MRD-guided treatment with ibrutinib + venetoclax: Updates from the FLAIR trial

Results from the multicenter, open-label, randomized, phase III FLAIR trial (ISRCTN01844152), which were previously covered by the Lymphoma Hub, demonstrated that measurable residual disease (MRD)-guided treatment with ibrutinib + venetoclax improved outcomes vs ibrutinib alone or fludarabine + cyclophosphamide + rituximab (FCR) in previously untreated patients with chronic lymphocytic leukemia (CLL).^1–3 Several updates from the FLAIR trial were presented by Hillmen¹, Evans², and Dalal³ during the 67th ASH Annual Meeting and Exposition 2025, December 6–9, 2025, Orlando, US.

The FLAIR trial was initially designed to assess FCR vs ibrutinib + rituximab and, due to a lack of benefit from adding rituximab, was adapted in 2017 to include an ibrutinib monotherapy arm and an MRD-guided ibrutinib + venetoclax arm.¹ Hillmen presented an analysis aiming to determine an optimal MRD-guided treatment approach.¹ Dalal presented an analysis of the impact of baseline gene aberrations on outcomes in the FLAIR trial.² Finally, Evans shared an analysis of treatment-related mutations in Bruton’s tyrosine kinase (BTK) as mechanisms of resistance in patients with progressive disease in the ibrutinib-containing arms.³

Results from these analyses suggest that MRD-guided ibrutinib + venetoclax is associated with deep and durable remissions across risk groups, may reduce the emergence of BTK-mediated resistance, and represents an effective treatment strategy for patients with previously untreated CLL.^1–3

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