So for patients who um are diagnosed with a new diagnosis of T follicular helper phenotype T-cell lymphomas, um, this current standard of care continues to be giving CHP-based um chemotherapy with the intention of these patients being cured with their initial therapy, and then, um, there have been ways that people have tried to augment um that. So, um, CHP-based therapy as we've seen it through multiple registry studies including um the International teeth. Cell Project, the um Swedish National Lymphoma Registry, the US Complete Registry, um, all pretty much show that the outcomes for patients who have peripheral T cell lymphomas is relatively poor, including those of TFH phenotype. Um, we know that the 5 year survival to CHP-based therapy is approximately 20% with the, um, about about 30% and a 5 year progression free survival being about 20%, leaving a lot of room for improvement, um. So what have been ways to try to improve on that? So, um the study, um, some studies have looked at the addition of a topoide to, to, to CHP-based chemotherapy, and this was really explored by the German non-Hodgkin lymphoma Study Group that did an analysis combining their studies that included patients with T cell lymphoma and assessing when the addition of a topoide, giving it like 3 days in a row at a dose of. 100 mg per meter squared um by IV, um, in addition to CHP, um, to see if that improved outcomes. And what they found was that it looked like that increased the complete remission rate in uh uh to the chemotherapy, um, and we think that's important because the complete remission rate is associated with improved um outcomes overall. And, um. And so that really seemed to impact patients who are under the age of 60, um, the most, uh, but there's a trend to improving um the care of all patients and so for fit patients or certainly patients who are under 60, we consider the addition of a topoy to top um chemotherapy. Um, the, um, the other ways that people have tried to augment, um, chop-based therapy is the consideration of adding brintuximab. So the Echelon, um, 2 study, which led to the approval of brintuximabiddotin, the antibody drug conjugate to CD30, um, to, um, in peripheral T cell lymphomas, randomized patients who have peripheral T cell lymphomas to either brintuximab. CHP, so without the CHP, without vincristine versus um CHOP, and this, this study included about 70% of the patients had anaplastic large cell lymphoma, which universally expresses CD30. A much smaller subset of patients had AITL, um, and at that time, um, the term TFH phenotype peripheral T cell lymphoma didn't. and so um these really, really we, we can focus on the AITL patients. So in the patients who have AITL who were treated with BBCHP versus the patients who got Cho, the, the outcomes were not statistically um significantly different, um, and the study certainly wasn't powered for these subset analysis, but there seems to be a. Um, a trend towards patients who got chopped doing slightly better, if anything, than the patients who got um BBCHP, suggesting the addition of renttuximab in AITL or angioimmunoplastic T cell lymphoma, is probably not improving the outcome significantly, and this has been published by Dr. Horowitz and colleagues. Extending the survival out, so the follow-up out to 5 years. Um, so that's been another strategy, and I would say in my practice I tend not to give patients with AITL BV, CHP, um, for that reason, although rituximab is approved for for all peripheral T cell lymphomas expressing CD 30, even 1% or greater um in the frontline setting. So what are some other ways that people have tried to augment um therapy? um there has been a um a push to consider um further treatment in patients who are chemotherapy responsive, mainly in terms of an autologous stem cell transplant. So for those patients who achieve a complete remission to chemotherapy, you know, do they have improved outcomes when getting a consolidated beam autologous stem cell transplant? And this was studied by the. Um, Nordic lymphoma group, um, initially and then um there have been multiple, um, single center multicenter prospective and retrospective studies that have all shown basically the same thing. Um, they show that at 5 years, um, the median progression free the 5 year progression free survival in patients treated with chemotherapy with the intent to transplant in first remission is about 20% higher. It improves by from about 25%. to about 45% in five years. That's been seen in um prospective registry studies where um like the Swedish National Registry where they, the physicians had to indicate, um, at the time of registration whether there was an intent to consolidate with transplant. Um, we did a series as well, and then of course the um series that was published by Dr. Demori um articulated very similar results, suggesting that for patients who are chemotherapy responsive. There may be a role for a consolidated autologous transplant. Um, however, this area, I would say continues to be hotly debated as well. Um, the, um, this has never been studied head to head in a randomized fashion. There's, um, concerns that the um data that we see may be biased by um physician and patient preferences, um, and, uh, patient characteristics that help physicians have a gut feeling about who to transplant and not to transplant. And so there are 22 randomized studies currently ongoing to explore that question. One is being led by Lisa in France, where patients who are in complete remission with peripheral T cell lymphoma are randomized to an auto versus not an auto, um, an observation, and then a similar study being led by Nora Beneni through the US Intergroup and ECOG, which also looks at the same question. So I think we'll have the answer. To that, um, soon, some of the more recent analysis from the um EBMT um that have been presented at Ash last year suggest that maybe the consolidated auto transplant actually helps the TFH patients a little bit more, but again, I think this is going to be better um vetted in the context of these um prospective randomized studies that are asking the same question, um, internationally. And then I would say the um. The other methods that we're thinking about and, and have been studying to augment um chop-based therapy include the addition of novel agents to chop. Um, so there have been studies um being led by GO1, adding azocytidine to CHOP. Um, Azocytidine has been um studied by Ari Melnick and colleagues to um potentially improve um the sensitivity of um chemotherapy. Responses, um, there's some thought that the changes in the methylation allowed the cells to be more susceptible to the damage of chemotherapy and um that has led to studies in older patients with diffuse large B cell lymphoma that are being run through the US Intergroup, but also um to your one study which showed that the complete remission rate um from um adding uh azocytidine to CHO in peripheral T cell lymphomas um was um almost 85%. Um, and these patients of the 20 patients in that study, 17 have TFH phenotype lymphoma. So we really think maybe um beneficial in that subset. Um, that has led to um the US Intergroup study, which I'm fortunate to lead, uh, where patients based on their age get either CHP or COA chemotherapy, and, um, 1/3 of the patients get chemotherapy alone, 1/3 of the patients get oral azocytidine with top orcho, and 1/3 of the patients get a PI3 kinase inhibitor. Called Duvali, which also seems to have preferential activity in TFH phenotype lymphomas, and um that study is currently uh accruing um called AO 51902, uh, and hopefully that will help us answer some of these questions about how to optimize therapy for TFH phenotype lymphomas and try to attack them at areas of vulnerability.
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