Hello. Good morning, everyone, dear colleagues, we are here in Barcelona for the 19th iwNHL workshop. This is the end of the first session, which was devoted to T-cell lymphomas. Doctor Francine Foss and I, Laurence de Leval were chairs of that session, and we are happy to discuss here with three of the Panelists. So, we had an interesting session dealing with some of the biological, pathological and clinical advances in the treatment of those diseases. Doctor Lemonnier, Doctor Sibon and Doctor Horwitz are here to discuss some of their talks. So maybe I will start the way it happened this morning. And I will ask David first because one of the topics was more specifically intestinal T-Cell lymphomas. And doctor Sibon reported their experience with the CD30 targeting in that disease. So, David, may I ask you to summarize the nice data you presented this morning that elicited a lot of interests by the audience with good results, unprecedented results you showed us.

Yeah. Thank you, Laurence. Yes. As a background, EATL (Enteropathy-Associated T-Cell Lymphoma) is a rare PTCL with a poor prognosis and usually the overall, the median overall survival is only seven months, and the two year OS is two years. 20%, sorry. So, we need to improve these results and EATL usually strongly express CD30. So there is a rationale to target this lymphoma with brentuximab vedotin. So we conducted a Phase II trial, using BV, combined with CHP and responders received two cycles of etoposide plus methotrexate, followed by autologous stem cell transplantation. The endpoint, the primary endpoint was a 2-year PFS. So, 14 patients were in world during three years. Most of them were at high risk or intermediate risk, so, with usually, a prognosis. And the results were pretty good because the two-year PFS was 64% and the two-year OS two. In terms of response, most of the patients responded, and only three patients were primarily progressive and finally died because they could not be effectively salvaged. Of note: two patients, in response, died from the toxicity of autologous stem cell transplantation. So, these results are good compared to a historical control, but we have to be cautious with the procedure of autologous stem cell transplantation. Interestingly, for the nine patients still in response after transplantation, there was no relapse after medium follow up. Reaching now, three years.

Can I ask you on that? You know, I think, it was interesting. I mean, the data looks quite good, but in the data on autotransplant, we typically think a patient in remission going to autotransplant, we would quote them a 2% risk of dying from a complication of transplant. Do you think it was bad luck, or is there something about the disease or the patients that that they’re truly a higher-risk category?

Yes, that’s a very good question. It’s difficult to respond, because we have, the effective is small only for the patient, so we cannot exclude, exclude chance. But also, I think there is some fragility, some frailty for the patient. For the two patients who died during the procedure, the infection came from digestive bacterial translocation, and we cannot exclude that the intestine is not as normal as other other patients without this lymphoma. So maybe it’s chance. But maybe there is a specific frailty, digestive frailty of these patients.

Thank you, David. Is there a follow-up to that study? That’s a rare disease that’s most prevalent in Europe, maybe Northern US. But how do you plan on?

Yes. Now the enrollment is closed. So now we will soon publish the results. Now, for us, now, it is a standard treatment to to use a BV as in this trial for the patient. Now, the question could be: Do we need, do we still need the autologous stem cell transplantation? Because elderly patients could not be eligible for this treatment and for example, can we replace it with BV maintenance? It’s another question. And it would be necessary to do another prospective study if it’s possible. But I think it could be an option. The other thing is that we need to improve the treatment for some high-risk patients because we add in the study six high-risk patients and three of them did not respond to BV-CHP. So we don’t know. We have not specific biomarkers and it’s difficult with only 14 patients. But it’s another challenge to identify not-responding patients.

Thank you very much. Let’s maybe move to the other topics and those that were discussed by Dr Lemonnier and, Horwitz that were more, maybe more closely related. You dealt with epigenetic drugs and used even cutaneous T-cell lymphomas and developments. These are mostly known to pertain to lymphomas that are derived from the non-innate in the adaptive immune system as compared to the extranodal intestinal, which are more separate specific categories. So would you like Francois to summarize the state of the art?

The current status for the topic of the talk was the epigenetic drugs in T-cell lymphomas T-cell lymphoma has the particularity to have very frequent alterations in epigenetics and so far, single agent therapy with HDAC inhibitors or DNMT inhibitors, such as azacitidine has efficacy in those diseases where there is very few efficacy in other types of cancers. A single agent. But I think there’s a consensus to say that the activity of this agent is probably not enough, and we can do better. And so now, probably, we’re moving to a combination between these epigenetic drugs and other drugs. That could be maybe came over. That could be maybe other targeting drugs. And so we need to set up clinical trials to assess the different combinations. I think it was a very interesting discussion during the session regarding okay, now, what can we do in the clinical practice? Because we have the patients. Now we know that these these agents have efficacy, but we could do better based on the previous results and combination trials. And so we’re still, you know, we are still in the difficulties with the lack of availability to drugs and I think there’s an emergency to set up trials and to have access to new drugs for combination.

Are we speaking first line or relapsed/refractory patients or both?

I think so far the discussion was more for the relapsed/refractory patients.

It’s a really good, it’s a good debate. So what is the best first line therapy still CHOP or A-CHP, the best therapy, Or maybe could we replace CHOP by other therapies? I think it would be the next questions, but so far I think we don’t have the good… Because in your talk you spoke about the Ro-CHOP trial. You said that’s a negative trial, which still some analysis showed some results for TFH lymphoma. So, what’s your approach to first line treatment of those patients? Is it influenced by those results, or?

