Melanie (Host): Welcome to the podcast series from the specialists at Penn Medicine. I'm Melanie Cole, And we have two Penn Medicine physicians here for you today to highlight T-cell lymphomas. Joining me is Dr. Colin Thomas. He's an assistant professor of clinical medicine in hematology oncology, and Dr. Gina Chung, she's an assistant professor of clinical dermatology.

Doctors, thank you so much for joining us today, and Dr. Thomas, I'd like to start with you. What are T-cell lymphomas And what really makes them different than other blood cancers?

Colin Thomas, MD: Yeah, sure. Thank you for having us and. to answer your question, T-cell lymphomas are a type of hematologic malignancy in which T cells, a vital component of our immune system become malignant. They represent about 10 to 15% of all non-Hodgkin lymphomas making them much less common compared to B cell lymphomas.

They're also quite heterogeneous involving a multitude of subtypes in which they're able to involve various compartments of the body, including lymph nodes, blood viscera, and skin.

Jina Chung, MD: I agree. And I think that what makes, cutaneous T-cell lymphoma really, interesting is that a lot of time, because a lot of the T cells live in the skin, sometimes it can present more like a rash, rather than, through abnormal blood tests or enlarged lymph nos.

Melanie (Host): Well, thank you both. And along those lines, then, Dr. Chung, we often refer to treatment journeys for patient's, but many cancers involve a diagnostic journey as well. Do the types of T-cell lymphomas originate from a distinct genetic mutation? What do we know about That? Is that where the diagnostic journey begins?

Tell us a little bit about that journey And what it's like for patient's with suspected T-cell lymphoma.

Jina Chung, MD: That's a really good question. So, we do have certain, uh, genetic phenotypes that are associated with certain cutaneous T-cell lymphomas such as T follicular helper type lymphomas, or. My S syndrome, but often genetic profiling is not the answer to achieving the right diagnosis. So it's just kind of part of the clue.

typically the diagnosis, at least for cutaneous T-cell lymph involve first begins with a skin biopsy. So typically patient's will present with a rash And then they get a skin biopsy and it looks atypical or concerning. For cutaneous T-cell lymphoma. And then they will get additional tests like immunochemistry. And sometimes we can also do molecular tests like T-cell receptor gene rearrangement studies to look for T-cell clonality.

And sometimes we might also add on genetic profiling as well, which can also sometimes have prognostic implications. So I would say that, genomic profiling is kind of part of the puzzle, but not necessarily, what, patient's begin with.

Colin Thomas, MD: Yeah, and, and I completely agree with what Gino said. Just to echo what, her comments were. You know, I think the diagnosis starts with the tissue biopsy and immunophenotyping with genetic testing really being a supportive tool for helping characterize subtypes And also for prognosis.

Melanie (Host): So Dr. Thomas, then, when we speak about that diagnostic journey, is it more complicated if it involves other institutions and their findings or primary care? How important are second opinions for T-cell lymphomas?

Colin Thomas, MD: Yeah, that's a great question. I, I think second opinions are extremely important for T-cell lymphomas. I strongly encourage any new diagnosis of a T-cell lymphoma to have a reflex consult to a tertiary care center, such as at our amazing team here at Penn. we try to make the diagnostic journey as easy as possible, when collaborating or acting as a consultant for outside institutions.

this can involve, having an outside biopsy tissue sent to our pathology team. a team That is familiar with assessing t-cell cancers, for a re-review. And as we help in, uh, trying to establish the specific diagnosis and treatment plan, just because it's a very heterogeneous group of cancers with many different subtypes, treatments, and prognosis really hinge on knowing exactly what the specific subtype is.

And I like the word journey too, because it really is, and. the journey from diagnosis to treatments, to trying to get the disease under control, you know, is a journey and having the right diagnosis is the map, I think, in that journey. And, really highlights the importance of having, again, a tertiary care center familiar with this disease.

given the assessment.

Jina Chung, MD: I totally agree, Colin. Yes, I think that we try to make it as easy as possible for the patient. We try to coordinate visits. typically, uh, when patient's are being referred to care, they might see dermatology and oncology. And typically we will try to obtain the outside biopsies so that we can be reviewed by our expert dermatopathologist and hematopathologists who have an expertise in cutaneous lymphoma.

Melanie (Host): That's so important. And so along those lines, Dr. Chung, Tell us a little bit about the multidisciplinary approach, which is so important for these patient's. Briefly discuss for us the coordination of that diagnostic and therapeutic care at Penn Medicine for these cancers. Who's involved And what makes it so unique about this?

Jina Chung, MD: That's a great question. So we typically have a, a lot of people involved in this multidisciplinary team, which involves care coordinators, who have a really important role of trying to coordinate visits with different specialties And also trying to coordinate to have the biopsy spends. Specimens, reviewed by our, uh, pathologist here, And then we also have our doctors from oncology and dermatology, And then sometimes radiation-oncology might be involved as well.

