Ibrutinib and Rituximab vs Fludarabine, Cyclophosphamide, and Rituximab in Previously Untreated Patients With CLL

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As reported in The Lancet Oncology by Peter Hillmen, MBChB, PhD, and colleagues, an interim analysis of the UK phase III FLAIR trial has shown significantly improved progression-free survival with ibrutinib and rituximab vs fludarabine, cyclophosphamide, and rituximab (FCR) in previously untreated patients with chronic lymphocytic leukemia (CLL).

Peter Hillmen, MBChB, PhD

Peter Hillmen, MBChB, PhD

Study Details

In the multicenter open-label trial, 771 patients were randomly assigned between September 2014 and July 2018 to receive ibrutinib/rituximab (n = 386) or FCR (n = 385).

Treatment consisted of either:

  • Ibrutinib at 420 mg/day for up to 6 years and rituximab at 375 mg/m² on day 1 of cycle 1 and at 500 mg/m² on day 1 of cycles 2 to 6 of 28-day cycles
  • Fludarabine at 24 mg/m² per day on days 1 to 5, cyclophosphamide at 150 mg/m² per day on days 1 to 5, and rituximab as above for up to six cycles.

The primary endpoint was progression-free survival in the intention-to-treat population.

Progression-Free Survival

At prespecified interim analysis for progression-free survival at a median follow-up of 53 months (interquartile range = 41–61 months), median progression-free survival was not reached in the ibrutinib/rituximab group vs 67 months (95% confidence interval [CI] = 63 months to not reached) in the FCR group (hazard ratio [HR] = 0.44, 95% confidence interval [CI] = 0.32–0.60, P < .0001). Rates at 4 years were 85.6% (95% CI = 81.3%–89.0%) vs 73.0% (95% CI = 67.7%–77.5%).

Hazard ratios for progression-free survival favored ibrutinib/rituximab across all subgroups examined. Subgroups for which hazard ratios were significant included: IGHV unmutated CLL (HR = 0.41, P < .0001), ATM deletion (HR = 0.29, P = .0010), and normal karyotype (HR = 0.38, P = .0010).

In the FCR group, 47 patients received targeted therapies (either a BCL2 inhibitor or BTK inhibitor) after disease progression or withdrawal from trial treatment. At the time of analysis, death had occurred in 8% of patients in the ibrutinib/rituximab group vs 8% in the FCR group. Rates at 4 years were 92.1% (95% CI = 88.6%–94.5%) in the ibrutinib/rituximab group vs 93.5% (95% CI = 90.1%–95.7%) in the FCR group (HR = 1.01, 95% CI = 0.61–1.68, P = .96).


  • Ibrutinib/rituximab significantly improved progression-free survival vs FCR.
  • Median progression-free survival was not reached vs 67 months; 4-year rates were 85.6% vs 73.0%.

Adverse Events

The most common grade 3 or 4 adverse event was leukopenia in both the ibrutinib/rituximab group (14%) and the FCR group (54%). Serious adverse events occurred in 53% vs 54% of patients. 

The 4-year cumulative incidence of other diagnosed cancers was 7.4% in the ibrutinib/rituximab group vs 17.3 % in the FCR group. Deaths in three patients in the ibrutinib/rituximab group and in two patients in the FCR group were considered probably related to treatment. A total of eight sudden unexplained or cardiac deaths occurred in the ibrutinib/rituximab group, with two occurring in the FCR group.

The investigators concluded, “Front-line treatment with ibrutinib and rituximab significantly improved progression-free survival compared with fludarabine, cyclophosphamide, and rituximab but did not improve overall survival. A small number of sudden unexplained or cardiac deaths in the ibrutinib and rituximab group were observed largely among patients with existing hypertension or history of cardiac disorder.”

Talha Munir, MBChB, PhD, of St. James’s University Hospital, Leeds, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Cancer Research UK and Janssen. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.