Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease
FLAIR Phase III RCT (n=523) found ibrutinib-venetoclax (duration of treatment dependent on time taken to achieve measurable residual disease) was superior to FCR chemotherapy in terms of progression-free survival (HR 0.13; 95% CI 0.07-0.24; p<0.001).
Source:
New England Journal of Medicine
SPS commentary:
This study, conducted in the UK, included patients with previously untreated CLL or small lymphocytic lymphoma, who were considered to be fit for treatment with FCR (fludarabine, cyclophosphamide and rituximab). It used an individualized duration of ibrutinib–venetoclax that is double the time taken to achieve undetectable measurable residual disease (MRD). Although it included an ibrutinib monotherapy arm, an interim analysis showed that the combination of ibrutinib and venetoclax was superior in achieving undetectable MRD. This publication reports the results of a planned interim analysis comparing RD-guided ibrutinib–venetoclax with FCR.
After a median follow-up of 43.7 months, disease progression or death occurred in 4.6% in the ibrutinib-venetoclax group and 28.5% in the FCR group. In a subgroup analysis, the benefit of ibrutinib–venetoclax with respect to progression-free survival was seen across all subgroups except patients with mutated immunoglobulin heavy-chain variable region (IGHV). 3-year overall survival was 98.0% vs. 93.0%, respectively (HR for death 0.31; 95% CI 0.15-0.67).
The MRD-driven approach led to 28.9% of the patients in the ibrutinib–venetoclax group to stop therapy by 2 years, and 58.0% by 3 years. The authors note that no plateau was seen in achievement of undetectable MRD in peripheral blood, suggesting that continued therapy informed by MRD is justified.
Consistent with previous findings, there were more cardiac serious adverse events reported with ibrutinib-venetoclax (10.7% vs. 0.4%), but these did not translate into an increased risk of sudden death.