ASH 2024 | The use of molecular immune signatures for frontline treatment selection in advanced-stage FL

There are currently three regimens approved by the FDA as a frontline treatment for patients with follicular lymphoma advanced stage and high tumor burden. Two of them are represented by chemoimmunotherapy, and they are represented by DR (bendamustine-rituximab), or R-CHOP. And this is based on results of two very large randomized Phase III pivotal trials. There’s been also a very large randomized Phase III trial called the RELEVANCE trial comparing chemoimmunotherapy to immunotherapy with a combination of lenalidomide and rituximab, also referred to as R-squared. Unfortunately, the study was not positive because immunotherapy was not superior to chemoimmunotherapy as a frontline treatment. As such, it’s not formally approved by the FDA as a frontline treatment, but because it was non-inferior, it’s currently part of the NCCN guidelines. So in the United States, unfortunately it’s not the same outside of the US, we are currently able to prescribe in frontline either BR, R-CHOP or R-squared. 

However, we currently have no clinical or biological markers that we can utilize to select treatment options. So in this study, we were able to retrospectively analyze by bulk RNA sequencing with the convolution, tissue biopsies that were collected before initiating frontline chemoimmunotherapy or immunotherapy in follicular lymphoma patients with advanced stage and high tumor burden. As a first step, we tried to understand if there was any biological difference across prognostic groups utilizing either FLIPI score, FLIPI-2 score, or Prima PI. What we saw was that patients who had high-risk disease by FLIPI score, they tended to have less B-cell receptor diversity and also a more regulatory T-cell type of signature. But beyond that, we didn’t see any major biological difference, pointing to the fact that we cannot really utilize prognostic factors to select treatment options. As a next step, we compared signatures across the treatment types. And what we saw is that patients who had a normal B-cell associated gene signature, they seem to perform much better in terms of progression-free survival when treated with BR as compared to immunotherapy. Whereas those who had very high T-cell associated signatures, they tended to do better, again, in terms of longer, significantly longer progression-free survival when treated with immunotherapy. Of course, this is still a small study. Overall, less than 40 patients were enrolled, and we need larger data sets and validation, but this is very promising. What this is pointing at is that we can most likely utilize immune gene signatures to select treatment options in follicular lymphoma patients.

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