Research Summary

MRD-Directed Therapy Improves Progression-Free Survival For Patients With Chronic Lymphocytic Leukemia vs Standard Treatment

Anthony Calabro, MA

In a recent phase 3, multicenter, randomized, controlled, open-label platform trial, researchers found that in untreated patients with chronic lymphocytic leukemia (CLL), measurable residual disease (MRD)-directed ibrutinib–venetoclax therapy had superior progression-free survival compared with the standard treatment, fludarabine–cyclophosphamide–rituximab (FCR).

The researchers set out to determine whether combining ibrutinib and venetoclax or ibrutinib monotherapy for the treatment of CLL improves key measures like progression-free survival compared with the standard FCR treatment for those with untreated CLL. Additionally, the researchers investigated whether personalizing the duration of ibrutinib–venetoclax therapy based on MRD would be more effective than FCR.

Between July 20, 2017, and March 24, 2021, a total of 523 patients recruited from 96 hospitals in the United Kingdom were randomly assigned in a 1:1:1 ratio to receive either FCR (n = 263), ibrutinib monotherapy, or ibrutinib–venetoclax (n = 260). The median age of the participants was 62 years (31% of the participants were older than 65 years of age) and 71% of the patient population were men.

In the ibrutinib–venetoclax group, patients initially received 2 months of ibrutinib monotherapy, followed by the addition of venetoclax for up to 6 years of therapy. The duration of ibrutinib–venetoclax treatment was determined by MRD assessment in peripheral blood and bone marrow, with the therapy lasting double the time required to achieve undetectable MRD. The primary endpoint was progression-free survival in the ibrutinib–venetoclax group compared with the FCR group, and key secondary endpoints included overall survival, response rates, MRD status, and safety.

Results from the trial showed that at a median follow-up of 43.7 months, disease progression or death occurred in fewer patients in the ibrutinib–venetoclax group (12 patients) compared with the FCR group (75 patients; hazard ratio [HR] = 0.13; 95% CI, 0.07 to 0.24; p < 0.001). The risk of death was also lower in the ibrutinib–venetoclax group (9 and 25 patients, respectively; HR = 0.31; 95% CI, 0.15 to 0.67). Additionally, the estimated 3-year progression-free survival was 97.2% (95% CI, 94.1 to 98.6) with ibrutinib–venetoclax and 76.8% (95% CI, 70.8 to 81.7) with FCR.

Importantly, 58.0% of patients in the ibrutinib–venetoclax group discontinued therapy at 3 years due to undetectable MRD. After 5 years of ibrutinib–venetoclax treatment, 65.9% of patients had undetectable MRD in the bone marrow, and 92.7% had undetectable MRD in the peripheral blood. The incidence of infection was similar between the two groups, but the ibrutinib–venetoclax group showed a higher percentage of patients with cardiac severe adverse events vs the FCR group (10.7% vs 0.4%, respectively).

“In this trial, MRD-guided ibrutinib–venetoclax, including individualized treatment duration beyond undetectable MRD, resulted in significant improvement in progression-free survival and an apparent benefit with respect to overall survival among patients with previously untreated CLL,” the authors concluded. “Benefits appeared to be particularly marked in patients who tend to have poorer outcomes with standard treatments.”



Munir T, Cairns DA, Bloor A, et al. Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. Published online December 10, 2023. doi:10.1056/NEJMoa2310063