Ibrutinib Plus Venetoclax with MRD-Directed Duration of Treatment Is Superior to FCR in Previously Untreated CLL

Combination of the Bruton Tyrosine Kinase inhibitor (BTKi) Ibrutinib plus the B-cell leukemia/lymphoma 2 (BCL2) inhibitor venetoclax improves chronic lymphocytic leukemia (CLL) outcomes compared to chemoimmunotherapy in patients with previously untreated CLL. It is hypothesized that defining treatment duration of ibrutinib + venetoclax using individual minimal residual disease (MRD) response would further optimize outcomes in this setting.1 Based on this rationale, the randomized phase 3 FLAIR (ISRCTN01844152) trial evaluated the efficacy and safety of MRD-guided treatment duration of ibrutinib + venetoclax compared to oral fludarabine, oral cyclophosphamide, and rituximab (FCR) in patients with previously untreated CLL. The study design was modified in 2017 to compare FCR to 2 treatments arms, ibrutinib alone and ibrutinib + venetoclax. The planned analysis results of this trial for the comparison of FCR to ibrutinib + venetoclax were presented at the 2023 American Society of Hematology annual meeting and summarized here.

The FLAIR study is a multicenter, controlled, open, parallel group trial that enrolled patients with untreated CLL at 96 UK Centers from July 20, 2017 to March 24, 2021; the study excluded patients with >20% 17p deleted cells.2 In the combination arm, venetoclax was added (4-week dose escalation to 400mg/day) following 2 months of ibrutinib lead-in; ibrutinib + venetoclax for 2 to 6 years thereafter, with duration of ibrutinib + venetoclax defined by MRD (<1 CLL cell in 10,000 [flow cytometry]).2 MRD was assessed at 12 months in peripheral blood (PB) and then every 6 months; if negative, assessment was repeated at 3 months in PB and 6 months in bone marrow (BM).2 If all were MRD negative, then the duration of ibrutinib + venetoclax was double the time between start of ibrutinib + venetoclax and the initial MRD-negative PB (ibrutinib + venetoclax duration: 2 to 6 years).2 The primary end point was investigator-assessed progression-free survival (PFS); key secondary end points were overall survival (OS), International Workshop on Chronic Lymphocytic Leukemia (IWCLL) overall response, MRD, and safety. Date of data-lock was May 23, 2023.2

A total of 523 patients were randomized to receive FCR (n=263) and ibrutinib + venetoclax (n=260).2 The median age of study population was 62 years; the majority of patients were male (71.3%), had Binet Stage C (42.1 %), and had unmutated IGHV (49.9%). FISH alterations identified were 11q del (18.2%), trisomy 12 (16.4%), and 13q del (35.8%).2 Following the MRD stopping rules, 49.9% of patients stopped ibrutinib + venetoclax at 27 months and 72.9% at 51 months.2

At a median 43.7 months, the PFS rate at 3 years was 97.2% in the ibrutinib + venetoclax arm and 76.8% in the FCR arm, with a hazard ratio (HR) for PFS of 0.13 (P<.0001).2 This PFS benefit was consistent across gender, age, or stage subgroups. PFS benefit also translated to significant improvement in OS with ibrutinib + venetoclax therapy versus FCR therapy (HR 0.31; P<.005); at 3 years, 2.0% versus 7.0% of patients in the 2 groups had died, respectively.2 PFS and OS benefit was also seen in patients with unmutated IGHV; PFS at 3 years was 98.3% with ibrutinib + venetoclax versus 70.9% with FCR (P<.001) and OS at 3 years was 99.2% versus 93.9% (P=.022), respectively.2 This benefit was not observed in patients with IGHV-mutated disease.2 PFS benefit was also observed in patients with FISH abnormalities with ibrutinib + venetoclax versus FCR; ATM(11q)deletion (P<.001), trisomy 12 (P=.002), and 13qdeletion (P<.001).2

At 9 months (3 months post-FCR), a similar proportion of patients in the FCR and ibrutinib + venetoclax groups achieved MRD negativity in BM (48.3% vs 41.5%); however, continued ibrutinib + venetoclax treatment resulted in a higher proportion of patients becoming MRD negative.2 The odds of MRD negativity at any time for ibrutinib + venetoclax versus FCR were 2.03 (P<.001) in BM and 3.91 (P<.001) in PB. At 9 months, a higher proportion of patients treated with ibrutinib + venetoclax therapy achieved complete response ([CR]; 59.2% vs 49%) and overall response (86.4% vs 76.4%), with an odds ratio estimate of 1.51 to achieve CR with ibrutinib + venetoclax (P<.05).2

More than half the patients reported serious adverse events (SAEs) in both the FCR and ibrutinib + venetoclax arms; these included infections (18.8% vs 22.2%), blood and lymphatic events (31% vs 5%), and cardiac disorders (0.4% vs 10.7%).2 Overall, 72 secondary malignancies were diagnosed in 56 patients; of these 39 cases were in the FCR cohort and 17 in ibrutinib + venetoclax cohort.2 The incidence of other cancers per 100 patient-years was greater for FCR than ibrutinib + venetoclax (5.4 vs 2.6).2 Overall, 8 cases of MDS/AML were reported in the FCR cohort versus 1 in the ibrutinib + venetoclax cohort.2 Seven deaths have occurred related to treatment (6 FCR, 1 ibrutinib + venetoclax).2 Two sudden/cardiac deaths occurred in the FCR group and 3 in the ibrutinic + venetoclax group; 2 of the 3 deaths in the ibrutinib + venetoclax group occurred after treatment was completed.2

These results indicate that MRD-guided treatment duration of Ibrutinib+ venetoclax significantly improved survival outcomes compared to FCR in untreated CLL. The authors concluded that “the efficacy seen in FLAIR is superior to previous phase 3 CLL trials indicating that ibrutinib + venetoclax with duration guided by MRD is a new gold standard for CLL treatment.”


  1. Munir T, et al. Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. 2023. doi: 10.1056/NEJMoa2310063. Epub ahead of print.
  2. Hillmen P, Cairns D, Bloor A, et al. Ibrutinib plus venetoclax with MRD-directed duration of treatment is superior to FCR and is a new standard of care for previously untreated CLL: report of the phase III UK NCRI FLAIR study. Presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, December 9-12, 2023; San Diego, CA: Abstract 631.

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