ASH 2025 | MRD-guided treatment with ibrutinib and other agents in previously untreated CLL: analyses of FLAIR

It’s my absolute pleasure to talk to you about the results of the FLAIR study. We presented a number of abstracts for FLAIR. One of the abstracts which I presented was the long-term follow-up data on ibrutinib plus rituximab comparison to FCR. And what we have presented in this data said that we’ve now got a median follow-up of 97 months, which is a very long follow-up on this study. And the ibrutinib in combination with rituximab had a superior progression-free survival as compared to FCR. So the median PFS for IR is reached at 112 months, which is in excess of nine years as compared to 80 months for FCR. This difference was really stark in unmutated IGHV patients. And again, we found an overall survival advantage for ibrutinib rituximab with 60 deaths in the IR arm as compared to 86 deaths in the FCR arm. And again, the difference is stark in patients with unmutated IGHV. In this follow-up, there was no new safety signals that we saw, but the strength of the study now is the very long follow-up. And what we find is that the ibrutinib, which is the first-in-class BTK inhibitor, especially in unmutated IGHV patients, is giving superior PFS and OS compared to FCR and sets a benchmark for other second-generation BTK inhibitors.

We also presented other abstracts at ASH, which were oral presentations. And one of the abstracts was looking at the MRD-guided approach with the combination of ibrutinib and venetoclax. And we looked at the genetic subtypes, which patients are benefiting from which combination of therapy. And what we looked at is the I plus V versus ibrutinib versus FCR. And we were able to assess all the analysis by next generation sequencing, as well as FISH analysis and somatic hypermutation for the IGHV as well. What we’ve seen in this data as well is that with I plus V, the benefit was stark in the unmutated IGHV group, and that was superior as compared to ibrutinib and ibrutinib rituximab arm as well as FCR arm, whereas the difference was less palpable in patients with IGHV-mutated disease.

We also presented for the first time the data on stereotyped receptor subset 2. And again, in this group of patients, giving I plus V in an MRD-defined way led to an improved outcome as compared to ibrutinib given as continuous therapy or FCR. Again, for the ATM mutated or deleted patients, the I plus V patients are doing the best and the outcomes are extremely good for the 70 patients who have been treated with I plus V on this arm of the study. So in total, what we found in all the subsets with the different genetic mutations, that the MRD-guided I plus V improved the progression-free survival and overall survival, especially in the ATM deleted or mutated group, stereotyped subset 2, SF3B1, NOTCH1, and even TP53 mutated deleted group. And this again highlights the effectiveness of this MRD-defined way in this study.

We also presented some BTK mutation data in patients who are achieving ibrutinib on this therapy. And what we find in this analysis is that there was no BTK-resistant mutations found at baseline. But then 21% of the patients who were progressing on ibrutinib had a BTK mutation at either C481, T474, or L528 residues. And the treatment, these mutations were seen a few months before the patients developed progressive disease. So we went back and looked at all of this mutation data at different time points, and we were able to pick up these mutations beforehand. And in some patients, when the treatment was stopped before disease progression, the allelic burden of the BTK mutations had started to decrease already. We did not find any mutations in the I plus V arm of the data.

And finally, we also presented data on using uMRD4 as a halfway treatment point for ibrutinib venetoclax, and we showed the MRD relapse data for both FCR arm and I plus V arm in this study. And what we find is that the dynamics of MRD relapse is different. But with FCR, we were able to show that once the patients are MRD negative, the IGHV unmutated patients are quicker to show MRD relapse and subsequent disease progression. Whereas when we look at the I plus V patients, the unmutated patients are the ones who benefit the most from the combination. And the unmutated IGHV patients continue to essentially have more MRD negativity with continuous therapy. But the recurrence of the MRD is also seen in this trial. And nearly at four years time, 72.1% of the unmutated IGHV patients had MRD relapse. And we also showed the data on whether these patients were able to get back into MRD negativity if we retreat these patients. So in short, we were able to show that the MRD recurrence can be used as a surrogate for progression-free survival. What we find in IGHV mutated patients, it takes an average of six years from MRD recurrence to progressive disease. It’s especially in FCR patients. And in IGHV unmutated patients, it takes about average of three years from MRD recurrence to progressive disease. And hopefully this will highlight further advancement in treatment of CLL using MRD-guided approach.

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