ASH 2025 | The impact of baseline gene aberrations on PFS and OS in patients with CLL in the FLAIR trial

So we’ve been looking at the molecular analysis of almost 1,500 patients which were recruited onto the FLAIR trial. FLAIR is a phase three multicentre trial looking at treatment naive, physically fit, CLL patients requiring therapy. And here we’ve looked at the impact of baseline mutations on five-year progression-free and overall survival in the different treatment arms of FLAIR. The trial initially opened in 2014 with just two treatment arms. This was comparing the covalent BTK inhibitor ibrutinib in combination with rituximab and the standard of care at the time, which was chemoimmunotherapy or FCR. In 2017, FLAIR was further adapted by the addition of the combination of ibrutinib plus the BCL2 inhibitor venetoclax and an ibrutinib monotherapy arm. The monotherapy arm was added as it was clear that there was no additional advantage of adding rituximab to ibrutinib. 

The ibrutinib-containing arms were MRD-guided in the FLAIR trial. So at the point at which a patient’s measurable residual disease in the peripheral blood was below one CLL cell in 10,000 leukocytes, or what we call MRD4, then their time on treatment was doubled. And so all patients were planned to stop therapy either according to MRD, so that’s between two and six years, or after completing six years of therapy. And if a patient became MRD positive again during this time, then treatment was restarted. And the modelling behind this treatment strategy was that the CLL levels would continue to fall at a similar rate after becoming undetectable, to a point where we had one cell, or CLL cell, in 100 million leukocytes, or 10 to the minus 8, and that this level might be potentially curative. 

In the current analysis, we looked at a panel of recurrently mutated genes at baseline, which included those that we know are associated with a poor risk in CLL, such as TP53, ATM, NOTCH1 and SF3B1. Additionally, we also looked at FISH for chromosomes 11q, 17p, 13q and chromosome 12, as well as IGHV somatic hypermutation analysis. And these were all again performed at baseline. And for the main part of the FLAIR trial, patients who were 17p deleted were excluded. As part of the IGHV analysis, we also looked at stereotype B-cell receptors and reported on stereotype subset 2. This is the most common stereotype subset that is associated with the poorer outcome following chemoimmunotherapy. 

Results from this study on the FLAIR trial have shown that MRD-guided treatment with a combination of ibrutinib and venetoclax was highly effective in overcoming the adverse prognostic effects associated with IGHV unmutated status, stereotype subset 2, and recurrent poor-risk genetic aberrations compared to FCR and ibrutinib monotherapy. We saw a significant improvement in five-year progression-free and overall survival across most genetic abnormalities, including TP53, ATM, SF3B1, and NOTCH1. Approximately two-thirds of the patients in these poor risk groups and half with TP53 mutations achieved MRD negativity and stopped treatment with ibrutinib plus venetoclax after two or three years. The results for the MRD guided I+V for patients with TP53 abnormalities are really promising. However, we need further follow up and more patients to make definitive conclusions, and to enable this, a high-risk arm for patients with TP53 aberrations was added to the FLAIR trial in 2021. Here we recruited an additional 21 patients who were randomized to either I+V or ibrutinib monotherapy, and we’ll be reporting on these patients soon.

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