iwNHL 2024 | Updates in T-cell leukemia/lymphoma

Francine Foss:

Hello, I’m Dr. Francine Foss from Yale University School of Medicine, and I’m here with my colleagues to talk about updates from the T-cell session from the iwNHL 2024. Let’s start with Thierry. You talked to us about LGL today, an area that I think a lot of us would like to learn more about, so can you touch on some of the highlights of your talk and some recommendations for folks as far as treating these patients?

Thierry Lamy:

Yes, of course. LGL leukemia is a disease which had been described more than 30 years ago, so combining neutropenia with the related infection and anemia. For the time being the backbone of the treatment relied on three drugs, methotrexate, cyclophosphamide, and cyclosporine, but we observed that the response rates are quite disappointing.

So over the 20 last years, there are many events in the molecular description of the disease with three mutations, STAT3 occurring in about two-thirds of patients with T-LGL leukemia and about 30% of patients with NK subtypes. TET2 mutation mainly observed in NK subtypes, about one-third of patients, less than 10% in NK subtypes, and the last one described two years ago was CCL22 observed mainly in NK subtypes and is mutually exclusive from STAT3 mutation in these patients.

So based on this observation, we can probably anticipate that we have to move forward and put the three drugs behind us and to adapt therapy regarding the occurrence of this disease. We have these mutations and we have now some good opportunity to test different targets such as PI3-kinase inhibitor, anti-CD94, monoclonal targeting, hypomethylating agents, and anti-STAT3 and so on. So probably it’s too early to recommend at the first line, but probably for refractory or relapsing patients, we can propose some drugs like ruxolitinib, which we have published this year with at least 70% of complete response rate. So I think it’s a good opportunity to move forward now.

Francine Foss:

And I believe ruxolitinib is now listed in the NCCN Compendia guidelines, in the United States. So which drug are you the most excited about that’s coming through the pipeline?

Thierry Lamy:

I think definitely JAK inhibitor like Ruxo is interesting. Probably a PI3-kinase inhibitor linperlisib is very exciting. There are some data from a Chinese group, very interesting. And we have also some cases with very good response to 5-aza, but I think we have to define which patients can respond because it’s not really easy to use such drug in the indolent disease. So yes.

Francine Foss:

Sure. Thank you, thank you. I’d also like to ask Lucy, who’s also dealing with a very rare disease, to talk a little bit about HTLV-1. We heard some very interesting data from you today about looking at HTLV-1 patients as well as carriers and how we might implement this information moving forward. So can you talk to a little bit about that?

Lucy Cook:

Yeah. What we were discussing was that it’s really hard to cure patients with current ATLL therapies. If you can get a patient to respond and in remission to chemotherapy, the aim is allogeneic transplant and complete remission, but it’s a real challenge to get patients there. Maybe only 15% of patients reach allograft. The rest are primary refractory disease or very early relapse. And all the current therapies, in terms of salvage, the new drugs, have some efficacy but not generally curative, and we really don’t understand how to combine them, how to sequence them, and what their role is and I think at the moment they’re largely palliative type treatments.

We have this cohort in the UK that we’re really fortunate to be able to follow up for healthy carriers of HTLV infection, and what we now understand is that we can identify the high-risk carriers based on some molecular phenotyping, a combination of proviral load, which is an estimation of the quantity of virally-infected cells in the blood, but also an oligoclonality flow assay, which will identify abnormally expanded pre-malignant populations in these otherwise healthy individuals.

And we think that it’s those individuals with these high-risk features that go on and transform to ATLL. And what we’re really trying to do is then refine an individual patient’s risk by combining that with some molecular profiling. And that’s the bit that still is a work in progress, really trying to give people an individual risk that means that giving them preemptive therapy is in their best interest. Because at the moment they’re healthy carriers and whatever we offer them can only make them sick, whatever the treatment is, be it transplant, be it mogamulizumab. So we have to be really clear that they have an exceptionally high risk and then we could potentially intervene early even with things like allogeneic transplant.

Kate Cwynarski:

You also mentioned about potential donors. So how you screen them before considering them as an allograft donor?

