EHA 2026 | Why have BTK inhibitors not had the same impact in FL as in other B-cell malignancies?

You know, follicular lymphoma is a unique lymphoma, of course. It comes from a germinal center B-cell. And the BTK pathway does not appear to be the driver, the main driver, at least in the majority of cases of follicular lymphoma. Follicular lymphoma does have its own mutational landscape. Mutations which occur in follicular lymphoma are often associated with germinal center evolution, some genes which are responsible for epigenetic reprogramming. And so it is different than, for example, mantle cell lymphoma or CLL, which are very B-cell receptor signaling BTK dependent. So follicular lymphoma, not as much. Although BTK clearly contributes to follicular lymphoma cell survival, it often is not the main driver. And however, it doesn’t mean that BTK inhibitors cannot be effective in follicular lymphoma. Again, it’s a very heterogeneous disease. And in the era of precision oncology, there would be some cases of follicular lymphoma which are more reliant on signaling through the B-cell receptor pathway due to the mutational landscape. And that is illustrated by the success of the ROSEWOOD regimen, which combined zanubrutinib with obinutuzumab in third-line plus follicular lymphoma and resulted in a progression-free survival median close to two years. I do think that BTK inhibitors can be good sensitizers, and I do think that is why partially this regimen is successful as obinutuzumab is obviously a very effective agent in relapsed follicular lymphoma and it is possible that zanubrutinib somehow enhances ADCC mediated and complement-dependent cytotoxicity mediated by obinutuzumab. So I think part of it is through the combination. So we’ll see what other studies occur in follicular lymphoma and how BTK class moves in this disease.

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