MRD-Directed Ibrutinib Venetoclax Therapy Improved Survival for Patients With Untreated CLL Compared With Fludarabine-Cyclophosphamide-Rituximab Therapy

According to a phase 3, multicenter, randomized, controlled, open-label platform trial, ibrutinib venetoclax therapy characterized by personalization of treatment duration according to measurable residual disease (MRD) improved progression-free survival (PFS), as well as demonstrated favorable results for overall survival (OS) as compared with fludarabine–cyclophosphamide–rituximab among patients with untreated chronic lymphocytic leukemia (CLL). 

In the ibrutinib–venetoclax group, after 2 months of ibrutinib, venetoclax was added for up to 6 years of therapy. To achieve undetectable MRD, the duration of ibrutinib-venetoclax was doubled. This was defined by MRD assessed in patients’ peripheral blood and bone marrow. The primary end point was PFS in the ibrutinib–venetoclax arm as compared with the fludarabine–cyclophosphamide–rituximab arm. Key secondary end points were OS, response, MRD, and safety.

This trial included 523 patients who were randomly assigned to the ibrutinib–venetoclax group or the fludarabine–cyclophosphamide–rituximab group. At a median of 43.7 months, disease progression or mortality was documented in 12 patients in the ibrutinib–venetoclax group and 75 patients in the fludarabine–cyclophosphamide–rituximab group (hazard ratio [HR], 0.13; 95% confidence interval [CI], 0.07 to 0.24; P <0.001). At 3 years, 58% of the patients in the ibrutinib–venetoclax arm had stopped therapy due to achieving undetectable MRD. After 5 years of ibrutinib–venetoclax therapy, 65.9% of the patients were noted to have achieved undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. 

Regarding adverse events, the risk of infection was similar in the ibrutinib–venetoclax group and the fludarabine–cyclophosphamide–rituximab group. The percentage of patients with cardiac serious adverse events was higher in the ibrutinib–venetoclax group than in the fludarabine–cyclophosphamide–rituximab group (10.7% vs. 0.4%). Death occurred in 9 patients in the ibrutinib–venetoclax arm and 25 patients in the fludarabine–cyclophosphamide–rituximab arm (HR, 0.31; 95% CI, 0.15 to 0.67). 

Talha Munir, PhD, Department of Clinical Hematology, Leeds Cancer Center, United Kingdom, et al concluded, “MRD-directed ibrutinib–venetoclax improved progression-free survival as compared with [fludarabine–cyclophosphamide–rituximab], and results for overall survival also favored ibrutinib–venetoclax.”

Source:

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