So we all work together to try to coordinate visits. So that patient's can be seen on the same-day, especially if it's like an initial visit And the patient is coming from far away. And then when patient's are being followed up, we still have a very good, strong team that continuously communicate with each other.

so we might see the patient's on the same-day on follow-up visits as well. And then we directly communicate with each other. We also have two more boards and contains lymph conferences where we view the pathology together And then we discuss complex cases.

Colin Thomas, MD: Yeah, exactly. And again, just to echo what Gina said, I mean, Gina and I have worked very closely together, which I think is a testament to the, the coordinated care effort that we have for our T-cell lymphoma patient's. it's multidisciplinary. It's a very complex heterogeneous group of cancers. That require a lot of minds on the case.

I mean, I think close collaboration with pathology, it's really helpful that Gina is a, derm pathologist too, which I think makes, collaboration really nice and easy. but also coordination with radiation-oncology, of course our hem o uh, team, which, which is what I'm part of, discussing these cases at tumor board.

we also have our more so informal T-cell, lymphoma, you know, research meetings that we have That is very, again, multidisciplinary where we talk about. Well, patient cases and research projects, clinical trials, and how we can improve outcomes for our patient's.

Melanie (Host): Dr. Thomas, as we've spoken about the diagnostic journey after that, tell us a little bit about some of the general frontline therapies. Is there a common framework for treating T-cell lymphoma? Are there varying types of therapy based on subtypes? Tell us a little bit about treatment and what's happening.

Colin Thomas, MD: Yeah, really good question. And if I had, oh, boy, I, I could talk about this for hours too, but I know we're, you know, constrained on time, I'd say. Approaches vary, between primary cutaneous T-cell lymphomas and nodal T-cell lymphomas, right off the bat. and when I'm referring to nodal T-cell lymphomas, I'm really referring to the subtypes of peripheral T-cell lymphoma, N OMFS, the T follicular helper cell lymphomas, anaplastic large cell lymphoma, the extra nodal NK T-cell lymphomas.

And again, treatments vary greatly, based on the specific subtypes of the T-cell lymphomas and nodal T-cell lymphomas. Which again, further highlights, I think the need for establishing the proper, specific diagnosis, especially with, a tertiary care center like here at Penn. but with regard to the T-cell lymphomas, the nodal T-cell lymphomas, frontline therapies can involve.

F different chemotherapy cocktails such as chop, chep, chep typically being reserved for younger patient's, typically 60 and under. B-V-C-H-P, the latter of which is a cocktail containing the antibody. Drunk conjugate. Uh, brentuximab. Vedotin, This is a cocktail eye typically reserved for patient's with anaplastic large cell lymphoma. And just to mention, extra nodal NK T-cell lymphoma, it's a subtype that requires a non anthracycline containing chemotherapy cocktail, such as a asparaginase containing regimen.

And we do that just because of this inherent resistant to anthracycline for that specific subtype of T-cell lymphoma. Again, really highlighting the importance of knowing exactly what this T-cell lymphoma is and regarding CTCL T-cell lymphomas, which are the cases, which can be, boy, I mean, these patient's can be very sick.

They can be very problematic to control, manage, and, Gina and I work really closely with these patient's. I would say, you I'm sure Gina can mention more about this, But when it comes to limited stage, early stage CTCL patient's, I know dermatology tends to be the quarterback, so to speak, with managing the therapies for these patient's.

But, when it comes to advanced stage or aggressive c TCLs or cutaneous T-cell lymphomas, you know, hemon, like myself, will typically help manage, these frontline therapies. you can use chemotherapy, but more often, we use novel therapies such as Odin and HDAC inhibitor, moga, omalizumab and antibody. That targets CCR four brentuximab, vedotin, again as a monotherapy, or pralatrexate and anti-metabolites, just to name a few.

But there's, certainly a toolbox of different medicines that we have, as systemic therapies for these patient's.

Jina Chung, MD: Yes, I totally agree. And Collin's put it very nicely that it's such a complex treatment me, ladder. And as Collin said, we typically treat kind of the earlier, disease, patient's with cutaneous T-cell lymphoma. so that includes either topical therapy or skin directed therapy, such as phototherapy, which we also have here.

We might refer patient's for radiation to our radon specialist here at Penn. And then we might also prescribe some oral therapies such as methotrexate or bine, which is a retinoid. And we sometimes prescribe injectable treatments such as interferon as well.

Melanie (Host): Dr. Thomas, sticking with you for a minute, what's the plan for treatment in relapse or refractory disease?

Colin Thomas, MD: Yeah. Also a very good question. and just to preface that question and, and giving an answer, T-cell lymphomas tend to have worse outcomes in general compared to B-cell lymphomas. Again, it's, more rare, it's more heterogeneous. It's, it's a bit harder to study and, and establish good clinical trials. but with that said, relapse refractory disease is not unusual.

I'm studying really the nodal T-cell lymphomas, just to talk about that for a moment. and I would say, treatments vary, again, based on the subtype, just like frontline therapy. but regardless, in any relapse refractory setting, we should always consider potential clinical trial options, of which we have many here at Penn.

and on this point, again, having a referral to our team, uh, sent, would be very important for the reason of exploring what trial options, uh, we have, you know, available for such a patient. but however, for standard to care treatment for relapse refractory, again, nodal T-cell lymphomas, just to mention that for a moment, chemotherapy based options, you know, can be used, still be explored, especially if, uh, there's reason to think they're still chemo sensitive.

