Untreated CLL
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Cycles 1–3 | |||
| Ibrutinib | 420 mg once daily | Oral | Continuous |
| Cycles 4–15 | |||
| Ibrutinib + venetoclax | Ibrutinib 420 mg; venetoclax with a 5-week ramp-up to 400 mg once daily | Oral | Continuous |
Measurable Residual Disease-Guided Therapy for Chronic Lymphocytic Leukemia
Munir T, Girvan S, Cairns DA, Bloor A, Allsup D, Varghese AM, et al. N Engl J Med. 2025. 393:1177-1190
- Study type
- Clinical trial
- Study name
- FLAIR
- Phase
- Phase 3
- Design
- Randomised, multicentre, open-label trial with three groups (ibrutinib–venetoclax, ibrutinib alone, FCR)
- Sample size
- 786 patients in the three compared groups (260 ibrutinib–venetoclax, 263 ibrutinib alone, 263 FCR)
- Source
- N Engl J Med · 2025
- Trial registration
- ISRCTN01844152
In plain words
In this large UK trial, the combination of two tablets, ibrutinib and venetoclax, taken for a length of time decided by very sensitive tests for leftover disease (MRD), controlled the disease better than ibrutinib alone or FCR chemo-immunotherapy: five years after starting treatment, about 94% of patients in the combination group had no disease progression.
Key results
93.9% (ibrutinib–venetoclax), 79.0% (ibrutinib alone), 58.1% (FCR)
Five-year progression-free survival
HR versus ibrutinib alone 0.29; versus FCR 0.13; median follow-up 62.2 months
66.2% vs 0% (ibrutinib alone) and 48.3% (FCR)
Undetectable MRD in the bone marrow within 2 years
P<0.001 versus ibrutinib alone
4.2% vs 9.9% and 14.8%
Deaths
HR 0.41 versus ibrutinib alone; 0.26 versus FCR
Drugs in this study:Cyclophosphamide (Endoxan)Ibrutinib (Imbruvica)Rituximab (Rituxan/MabThera)Venetoclax (Venclexta)
Dose and schedule cards
Fixed-duration ibrutinib + venetoclax (GLOW; FLAIR with MRD-guided duration)
Untreated CLLCycle length: Every 28 daysOn the page “Blood cancers (leukaemia, lymphoma and myeloma)” · Treatment regimens and dosing in leukaemias
Fixed-duration ibrutinib + venetoclax (GLOW; FLAIR with MRD-guided duration)
Untreated CLL; in GLOW, patients aged 65 years and older, or aged 18 to 64 years with a CIRS score above 6 or CrCl below 70 mL/min, ECOG ≤2On the page “Leukaemia” · Regimens and dosing in CLL: fixed-duration targeted therapy
Untreated CLL; in GLOW, patients aged 65 years and older, or aged 18 to 64 years with a CIRS score above 6 or CrCl below 70 mL/min, ECOG ≤2
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Cycles 1–3 (lead-in) | |||
| Ibrutinib | 420 mg once daily | Oral | Continuous |
| Cycles 4–15 | |||
| Ibrutinib | 420 mg once daily | Oral | Continuous |
| Venetoclax | 5-week ramp-up to 400 mg once daily | Oral, with food | Continuous |
The doses are from the GLOW abstract; in FLAIR, treatment duration was guided by MRD monitoring, and the details are in the full text of the paper. This combination is not in the US FDA label.
On the page “Leukaemia” · Regimens and dosing in CLL: fixed-duration targeted therapy
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Treatment arms and regimens
1Ibrutinib + venetoclax
Ibrutinib 420 mg orally daily for 8 weeks, then addition of venetoclax with a 5-week ramp-up to 400 mg per day. Ibrutinib–venetoclax continued for up to 6 years unless MRD-based stopping rules were met (treatment continued for twice the time needed to reach the first undetectable MRD in the blood) or unacceptable toxicity or disease progression occurred; if treatment was stopped and needed restarting based on MRD, ibrutinib–venetoclax was given again (260 patients).
2Ibrutinib alone
Ibrutinib 420 mg orally daily for 6 years, with MRD-based stopping rules, or until unacceptable toxicity or disease progression; on restart, ibrutinib alone was given (263 patients).
Fludarabine 24 mg/m² per day and cyclophosphamide 150 mg/m² per day orally on days 1 to 5, with IV rituximab 375 mg/m² on day 1 of cycle 1 and 500 mg/m² on day 1 of cycles 2 to 6; every 28 days, 6 cycles in total. If nausea, vomiting or diarrhoea occurred in the previous cycle, fludarabine and cyclophosphamide were given IV from the next cycle (because of concern about inadequate absorption) (263 patients).
Source of the regimen details: Ibrutinib and venetoclax: full text of the accepted manuscript (White Rose repository, Randomisation and Procedures section); FCR doses: the published FLAIR protocol (Trials 2017; PMC5568356); MRD stopping and restart rules: the FLAIR methodology paper (Trials 2021; PMC7792072)
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Study population
Patients aged 18 to 75 years with untreated chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma requiring treatment according to IWCLL criteria (Binet stage B, C or progressive A) and considered fit for FCR; 99 hospitals in the UK. Key exclusion criteria: Richter transformation, symptomatic cardiac disease and 17p deletion in more than 20% of cells (FISH); from a September 2014 amendment, long-term oral anticoagulation and a cardiac event requiring dual antiplatelet therapy were also exclusion criteria.
Endpoints
Primary endpoints: undetectable MRD in the bone marrow within 2 years (ibrutinib–venetoclax versus ibrutinib alone) and progression-free survival (ibrutinib–venetoclax versus FCR). Powered secondary endpoint: progression-free survival of ibrutinib–venetoclax versus ibrutinib alone; other endpoints included overall survival.
Safety and side effects
The most common grade 3 to 5 adverse event in the first year was neutropenia: 27.2% (ibrutinib–venetoclax), 6.5% (ibrutinib) and 47.3% (FCR); grade 3 febrile neutropenia: 1.9%, 0.4% and 6.3%. Hypertension 17.1%, 20.8% and 1.7%; atrial fibrillation or arrhythmia 13.6%, 12.7% and 1.7%. Serious cardiac adverse events in the two ibrutinib-containing groups 10.4% and 10.9% versus 0.4% with FCR; 14 major bleeds (5, 6 and 3 cases). In the ibrutinib–venetoclax group, clinical tumour lysis syndrome occurred in 1 patient and laboratory tumour lysis syndrome in 14, all of which resolved. Sudden death occurred in 3, 8 and 4 participants in the ibrutinib–venetoclax, ibrutinib-alone and FCR groups, respectively.
Clinical significance and place in guidelines
FLAIR showed that all-oral ibrutinib–venetoclax with MRD-guided duration gives longer progression-free survival than FCR and than continuous ibrutinib, and it supports the use of fixed-duration targeted therapy in first-line CLL.
Limitations
The trial was open-label; treatment duration in the ibrutinib–venetoclax group was individualised based on MRD monitoring, which requires sensitive laboratory assays.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.