Lucy Cook:

One of the great, it seems to be a great advance, is the use of haploidentical transplantation in ATLL simply because at least the one-year survival is substantially higher. The challenge with individuals with HTLV is often siblings or other the relatives are also going to be HTLV carriers, probably 20-30% of siblings. So we need to be really clear that the donor that we are using is a safe donor. So we recommend that you look at the proviral loads, the amount of virus in the blood, and if it’s high, to look, using a clonality metric, to identify that they are a safe individual that is not themselves at risk of future ATLL. If they’re low load, low risk, safe to proceed. And we have done that. But in individuals that are high risk, we would suggest perhaps trying to find an unrelated donor or an alternative.

Francine Foss:

Are we ready right now to implement these new findings of yours to be able to screen patients?

Lucy Cook:

In terms of donors? Yeah, we are. Certainly in the UK, these assays are all accredited. We are looking to try and do this in the US too. So we’re trying to collaborate with centers to try and get these assays up and running, but there are no commercial assays. This is the real challenge. So again, it means working with the WHO to get a commercial assay that everyone can run in their labs, well validated, good reference material. So that’s kind of a big piece of work that needs to happen, but there are plans in place to do so.

Francine Foss:

And hopefully we’ll be able to implement some of these in the guidelines that we have for who’s going to bone marrow transplant, and as you said, how to screen those donors.

Lucy Cook:

Actually, it’s mentioned that this is something that should be done in the JCO Consensus Document from 2019. It suggested it should be done, but the technicalities are not in there.

Kate Cwynarski:

We also feel grateful that we can refer our relatives to, because as you say, vertical transmission is an issue. So in terms of explaining to people not to breastfeed, if they are HTLV-1 positive, et cetera.

Francine Foss:

Yeah, very important.

Great. And Kate, there’s a dearth of CAR-T therapy in T-cell lymphoma, there’s a dearth of cellular therapy of any kind, and you’ve been pioneering a novel CAR-T. Can you talk a little bit about what you’re doing?

Kate Cwynarski:

Yeah, as you say, it’s challenging because either the target is a pan T-cell target, but as you say, there’ve been very few. I’m fortunate, I’ve worked with Martin Pule and Paul Maciocia who identified and created a TRBC1-positive CAR, and that relies on the fact that there is duplication of the beta chain of the constant region in the T-cell receptor. So the fact is that you have a clonal tumor, but our normal healthy T-cells are both TRBC1 and TRBC2. So when you have a TRBC1-targeted CAR, you will retain TRBC2 normal healthy tissue.

We have only just done a Phase I study. It was both conducted in the UK and in Spain, and it was 10 patients who we treated. We showed really impressive efficacy in the patients who received the top dose of 450 million. So of four patients treated, three of those achieved complete metabolic remission at the day 28 time point and two have ongoing remission up to 18 months. I think one of the other things that’s been really promising is the toxicity was really low. It was very well tolerated. Of those 10 patients, there was one grade 3 CRS and no ICANs. So really promising as a potential therapeutic approach. I think the issue is, is that there’s heterogeneity, as you know, within T-cell lymphoma, and we only included patients with PTCL, the T follicular, and ALCL, and it’s important to think of, is this a modality for cutaneous T-cell lymphomas, etc.

Francine Foss:

You also talked a little bit about the targeting and detecting the CAR in tissue and in blood. Can you elaborate a little bit on that?

Kate Cwynarski:

Yeah, so we didn’t detect persistence of the CAR in the peripheral blood, but we could see homing to the lymph nodes to the infected tissue. So I think we can show the CAR was there, but we didn’t see a reversal in the TRBC1, TRBC2 peripheral blood ratio, and we didn’t see persistence in the peripheral blood. So I think doing further studies, we need to do more translational correlates to understand better, but I think it really is, as a clinician, the patients who are in remission beyond 18 months were refractory to three to four lines of therapy and in other therapeutic approaches, I haven’t seen such encouraging approaches. So it’s really exciting, but really very early.

Francine Foss:

So we’re hoping to hear more from you in the future about this.

Kate Cwynarski:

I’d love to say so, yes.

Francine Foss:

Thank you. Well, I think we’ve touched on some of the highlights from this session. It was a really exciting session mixing science and clinical acumen as well as a session where we’ve come up with some new ideas, I think, to establish some workshops and some focus groups. Thank you very much for your participation and thank all of my speakers.