Measurable Residual Disease-Guided Therapy for Chronic Lymphocytic Leukemia

Background

An interim analysis of progression-free survival in this trial showed that ibrutinib–venetoclax was superior to fludarabine–cyclophosphamide–rituximab (FCR) among patients with chronic lymphocytic leukemia (CLL). Whether ibrutinib–venetoclax is more effective than ibrutinib alone is unclear.

Methods

In this phase 3, multicenter, open-label trial, we randomly assigned patients with CLL to receive ibrutinib–venetoclax, ibrutinib alone, or FCR. The primary end points were undetectable measurable residual disease (MRD) in bone marrow within 2 years in the ibrutinib–venetoclax group as compared with the ibrutinib-alone group and progression-free survival in the ibrutinib–venetoclax group as compared with the FCR group. A powered secondary end point was progression-free survival in the ibrutinib–venetoclax group as compared with the ibrutinib-alone group. Other secondary end points included overall survival.

Results

A total of 172 of the 260 participants (66.2%) in the ibrutinib–venetoclax group had undetectable MRD in bone marrow within 2 years, as compared with none of the 263 participants in the ibrutinib-alone group (P<0.001) and 127 of the 263 participants (48.3%) in the FCR group. With a median follow-up of 62.2 months, disease progression or death occurred in 18 participants (6.9%) in the ibrutinib–venetoclax group, as compared with 59 (22.4%) in the ibrutinib-alone group (hazard ratio, 0.29; 95% confidence interval [CI], 0.17 to 0.49; P<0.001) and 112 (42.6%) in the FCR group (hazard ratio, 0.13; 95% CI, 0.08 to 0.21; P<0.001). Progression-free survival at 5 years was 93.9% with ibrutinib–venetoclax, 79.0% with ibrutinib alone, and 58.1% with FCR. Death occurred in 11 participants (4.2%) in the ibrutinib–venetoclax group, as compared with 26 (9.9%) in the ibrutinib-alone group (hazard ratio, 0.41; 95% CI, 0.20 to 0.83) and 39 (14.8%) in the FCR group (hazard ratio, 0.26; 95% CI, 0.13 to 0.50). Sudden death occurred in 3, 8, and 4 participants in the ibrutinib–venetoclax, ibrutinib-alone, and FCR groups, respectively.

Conclusions

With extended follow-up and increased enrollment, our trial showed that undetectable MRD and extended progression-free survival were more common with ibrutinib–venetoclax than with ibrutinib alone or FCR. The results for overall survival were also consistent with a benefit of ibrutinib–venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.)