Does Ibrutinib-Venetoclax Therapy Improve Outcomes in Untreated Chronic Lymphocytic Leukemia Compared With Fludarabine-Cyclophosphamide-Rituximab?

A recent phase 3 trial comparing ibrutinib-venetoclax (IBR-VEN) with fludarabine-cyclophosphamide-rituximab (FCR) for untreated chronic lymphocytic leukemia (CLL) found that ibrutinib-venetoclax therapy directed by measurable residual disease (MRD) improved progression-free survival (PFS) compared to FCR. Overall survival (OS) also favored the IBR-VEN regimen.

Treatment for CLL has evolved with targeted therapies such as ibrutinib and venetoclax, which have shown improved outcomes compared to traditional chemoimmunotherapy. However, the combination of ibrutinib and venetoclax, with treatment duration personalized based on MRD, had not been compared directly with FCR. This study aimed to assess whether this personalized approach with ibrutinib-venetoclax could lead to better outcomes, specifically progression-free survival and overall survival, than the standard FCR regimen.

This phase 3, multicenter, randomized, open-label study involved 523 patients with untreated CLL, randomly assigned to either the ibrutinib-venetoclax or the FCR group. In the ibrutinib-venetoclax group, after 2 months of ibrutinib, venetoclax was added, and therapy continued based on MRD levels. The duration of therapy was personalized to be twice the time required to achieve undetectable MRD in both peripheral blood and bone marrow. The primary endpoint of the study was progression-free survival in the ibrutinib-venetoclax group compared with the FCR group, with secondary endpoints including overall survival, MRD, response rates, and safety.

After a median follow-up of 43.7 months, disease progression or death occurred in 12 patients in the ibrutinib-venetoclax group and 75 patients in the FCR group (hazard ratio [HR], 0.13; 95% CI, 0.07 to 0.24; P < .001). Death occurred in nine patients in the ibrutinib-venetoclax group and 25 patients in the FCR group (HR, 0.31; 95% CI, 0.15 to 0.67). At 3 years, 58.0% of patients in the ibrutinib-venetoclax group had undetectable MRD, and at 5 years, 65.9% had undetectable MRD in the bone marrow and 92.7% in peripheral blood. The infection rates were similar in both groups, but the ibrutinib-venetoclax group had a higher incidence of serious cardiac adverse events (10.7% vs. 0.4%).

“MRD-directed ibrutinib-venetoclax improved progression-free survival as compared with FCR, and results for overall survival also favored ibrutinib-venetoclax,” the study authors concluded.

Reference

Munir T, Cairns DA, Bloor A, et al. Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. 2024;390(4):326-337. doi:10.1056/NEJMoa2310063