I don’t think people still do romidepsin CHOP as first line therapy, you know. Now, maybe the CC486-CHOP presented, you know, it’s only 20 patients, 17 TFH PCL patients, so it’s a small service, but the result was really good. So I think it has to be investigated, maybe in a larger study. Um, so for the first line. But personally, you know, I’m not sure the CHOP is the good option for T-Cell lymphomas. and just we still need to find the good treatment. And I really believe that combination based on epigenetic therapy is a good approach for those lymphomas.

Yeah. No, I largely agree, though. I think, you know, like we saw with the data and we see with ECHELON-2 and even in Ro-CHOP, the CHOP arm, there is a cure rate there. There’s a percentage of people that are cured with CHOP and, you know, at least for us, in the relapse setting, we don’t see cures with epigenetic therapy. We see responses, and we see maintained responses. But we don’t see unmaintained responses, and we don’t think we see cures. And I kind of think like a good lesson can come if we look at ECHELON-2 and we look at Ro-CHOP ECHELON-2 added a drug that didn’t add any more toxicity with BV, and its selected patients who were most likely to respond. And there was a statistical benefit. And with Ro-CHOP, just the knowledge at the time, it didn’t select patients based on likelihood of response, which maybe we now know who’s more likely, and it did add toxicity and there’s not a benefit. But in the follicular helper, there’s almost a benefit. So I imagine that if you had a drug like maybe it’s Azacitidine or CC486 or maybe it’s an EZH inhibitor or that added efficacy and no toxicity, that maybe in TFH it’s upfront. So it would be great to get away from CHOP, I think, from front line therapy. But we would need something better in curative and the cure rates with CHOP, like even in EATL, what you showed, you know, more than half of those patients are live in remission and, yeah. So, I think in the relapse we’re learning what drugs work and in who and how to select those patients. And then I still favor for front line until we have something else curative that we move that in with some sort of chemotherapy and, you know, in the context of trials, I mean, that’s I think, I think to me that’s where we are now, maybe not five years from now, but probably two years from now.

So maybe because it’s about epigenetics, Francois, as you know, I was quite interested in that SETD2 gene, which is mutated and inactivated in many highly aggressive T-Cell lymphomas. From the pathologist perspective, I read, I saw that this gene, also altering solid tumors, can be targeted by therapies. Do you think that potentially useful for lymphomas? Could it have implications for us?

For sure, MEITL is an unmet medical need. And so the question is how to target the SETD2 mutations. I understand some, there’s reports saying that SETD2 alterations is correlated with dependency to WEE1. And maybe it could confer sensitivity to WEE1 inhibitors. So definitely it could be, you know, it could be a way to explore in a clinical trial or to… but still, we need to have access to a good work to test. But definitely this is an interesting approach. And the other question, it’s personal, but I really think that the mutational landscape of the MEITL actually is ready to add Hepatosplenic T-cell lymphomas, the SETD2 mutations, STAT5B mutations. And now, and I think the clinical experience of MEITL with CHOP is not good. So I believe that, based on the relationship between MEITL and Hepatosplenic T-cell lymphoma, maybe we should treat the MEITL patients such, uh, in the same way that we treat the HSTL patients so to avoid CHOP as first-line and maybe in favor of azacitidine-based combinations.

Yeah. No, I agree. And I guess, contrary to what I just said about building on a CHOP backbone, I think there’s a handful of diseases where we think CHOP is not effective. We don’t see survival. And that’s MEITL and ATL and hepatosplenic and those. Yeah.

So, Steve, maybe would you like to summarize the broad overview you gave us about the new developments in the treatment of cutaenous T-cell lymphomas?

Yeah, Sure, I’m happy to. Thank you for the question. I was, you know, I was asked to kind of talk about what’s new. So it wasn’t really therapy-directed. It was just the disease side of cutaneous T-cell lymphoma. So I talked a little bit about the heterogeneity of the diseases which I think we have in T-cell lymphoma. And I think the earlier talks showed really nicely that different subtypes will probably be approached differently if we’re going to make progress. And then just went over some of the data that we have with some of the signaling targets with JAK stat inhibition or PI3 kinase inhibition. And if anything, those have been maybe more effective in some of the peripheral T-cell lymphomas, less active as single agents in cutaneous T-cell lymphomas. But we’re still learning about that. I talked a little bit about the very specific JAK2 fusions in the aggressive epidermotropic CD8-positive T-cell lymphomas, which is a very rare subset that seems to have a very specific

That was very impressive. The data you showed.

Uh, yeah, it really looks like in that very rare population where there’s this JAK2 fusion that that targeting that is going to be effective, very hard to study, because that’s such a rare disease. So we now have this cohort on our study open for anyone with a JAK2 fusion to go on. But if we get five patients in a year, that will be a lot. So you know, we’ll see if if we can build upon that, um and then I think the idea in immune therapy for cutaneous T-cell lymphomas makes a lot of sense. We get it, it’s a chronic disease. We really don’t want cytotoxic therapies. Those patients are at higher risk of complications from cytotoxic therapy because of the poor skin barrier. So really looking at data with checkpoint inhibitor, which is okay, And then some very early data with interrupting the CD47 pathway or cell therapy. And those are really Phase I studies, but idea is to try to get some long term remissions by looking at the immune response.

Thank you, Steve. And maybe to close this summary, one of the Panelists could not be present onsite doctor Cwynarski from London talked about the clinical trial with Car-T cells targeting TRBC1 and showed the results that we’re presenting at EHA. There was a lot of debate how to monitor the efficacy of those Car-T cells. And of course, the results are quite preliminary, with only a small number of patients. So thank you all for participating to this session.