ICML 2025 | Analysis of MRD data from the ENRICH trial: ibrutinib-rituximab vs R-chemotherapy in frontline MCL

So I presented the primary outcome of the ENRICH study at ASH in San Diego. So the ENRICH study was a randomized study in the first-line treatment of mantle cell lymphoma, randomizing investigator choice of R-CHOP chemotherapy or R-bendamustine chemotherapy versus Ibrutinib-rituximab in a stratified way. And the primary endpoint was positive, so we demonstrated an improvement in progression-free survival for patients who had ibrutinib-rituximab versus immunochemotherapy. Now, really importantly, that was completely driven, really, by the difference between the patients who had Ibrutinib-rituximab compared to R-CHOP. The comparison between Ibrutinib-rituximab and R-bendamustine was actually very similar in terms of progression-free survival. So although the study was positive, it was driven by the patients who had R-CHOP actually doing worse than we expected them to, and the improvement in progression-free survival of I-R over R-CHOP. 

So what I’m going to present at Lugano is we’ve also collected minimal residual disease data in these patients. The way we collected this was we collected it using eight-color flow cytometry, which has a sensitivity of 1 times 10 to the minus 5. And we collected that data at baseline, we collected it at the mid-induction time point, we collected it at the end of induction time point and at the end of maintenance. What we’ve shown actually is really quite large differences in the clearance of MRD based on the treatment type. So patients who have R-CHOP actually have relatively poor rates of MRD negativity, both at the mid-induction and end of induction rate time point. If you look at the patients who have R-bendamustine, almost universally they clear MRD positivity very quickly. So most patients are MRD negative by the mid-induction time point and they stay MRD negative all the way through. Now, the ibrutinib treated patients, despite the fact they had actually an improved PFS compared to the R-CHOP treated patients in particular, actually have much, much lower rates of MRD negativity and are much slower to convert to MRD negative. So significant proportions of the I-R treated patients actually remained MRD positive all the way through the induction time point, and there were still some MRD positive patients even at the end of maintenance. Although what we saw with the I-R treated patients was that they did gradually convert to MRD negativity as time went on, as you might expect, but that conversion was much, much slower than it was with patients who were treated with R-bendamustine. 

Now, when we started looking at the impact that this had on progression-free survival, actually, overall, when you look at the MRD positive versus MRD negative population, there wasn’t a huge difference. But when you split it by treatment type within the patients who had immunochemotherapy, there was quite a marked difference in progression-free survival based on MRD negativity at the end of induction. And when you look to the Ibrutinib-treated patients, that difference was not so marked. But actually, when you split that down by exactly what those progression events were, it’s quite interesting because MRD negativity really did strongly predict for a reduction in progression events. 

Now, one thing I haven’t mentioned yet is that the ENRICH study was conducted at the height of the COVID pandemic, and we had significant numbers of COVID-related deaths. And what’s interesting and quite sad actually is that a large number of the PFS events in the MRD-negative patients who were treated with Ibrutinib were actually COVID deaths. So we were losing large numbers of patients because of non-mantle cell lymphoma-related reasons while they were MRD negative on Ibrutinib and that completely cancelled out the PFS difference. So if anything what this study suggests is that actually in the future what we might use MRD for in BTK treated patients in first line is actually to interrupt treatment or even stop it if they’re MRD negative so they don’t then have a higher risk of dying of other things.

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