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ASH 2022 | Highlights in T-cell lymphoma: unmet needs, clinical trial updates, and future outlooks

Kate Cwynarski, FRCP, FRCPath, PhD, University College Hospitals London NHS Foundation Trust, London, UK, and Swaminathan Iyer, MD, The University of Texas MD Anderson Cancer Center, Houston, TX, discuss key updates in T-cell lymphoma presented at the 2022 ASH Annual Meeting. First, Dr Cwynarski and Dr Iyer discuss the importance of real-world data (RWD) in this space, and the need to further address CNS relapse in patients. Following this, the experts comment on treatment options for patients with relapsed disease, and the need to design studies that incorporate more information on disease biology. To conclude, Dr Cwynarski and Dr Iyer discuss exciting novel approaches being explored in T-cell lymphoma, including combination therapies with anti-PD1 inhibitors, and the role of AUTO4, a novel TRBC1-targeting CAR-T cell therapy, in this space. This discussion took place at the 64th ASH Annual Meeting and Exposition congress held in New Orleans, LA.

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Transcript (edited for clarity)

Kate Cwynarski:

Hi. I’m Kate Cwynarski. I am the lymphoma lead at UCLH. I’m delighted to be here with Dr Swami Iyer, who leads the T-cell lymphoma program at the MD Anderson and we’re delighted to speak to VJHemOnc on highlights in T-cell lymphoma at ASH 22.

Swaminathan Iyer:

Thank you, Kate. It’s also an important conversation this morning on T-cell lymphomas...

Kate Cwynarski:

Hi. I’m Kate Cwynarski. I am the lymphoma lead at UCLH. I’m delighted to be here with Dr Swami Iyer, who leads the T-cell lymphoma program at the MD Anderson and we’re delighted to speak to VJHemOnc on highlights in T-cell lymphoma at ASH 22.

Swaminathan Iyer:

Thank you, Kate. It’s also an important conversation this morning on T-cell lymphomas. Kate, what do you think has caught your eye so far?

Kate Cwynarski:

Well, there’ve been a number of exciting things. I think it’s important to highlight initially the real-world data we’ve had. I mean really highlighting how miserable the prognosis for many of our patients with T-cell lymphoma still is. So there’s a huge cohort of, I think, over 800 patients with HTLV-1. Really reminding us that throughout the world their prognosis is really poor with median overall survival in months. Not even in years and really not very different in the US to the Caribbean or Japan. I also think it was really helpful to have the update from the Nordic study, which was a prospective study. Initially published in JCO, but we had more than ten-year follow-up. But again, a reminder that more than 50% of patients are going to relapse so thinking about that when we first see patients. These are even the fit transplant-eligible patients and less than 50% are alive and disease-free.

And one of my other highlights was the data about CNS relapse in T-cell lymphoma. We’ve always sort of thought it’s similar in terms of the risk factors to patients with B-cell lymphoma, but there was a really large dataset from Upenn. Which was helpful to clarify risk factors for CNS relapse and also give us some sense of the incidence. But I think again, I’ve mentioned about relapsed T-cell lymphoma, what about your highlights for how we can deal with this really challenging reality?

Swaminathan Iyer:

I agree and I think it’s given that patients with T-cell lymphoma relapse, and I’m sure many of you understand this problem. The promising studies that we are looking for, I think the update from the [inaudible] led by Dr Lemonnier and looked at azacitidine. Azacitidine is an old drug but it’s an oral formulation. Those compare the best supportive care, gemcitabine, romidepsin. And the pre-specified endpoints were not met. However, the pre-specified endpoint was the PFS, it’s about five and a half months to two months comparatively. But the oral survival is pretty long for oral azacitidine. So I think this is something that I think through treating relapsed/refractory lymphoma patients, and I’m sure you’ve seen this. We have to design studies, you can’t have very high expectations, you want to bring new drugs to the clinic. So how do we design studies in such a way that the design doesn’t pull the whole idea down. I would still say that oral aza is a good agent and perhaps the overall survival is one example for this. And want to see how this is going to go forward. Also…

Kate Cwynarski:

I was just going to say also it was very much biology driven as in it was only for the T follicular, and in terms of anti-immunoblastic. And do you think that we are going to have trials in the future targeted to specific entities?

