissions and limiting clonal evolution. We present the final results of a prospective fixed duration MRD-guided ibrutinib and venetoclax (IVen) compared with a retrospective cohort treated with continuous ibrutinib monotherapy (Imono). Eligible patients had CLL with high CK (≥ 5 aberrations) or CK with deletion 17p. The IVen cohort received 3 months of ibrutinib followed by up to 24 months of IVen combination therapy or until three consecutives undetectable MRD (uMRD) bone marrow assessments. Patients with detectable MRD after 24 months continue ibrutinib alone. A total of 106 patients were included (IVen n = 50; Imono n = 56). With a median follow-up of 42.1 months, IVen significantly improved PFS (median 33.9 months vs not reached; HR 0.23, p < 0.001) and OS (median 47 months vs not reached; HR 0.48, p = 0.0186) compared with Imono. uMRD was achieved in 66% of patients with IVen. CR/PR and discontinued therapy. Toxicity, mainly infections, were manageable and similar to those recorded in the Imono. These results support MRD-adapted IVen as an optimal strategy for high-risk CLL.