So TFH derived or follicular helper T cell derived uh peripheral T-cell lymphomas with angio angioimmunoblastic AITL being probably the most common group within that category. Um, they're a very interesting, uh, group. They're all derived, as I say, from this follicular T helper cell. It's the T cell that gives help to the developing B cell as it encounters antigen and makes its way through the germinal center to become either a memory B cell or a plasma cell. Now, its very job is to secrete cytokines to cause those B cells to develop. So actually when the TFH cell becomes malignant, it starts secreting cytokines in a fairly unregulated way. And this leads to a number of interesting clinical characteristics which you see in TFH derived lymphomas as opposed to non-TFH. So for example, you see breaking of tolerance, so you see development, for example, of autoimmunity. The classic ones being ITP when you have low platelets or autoimmune hemolytic anemia. You also see a polyclonal hypergammalobu anemia is very common, and a rash and the lymphadenopathy, certainly in AITL you do see it, but it tends to be relatively low volume. So we sometimes have a reasonably good clinical idea when something's gonna, gonna turn out to be an AITL, uh, this, as I say, commonest subtype of a TFH uh derived T cell lymphoma. Now, once that's been confirmed and the, the sort of biomarkers, the immunoh to chemical markers that the pathologist does in the center that I work at, they would typically apply a PD1 antibody, CD10, BCL-6. Those are the ones we tend to use. There are other markers though, that you can use CXCL 13, for example, ICOSS. We tend to not use those routinely in our in our pathology laboratory, but other centers will probably have their own sort of concoction which they can add. So if we see two or more of those markers, and also we want to look at the morphology, so AITL, for example, the clue is in the name. AO means there are a lot of blood vessels around, more than you would expect. Immunoblastics, so immunoblasts are large B cells, they're usually EBV positive, uh, and the contribution of that, those EBV positive immunoblasts to the pathogenesis is really quite unclear at the moment. And then of course there are uh abnormal T cell, uh T cells and it is a T cell lymphoma, so it's angioimmunoblastic T cell lymphoma. So the typical markers in the right morphological context, uh, would lead to the diagnosis. And then we would typically treat with chopp chemotherapy. Up front there is no. Uh, sort of AITL or TFH specific, uh, treatment that, uh, is licensed or used. We hope that as research develops, uh, and there are more subtype specific trials, uh, that we may be able to define a more TFH specific first line treatment. And actually, that's one point I would want to make is trials in the frontline treatment of peripheral T cell lymphoma. are very challenging. It's a rare disease, so the temptation is always to lump all the patients in together, the PTCL NOS's or and the ALCLs and the um TFH derived. But actually, because the biology is so different with each of these different subtypes, it's probably the wrong thing to do. And I think we're gonna be splitting up those subtypes more and looking at subtypes specific clinical trials. That's, I think, where the field needs to go. But of course it does need extensive international collab. Uh, if we're going to ask the right questions and actually recruit the right number of patients into those trials. One example I'd give there is the French did a very uh interesting study combining Romidepsin with COP, so-called Road Cop. This was, this was a, a sort of a lumper trial in that all the different types of PTCL went into the trial. Uh, it was compared with COP. It was a randomized phase 3, so a really good effort from the French. Uh, however, it showed no difference in progression free survival. However, when you took out, uh, and did a subgroup analysis of the TFH derived, particularly the AITLs, it looked. Like there may be a survival advantage starting to emerge, but because they hadn't powered the trial to look at that group, then really we couldn't say with any certainty, and that has not led to a change in practice as a result. So really important as we go forward to look at these individual subtypes. So with COP chemotherapy, what would I expect? I would expect an overall response rate of about 80%. I would expect most patients to actually respond. Um, and a CR rate, and that's what I really want. I would really want complete remissions of around the sort of 40 to 50% mark. But of course, what we really want is durable remissions, um, whereas actually the medium PFS from frontline treatment of Chop alone, uh, is, is, is a little less than a year really. So unfortunately, most patients do relapse, and I would expect to cure around 30% of patients with AI. TL or other, um, uh, TFH derived peripheral T cell lymphomas with COP alone. I wouldn't expect that to significantly increase with CHOEP and I also wouldn't expect it to significantly increase with BV chip. As I say, in the FDA CD30 positive, uh, peripheral T cell lymphomas, um, BV chip is licensed, but when you look at the subgroup analysis from the original trial of BV chip versus CHOP, Uh, all the benefit really was seen in the anaplastic large cell lymphomas, the AITLs as representative of the TFH lymphomas, didn't seem to benefit over CHOP, hence why, uh, in Europe and the UK the license is restricted to, uh, ALCL. So we're left with a population really of high end met need because what do we give when patients relapse? Uh, well, here in Europe and the UK we don't have many options. We really are left with chemotherapy, um, such as gem cytabine, such as potentially bendamustine. If I have a younger or fitter patient, I would be trying to get them to an allogeneic stem cell transplant. And so I may use combination chemotherapy second line to try and get them there, such as GDP, which is gem cytsine, cisplatin, dexamethasone, or gem ox gem cytopine oxaliplatin. And if the patient responds, great, then we might be able to bridge them to an allogenetic stem cell transplant, but that takes time. We need to find a donor, um. Uh, and, and, and, and it needs to be the right donor, and we need to book them in, uh, to the unit to have the alloe. And sometimes the, the patients unfortunately become chemo refractory and start progressing. So it's actually quite challenging to get patients to an allergenetic stem cell transplant, and often the patient actually isn't fit for what is a very intensive form of treatment anyway, in which case we really are left with single agent, uh, chemotherapy options. Sometimes in the third line setting, we might be able to use Brentuximab thedotin, the anti CD30. Antibody drug conjugate, but responses are modest and not particularly durable, and I certainly wouldn't expect to cure anybody, either with second line chemotherapy alone or with uh Brenttuximabvodotin alone. Other agents may prove active, so lenalidomide, for example, uh, which is an oral uh immunomodulatory drug, uh, has a response rate, probably a little under 50% if you look at most, um, uh, case studies in the literature. Uh, but some of those responses may be reasonably durable, albeit again, it is not a cure, and it has its own toxicity profile of fatigue, constipation, neutropenia, uh, etc. And that is not licensed, uh, for use in Europe and the UK, but we can sometimes use it off license, and now it's not on patent, it is actually relatively cheap and individual hospitals may, uh, agree to fund that or a patient may self-fund it. So, you know, we are in desperate need actually of new agents um in relapse refractory uh TFH derived uh peripheral T cell lymphomas.
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