Swaminathan Iyer:

Absolutely. I think that’s the way to go. We have 32 different entities in T-cell lymphoma, the WHO, the ICC classification. The TFH is now carved out of a little bit from the PTCL NOS as a TFH subtype and the follicular T-cell lymphoma. And now it’s the largest entity in the nodal variety of T-cell lymphomas and about 40% percent. And some of these agents growing the azacitidine including the studies that Dr Agbedia from MD Anderson, is presenting this evening, are all focus on that part. And you are seeing responses and particularly with the biologics because it enables a better way of tackling the microenvironment. And also because the T follicular helper is just sitting in a very rich microenvironment.

So studies such as pembrolizumab, which tackles the T-cells in the microenvironment and romidepsin, perhaps are ways to go forward. And in fact, the data that you’ll see, it shows an overall survival advantage of about 21 months in this relapsed/refractory population.

Kate Cwynarski:

So you mentioned about PD-1 inhibitors and we know in terms of NKT, its efficacy, but I always remember the report in ATL about hyper-progressions. So as you say, in terms of your study, which you know are presenting here, so the romidepsin with the PD-1. In terms of… Are you excited about that combination?

Swaminathan Iyer:

Oh, absolutely. And I think the hyper-progression is maybe as relevant biologically to ATLL. But TFH, some of these cells actually express PD-1. That’s one of the identifying markers for a T follicular helper phenotype. In the study there were two patients that are clinically called hyper progressors, but it is a clinical call, not verified. It could have been a pseudo of progression, could have been a tumor flare. But the study design was tweaked to have pembrolizumab on day one, romidepsin on day eight. And that changed the kinetics. We didn’t see the hyper-progression that is reported. So I clearly think that PD-1 by itself may not be sufficient. I think it’s the combination that gives you the synergy. And I think that brings us to several other checkpoint therapies including the Do Not Eat Me inhibitor. And also I would say your CAR-T. I think Kate your expecting…

Kate Cwynarski:

Yeah, in my very objective way, I’m very excited about that. So I presented some data at EHA and we have a poster presentation sort of updating a bit. So it’s an AUTO4, so it’s TRBC1-directed CAR-T. Although it’s only Phase I, I mean we’ve treated 10 patients and four of those I’ve treated and seen clinical responses in three of those four that are durable beyond nine months. So it’s the durability in, certainly for the cohort of patients I’ve treated where they’ve never been in remission. And I’m now seeing, we had to ask the question, “Should we allograft these patients?” And they were older, we didn’t have a donor for some. But seeing such durability I find exciting.

Swaminathan Iyer:

Oh, it’s very encouraging. And so kudos to you and your team that’s brought this forward and hopefully it’s going to help more patients. And that brings us to a very important point. I think we have discussed this before. How can we enable all these newer therapies and the biology, the newer information and biology out to everybody. And I think one of the efforts, and maybe you can elaborate on this, is to… This trifecta of science, the platform and the collaboration, not just in a few centers but across the world. So we have the ability to collect prospective data, intricate the biology. Even at the histopathology level and then bring therapies. And I think these are great efforts. And Kate, you want to add to that?

Kate Cwynarski:

Well, I would say that, I mean I’ve worked a lot in CNS lymphoma and our collaborations with our European colleagues and conducting large trials in a rare disease has been a really satisfying experience over the last decade. I’m really sort of challenged by the reality that in T-cell lymphoma over decades, we haven’t really made progress for our patients. And we do really need to improve the outcome for our patients. And I really welcome the conversation, the collaborations and as you say, sort of embracing our biological insights and science in terms of international collaboration.

Swaminathan Iyer:

Absolutely. Thank you very much for that.

Kate Cwynarski:

Pleasure.

Swaminathan Iyer:

Thank you.

Kate Cwynarski:

Thank you.

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