MRD-Guided Ibrutinib plus Venetoclax in Untreated CLL

Targeted therapeutics — Bruton tyrosine kinase inhibitors (BTKi), anti-CD20 monoclonal antibodies, and the BCL2 inhibitor venetoclax — have become the mainstays of treatment for chronic lymphocytic leukemia (CLL). To investigate the combination of the BTKi ibrutinib plus venetoclax (Ibr/Ven) versus fludarabine, cyclophosphamide, and rituximab (FCR), investigators in the U.K. conducted a multicenter, open-label, partially industry-funded, phase 3 trial in 523 patients with previously untreated CLL.

In the Ibr/Ven group, the duration of treatment was determined by measurable residual disease (MRD) assessed by multiparameter flow cytometry in peripheral blood and bone marrow (maximum treatment, 6 years). Patients with >20% del(17p) were excluded from the study.

At a median follow-up of 44 months, disease progression or death had occurred in 12 patients in the Ibr/Ven group versus 75 in the FCR group (hazard ratio, 0.13). Estimated 3-year progression-free survival was 97% vs. 77%, respectively. Overall survival favored Ibr/Ven, with an estimated rate at 3 years of 98% versus 93% with FCR. At 3 years, 58% of patients in the Ibr/Ven group had stopped treatment because they achieved undetectable MRD (sensitivity threshold, 1 in 10⁴ cells). Serious blood and lymphatic events occurred in 5% of the Ibr/Ven group versus 31% of the FCR group, whereas serious cardiac events occurred in 10.7% versus 0.4%. Secondary cancers including myeloid malignancies were more frequent in the FCR group.