Paper Details

ABSTRACT

Introduction
The phase III FLAIR trial (ISRCTN01844152) evaluated first-line treatment strategies for fit patients with chronic lymphocytic leukaemia (CLL). In 2017, the protocol was amended to include an ibrutinib-only (IBR) arm and a measurable residual disease (MRD)-guided ibrutinib-venetoclax (I+V) arm. Earlier analyses demonstrated that MRD-guided I+V significantly improved response rates, progression-free survival (PFS), and overall survival (OS) compared with IBR or fludarabine-cyclophosphamide-rituximab (FCR). With extended follow-up, the dataset is now mature, with up to 7 years of follow-up across all treatment arms.

FLAIR enrolled 1487 participants across four arms; for this analysis, IBR and IBR-rituximab (IBR-R) are combined. A total of 578 participants received FCR, 649 received IBR/IBR-R, and 260 were randomised to MRD-guided I+V. MRD-guided end-of-treatment (MRD-EoT) occurred at twice the time required to achieve confirmed uMRD4 (defined as sustained PB uMRD4 for ≥6 months with BM confirmation), with a minimum of 2 years and maximum of 6 years of therapy.

This analysis reports updated PFS, OS, MRD kinetics, and retreatment outcomes for MRD-guided I+V after a median follow-up of 74 months.

Methods
Participants were randomised 1:1:1:1 to MRD-guided IBR, MRD-guided IBR-R, MRD-guided I+V, or FCR. The primary endpoint for I+V vs FCR was PFS. Secondary endpoints included PFS for I+V vs IBR/IBR-R, OS, MRD relapse patterns, retreatment outcomes, health-related quality of life, and cost-effectiveness. Participants experiencing MRD relapse within 6 years in the I+V arm were permitted to restart I+V to complete 6 years of combination therapy. This update reports clinical and MRD outcomes at final analysis.

Results 
With a median follow-up of 74 months (IQR, 51-93), median PFS was 74 months for FCR, 112.8 months for IBR-R and not reached for I or I+V. At the date of download, 335 progressions occurred in the FCR arm, 177 in IBR-R, 79 in IBR, and 26 in I+V, with estimated 7-year PFS rates of 45.3%, 70.0%, 66.8% and 91.7%, respectively. MRD-guided I+V was superior to FCR (HR 0.16, 95% CI 0.11–0.24; p<0.001), to IBR-R (HR 0.37, 95% CI 0.24–0.57; p<0.001) and to IBR (HR 0.29, 95% CI 0.19–0.45; p<0.001).

In IGHV-unmutated (UM) CLL, I+V was superior to FCR (HR 0.11, 95% CI 0.06–0.19; p<0.001), to IBR-R (HR 0.29, 95% CI 0.16–0.53; p<0.001). and to IBR (HR 0.26, 95% CI 0.13–0.49; p<0.001). In IGHV-mutated (M) CLL, I+V remained superior to FCR (HR 0.38, 95% CI 0.20–0.70; p=0.0020), to IBR-R (HR 0.62, 95% CI 0.32–1.19; p=0.0024)  and to IBR (HR 0.40, 95% CI 0.20–0.80; p=0.0095).

At the date of download, deaths occurred in 134, 66, 30 and 12 participants in the FCR, IBR-R, IBR, and I+V arms, respectively. CLL-related deaths were reported in 14 participants (7 FCR, 7 IBR-R). The leading causes of death was infection for FCR (15), cardiac-related death for IBR-R (11), IBR (5) and I+V (3). MRD-guided I+V improved OS compared with FCR (HR 0.26, 95% CI 0.14–0.48; p<0.001) , with IBR-R (HR 0.42, 95% CI 0.22–0.80; p=0.0077). and with IBR (HR 0.36, 95% CI 0.19–0.71; p=0.0029).

In the I+V arm, 112, 139 and 159 participants have stopped therapy at 2, 3 and 4 years respectively per MRD stopping rules, while 29 discontinued early due to toxicity or death. MRD-guided discontinuation was more frequent in IGHV-UM than IGHV-M CLL.

MRD relapse occurred in 20 participants in the I+V arm and 4 in the IBR/IBR-R arm. Among I+V participants, 17 had IGHV-UM CLL, 2 had IGHV-M CLL, and 1 had unclassifiable IGHV status. All restarted I+V. Median time on treatment before stopping was 24 months, and median time from stopping to MRD relapse was also 24 months. 96/112 (85.7%), 115/139 (82.7%) and 127/159 (80.0%) participants respectively who stopped I+V at 2, 3, or 4 years remain MRD-relapse-free and progression-free at current follow-up. 

Conclusions
This 74-month update from FLAIR demonstrates the durability of responses achieved with MRD-guided I+V. MRD relapse remained uncommon, including in IGHV-UM CLL, despite treatment cessation. The depth and persistence of MRD responses suggest that fixed-duration, MRD-guided I+V may confer functional cure in a subset of patients. Further updated analyses will be presented at the ASH meeting.