One of the things we're doing is, you know, as you see with CD30 uh directed therapy is moving away from one size fits all. So when we had limited therapies and uh T cell lymphomas were all treated the same, everyone will get the same combination chemotherapy with variable outcomes. And now we're just moving into more sub subtype directed therapy. So I think the first step was ALCL or CD30 directed therapy. I think the next thing that's sort of coming around the horizon is with follicular helper T cell lymphomas. So we know that what was called angioimmunoblastic T cell lymphoma and now still is that for one subtype and then some similar lymphomas called um TFH or follicular helper T cell lymphomas, that those really develop on a backbone of epigenetic dysregulation. Most patients have underlying clonal hematopoiesis, so they have founder mutations and things like TE 2 and DNMT3A, which may be in the broader um uh hematopoietic progenitor cells. And then usually when they get a T cell lymphoma, they get private mutations where things like row A, IDH2, or additional mutations, and those would be specific to the T cell lymphomas, uh, different than when people get myeloid disease, uh, uh, with underlying clonal hematopoiesis. And what we've seen is that those patients can respond to combination chemotherapy. The cure rates are not as good as they are with ALCL, um, but they also respond in the relapse setting to epigenetically targeted therapies, um, things like azocytidine or histone deacetylase inhibitors like Romodepsin or biliostat. And now we're starting to see higher responses to other, um, uh, types of therapy that aren't epigenettically targeting necessarily like PI3. Kinase inhibitors. Um, right now, those therapies have not migrated into the first line setting, um, in terms of showing benefits in PFS or OS, um, but I think that's coming. Um, one example of that was a study done in France, uh, adding Romipsin to CHOP versus CHOP. So this was a randomized study, standard dose CHOP or COP plus Romipsin, which is a histone deacetylase inhibitor. Uh, took sort of all comers with different types of T cell lymphoma, uh, and it was a negative study. There was really no difference in response rate or PFS or OS, um, um, uh, when you add Romodepsin, um. However, they did a subset analysis unplanned, so this is hypothesis generating, but retrospectively look at the fol looked at the follicular helper T cell lymphoma patients, which ended up being about half the patients on the study. And when you look at those patients, they have about a doubling of their progression free survival when. You give Romodpsin plus CHO versus chop alone. If you look at the other non-TFF TFH patients, they actually do a little worse with Romodpsin plus CHop, probably because the Romodpsin added toxicity, mostly hematologic toxicity that reduce the uh dose intensity of the chemotherapy. So that was a negative study, but with a possible clue as a way to go forward, um, so that, that, um, concept is still out there. Can you add something to combination chemotherapy that specifically targets TFH lymphomas or particularly effective in TFH lymphomas, and can we do better in that subset? Um, there's some early attempts looking, there's a uh. A cooperative group study going on in the US, uh, which randomizes patients to a cytidine plus CHO or COE, Duvollicid plus Chopper COE or Chopper COEs. It's a randomized phase two, so it won't be conclusive, but it's kind of, uh, looking at these strategies. Can we take medications in the, um, that we think are better for a subtype in the relapse setting and move them up front, um. And then that kind of brings us to uh peripheral T-cell lymphoma, not otherwise specified which is um shrinking in terms of its incidence because we're starting to better define other subtypes. So it is sort of a waste vascular, it's a group of T cell lymphomas that have different biologies, um. Still approach those patients with combination chemotherapies, but not as many advances in ways to specifically target um that subset of diseases. Probably we need to um uh subset it down a little further, understanding different biologies. There is some work going on, looking at different expression patterns or different uh um uh mutation patterns to try to predict how we may more individualize that treatment. Right now, we mostly have things like predictors of poor response to chemotherapies, things like, uh. T53 alterations or CDKN2A or something called TP 63, where some of these alterations and tumor suppressor genes, um, uh, define a group of patients that have lower chance of cure with combination chemotherapy. But right now for that subset of disease, we don't have tremendous targets of things that we think could really move forward in the frontline setting. So, um, uh, those patients tend to be treated with standard combination chemotherapies, hoping for a cure, but then looking at new agents and relapse refractory setting if patients are not cured.
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