Research Summary

Ibrutinib–Venetoclax Outperforms Ibrutinib Alone and FCR in CLL: Long-Term Results from Phase 3 FLAIR Trial

Anthony Calabro, MA

Key Highlights

  • At 5 years, progression-free survival was 93.9% with ibrutinib–venetoclax versus 79.0% with ibrutinib alone and 58.1% with fludarabine–cyclophosphamide–rituximab (FCR).
  • Undetectable measurable residual disease in bone marrow within 2 years was achieved in 66.2% of the ibrutinib–venetoclax group, compared with 0% with ibrutinib alone and 48.3% with FCR.
  • Death occurred in 4.2% of participants treated with ibrutinib–venetoclax versus 9.9% with ibrutinib alone and 14.8% with FCR.
  • Ibrutinib–venetoclax showed superior disease control and survival outcomes compared with both standard and monotherapy options.

In this phase 3 multicenter trial published in the New England Journal of Medicine, treatment with the combination of ibrutinib and venetoclax resulted in significantly improved rates of undetectable measurable residual disease (MRD), progression-free survival (PFS), and overall survival (OS) in patients with chronic lymphocytic leukemia (CLL) compared with ibrutinib monotherapy or fludarabine–cyclophosphamide–rituximab (FCR). After a median follow-up of 62.2 months, the ibrutinib–venetoclax group demonstrated a 5-year PFS of 93.9%, compared with 79.0% for ibrutinib alone and 58.1% for FCR. Furthermore, MRD was undetectable in 66.2% of patients in the combination group within 2 years, a level not achieved by any patients in the ibrutinib monotherapy group.

While previous analyses had already shown superiority of the combination over FCR, the benefit over ibrutinib monotherapy remained unclear, particularly with respect to MRD status and long-term survival outcomes. The need to optimize frontline therapy for CLL, balancing efficacy and long-term disease control, formed the rationale for this investigation.

Participants were randomized to receive ibrutinib–venetoclax, ibrutinib alone, or FCR. The primary endpoints were the rate of undetectable MRD in bone marrow within 2 years when comparing the combination vs ibrutinib alone, and PFS when comparing the combination vs FCR. A powered secondary endpoint included PFS comparison between the combination and ibrutinib monotherapy, with additional secondary endpoints evaluating overall survival.

Out of 260 patients receiving ibrutinib–venetoclax, 172 (66.2%) achieved undetectable MRD in the bone marrow, versus none of the 263 patients on ibrutinib alone and 127 (48.3%) of the 263 patients on FCR. Disease progression or death occurred in only 6.9% of the ibrutinib–venetoclax group, compared with 22.4% in the ibrutinib-alone group (HR, 0.29; 95% CI, 0.17–0.49; P < .001) and 42.6% in the FCR group (HR, 0.13; 95% CI, 0.08–0.21; P <.001). Additionally, death rates were lower in the combination group (4.2%) than in the ibrutinib-alone (9.9%) and FCR (14.8%) groups. Sudden deaths were infrequent across all arms but lowest in the combination group.

“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 study authors concluded.

References
Munir T, Girvan S, Cairns DA, et al. Measurable residual disease-guided therapy for chronic lymphocytic leukemia. N Engl J Med. Published online June 15, 2025. doi:10.1056/NEJMoa2504341