EHA 2022 | Genetic lesions driving PMBCL pathogenesis and outcomes

Well, we have identified genetic lesions in a number of pathways that fuel the PMBCL pathogenesis and these pathways are also in RNA expression profiles, also, upregulated, which is NF-kappa-B pathway, the JAK-STAT interferon pathway. And, we have also identified, and this was also known before that PMBCL uses a lot of genetic lesions that help them to escape the immune system. And there’s also a starting point for future therapies. And these are already starting right now in PMBCL. So there’s a big genetic landscape with a lot of driver mutations from different pathways that fuel the lymphoma genesis in this disease. And we discovered, by correlating some, or many, of these mutations, genetic lesions, we started to uncover which one might have a prognostic impact in PMBCL.

And I think, especially with the advent of immunotherapies, I’m not sure if one should use these markers we have identified in multi-variable analysis. I’m not sure if one should use them for risk stratification right now, because it was a retrospective trial and not a randomized control trial. But they certainly can inform about biologically active pathways that might help to develop future therapies. I think it will be vital for future studies to take these results that we have generated and to try to validate them in prospective and randomized clinical trials, if they ever exist in PMBCL because it is a very rare lymphoma. But also, I think it will be vital to also consecutively sequence patients that are relapsing, that are refractory, that are relapsed and see which kind of markers or genetic lesions have an impact on the relapse rate in these patients.

And because relapses are not that common in this disease. Most of the patients are cured with primary immunochemotherapy. And of course, we want to reduce toxicity in these patients and want to see, well, maybe R-CHOP for this one is enough, maybe the other one needs a little bit more dose intensified regimens. But we also ultimately want to totally avoid, if possible, these relapse cases, because they do very, very poorly. And this question, I cannot answer, how to prevent these relapse cases with the study we just made. We have to answer this in future studies in when we sequence relapsed and refractory, especially refractory patients.