Minimal residual disease – guided ibrutinib and venetoclax in patients with chronic lymphocytic leukaemia and complex karyotype

Complex karyotype (CK) is a strong predictor of early progression and poor survival in chronic lymphocytic leukaemia (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 MRD-guided ibrutinib and venetoclax (IVen) compared with a retrospective cohort treated with 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 consecutive undetectable MRD (uMRD) bone marrow assessments. Patients with detectable MRD after 24 months continue ibrutinib alone. Baseline characteristics showed numerical differences between cohorts that did not reach statistical significance. 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 progression-free survival (PFS) (33.9 months vs. NR; hazard ratio [HR] 0.23, p < 0.001) and overall survival (OS) (47 months vs. NR; HR 0.48, p = 0.0186) compared with Imono, although comparisons are limited by the retrospective control design. uMRD was achieved in 66% of patients with IVen. These results support MRD-adapted IVen as an optimal strategy for high-risk CLL.