So one quite interesting class of drugs, uh that is being investigated in peripheral T cell lymphoma, in particular, the TFH derived subtypes uh are are PI3 kinase inhibitors. We've actually had PI3 kinase inhibitors around for quite a while. They've been developed for use in chronic lymphocytic leukemia and other indolent, uh, B cell non-Hodgkin lymphomas, but it makes sense to look at them in T cell lymphoma, because, uh, peripheral T-cell lymphomas are often at least partly driven by activation of the T cell receptor. Uh, and that involves the PI3 kinase pathway, which also includes MTOR and other, um, kinase enzymes. Now, uh, the one that's of particular interest at the moment is duvaicip, which particularly inhibits the gamma and delta isoforms of, um, of PI3 kinase. Um, it's an oral drug, uh, as I say it, um, managed to get a license for a lapse refractory, uh, CLL. And we've known for some time as well that one issue with PI3 kinase inhibitors is that there is a a a a a very sort of toxicity, uh, quite unique toxicities associated with them. So these toxicities include things like deranged liver function tests and neutropenia. Now that's fairly common to many agents. Uh, but also autoimmune reactions such as a pneumonitis or a colitis that are not always, uh, infectious. But there are also uh signals of infection. So for example, atypical infections with PJP in the lungs, pneumocystis, uh, or with, uh, CMV colitis, for example, are also a signal that you do see with PI3 kinase inhibitors. So, uh, it, it's generally fallen out of favor to use these in, in sort of fairly good prognosis lymphomas, but here we have a really very poor prognosis lymphoma, relapse refractory, uh, peripheral T cell lymphoma, TFH subtype, um, and the Primo study was a phase two study which was investigating. Um, the signal of activity really and the safety of using juvelici in relapsed refractory peripheral T cell lymphoma, not just AITL. Now we actually had the data presented from, from, from their expansion cohort, um, in 2024 at the main American Society of Hematology meeting. Now this was a fairly large study. Remember, it's a rare disease, so it was just over 120 patients. Uh, this was using, uh, the sort of optimized dosing of 75 mg, uh, twice a day for the first two cycles, falling to 25 mg twice a day. The idea there being that the initial higher dose would achieve some tumor control, and then the lower dose would hopefully, uh, maintain that tumor control, but also reduce the risk of side effects. And what they showed is in the combined group of relapsed refractory peripheral T cell lymphoma, there was an overall response rate of just under 50%, uh, and a complete response rate. Uh, of just over 30%. Now that's actually a very interesting signal of activity for what is a very high risk, uh, disease. I think there was a median number of lines of treatment of two, so these really were quite a high risk, uh, patient group. Uh, what was very intriguing, however, is when they broke those patients down and had a look at the individual subtypes, so NOS versus AITL, and AITL Aromenoblastic T cell lymphoma, was the second commonest subtype represented in that patient group. The overall response rate rose to over 60%, which is a very interesting signal of activity. Uh, and the progression free survival, which was only just about 3.5 months in the whole cohort, went to just over 8 months, uh, in the AITL cohort. That really does make us, uh, sit up and take notice of this agent. Um, and this could represent, uh, uh, uh, you know, a new standard if it's, uh, investigated properly and goes, goes through the, uh, developmental, uh, hurdles. And the other reason I just want to point out why it's so important that we look at these molecularly targeted agents is by this point, patients are chemo refractory, and that's really the big problem we have, uh, with T cell lymphoma is. Compared to B cell lymphoma, uh, T cell lymphoma is relatively chemo refractory, particularly when you've used your best chemo, which is COP or COE or BV chip upfront. Once that fails, actually trying to get chemotherapy to work, uh, usually is, is unsuccessful. So we need these novel, targeted agents, uh, to really try, uh, and get some benefit for patients in this very difficult area.
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