Measurable Residual Disease–Guided Therapy for Chronic Lymphocytic Leukemia

Introduction 

The phase 3 FLAIR trial investigated whether measurable residual disease (MRD)–guided therapy with ibrutinib and venetoclax offers superior outcomes for patients with previously untreated chronic lymphocytic leukemia (CLL), compared to ibrutinib monotherapy or standard fludarabine–cyclophosphamide–rituximab (FCR) chemotherapy. Ibrutinib, a BTK inhibitor, and venetoclax, a BCL2 inhibitor, act on different disease pathways. Earlier studies, including GLOW and CAPTIVATE, showed the potential of this combination, particularly when MRD is used to guide treatment duration.

Methodology

A total of 786 patients aged 18 to 75 were randomized into three groups: ibrutinib–venetoclax, ibrutinib alone, or FCR. Treatment in the ibrutinib arms could be stopped early based on MRD response, using a predefined algorithm. The primary endpoints were undetectable MRD in bone marrow within two years (ibrutinib–venetoclax vs. ibrutinib) and progression-free survival (PFS) (ibrutinib–venetoclax vs. FCR). A key secondary endpoint was PFS in the ibrutinib–venetoclax vs. ibrutinib comparison.

Results

MRD negativity in bone marrow within two years was achieved in 66.2% of patients in the ibrutinib–venetoclax group, compared to none in the ibrutinib-alone group and 48.3% in the FCR group. After a median follow-up of 62.2 months, disease progression or death occurred in 6.9% of patients in the combination group, 22.4% in the ibrutinib-alone group, and 42.6% in the FCR group.

Five-year PFS was 93.9% with ibrutinib–venetoclax, 79.0% with ibrutinib, and 58.1% with FCR. Five-year overall survival (OS) was also higher in the combination group (95.9%) compared to ibrutinib alone (90.5%) and FCR (86.5%). Patients with unmutated IGHV benefited most from the combination therapy (ibrutinib–venetoclax), showing better outcomes than ibrutinib alone.

In terms of safety, ibrutinib–venetoclax had fewer grade ≥3 adverse events than FCR, especially neutropenia (27.2% vs. 47.3%). Common adverse events of any grade were fatigue and neutropenia. The most common serious adverse event was infection, which was reported in 172 participants (61 in the ibrutinib–venetoclax group, 66 in the ibrutinib-alone group, and 45 in the FCR group).

Conclusion

MRD-guided ibrutinib–venetoclax therapy significantly improved undetectable MRD, progression-free survival, and overall survival compared to both ibrutinib monotherapy and FCR. The approach was particularly effective in patients with unmutated IGHV and allowed for treatment personalization based on MRD response.

Although this strategy involves longer treatment and MRD monitoring, its clinical benefits and favorable safety profile suggest it may represent a new interesting option for CLL treatment.

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