Or if there are patient who has, aggressive, rapidly growing disease and they're in the inpatient setting, you need something to potentially work a little bit faster. but with that said, in the relapse refractory setting, we tend to use non-chemo options. these include treatments like Duval, API three K inhibitor, or HA inhibitors such as Roma Din and Belinostat to name a few.

And in some cases we use doublet therapies, where we combine targeted therapies to maximize efficacy. A few examples would be essin with dubal or essin with ruxolitinib, a JAK inhibitor. But really what's important to mention is that in the relapse refractory nodal T-cell lymphoma setting, This is a, a subset of disease relapse refractory disease That is not curative, with these therapies, with targeted therapies with more chemotherapy.

and these are, patient's, these are cases that ultimately require an allogeneic bone marrow transplants as a hope. For achieving long-term remission, assuming they're eligible for such a procedure. and I'm sorry, This is a little bit of a long-winded answer, But when I think truly trying to bridge someone to a transplant, you know, in aoe, I'll typically try to be a bit more aggressive and use a doublet therapy like with Essin to, again, try to maximize our, efficacy and, and our chances of trying to get to an AOE again, if they are an AOE candidate That really is in the nodal T-cell lymphoma landscape.

A little bit of a long answer. I know there's a lot to unpack, even CTCL, but I'll pause there 'cause I know, I'm sure Gina would, have, comments to mention at least in the C TCL L space. Absolutely.

Jina Chung, MD: Yeah, I think that, CTCO is very hard to treat because it's often not a curable, lymphoma unless you, go to a, a transplant as Dr uh Thomas mentioned. so we often have treatment refractory disease. So, And that typically does require escalation of therapy. so sometimes when we have patient's who.

Progress or refractory on, skin directed therapy. We might progress to oral agents like bine and methotrexate, interferon. We might also add on, treatments like photo extra corporeal photophoresis, which we also have here at Penn. and it really does require kind of coordination of care with oncology. I can't stress this enough that This is a multidisciplinary team approach.

Colin Thomas, MD: just to add one more comment about what Gina said it. Yeah, the, the CTCL space is, is very complicated. it's a really difficult disease to manage the treats and, for the patient's themselves. You know, it's a very, it's a very problematic disease. You know, it's, it causes a lot of symptoms, a lot of issues, and it's heartbreaking to see this for our patient's.

I think, like Gina was saying, And we have a toolbox of different medicines to use different systemic therapies. I know g as you know, mentioned some and. really trying to figure out a good sequence of what medicines to use first And then later on, you know, it is really something you really want to think about at their diagnosis.

cause it's fair to say that, you know, any systemic therapy you use for, let's say an advanced stage aggressive CTCL, aggressive mycosis, fungoides patient's. It's fair to say that any of these treatments are not gonna be curative. Odin for example, or moga omalizumab, they can work well in a lot of patient's, but eventually they stop working And then you have to use a different systemic therapy.

And again, we have a lot of different systemic therapies, that have, a varying degree of efficacy or, safety profiles. but ultimately, for patient's who are eligible for this, eventually you might need to do an allo, bone marrow transplant if you need long-term remission or some sort of chance of cure, which again, allos are, no walk in the park.

You know, they have a lot of risk involved. They don't always work, of course. but again, and, as I kind of wanted to close on this, this. Comment, uh, clinical trials, of which, you Gina and I are, are part of many, you know, here at Penn, it's, it's one of the benefits of such a, an amazing cancer center here, especially in the T-cell space.

We have a lot of clinical trial options for our patient's which we hope will, I think, contribute to the therapies that can improve outcomes and help our, our patient's in.

Melanie (Host): It's so interesting as we explore all of these tools in your toolbox and Dr. Chung. Speak a little bit about the follow-up. What's that like for the patient after the initial treatment? How do you coordinate the long-term follow-up with outside institutions, their primary care or derm? Tell us a little bit about how that all works.

Jina Chung, MD: Yeah, so sometimes our patient's come from very far away and, sometimes, that requires us to coordinate with local providers. so sometimes I have patient's who see a local dermatologist And then follow-up with me via telemedicine visit. And then send me photos and I stay in close communication with the local dermatologist.

and sometimes patient's might, choose to get treatments locally such as phototherapy or sometimes infusion based treatments such as omalizumab, or sometimes they might choose to get radiation locally. because if it's something that requires frequent visits, it might be hard for them to travel here. and when they come back to see us for follow-up, which are our best to try to coordinate visits, between dermatology, oncology and radiation-oncology, so that the patient's are not burdened by, too many trips.

Melanie (Host): This is such an interesting topic And so enlightening everything you're discussing here today. A really exciting time in your fields, and I'd love to give you each a chance for a final thought. And Dr. Thomas at Penn Medicine, we often think of T cells in the context of cancer treatment.

Is CAR T therapy being investigated for T-cell lymphomas? And what would you like other providers to know about the exciting work that you're doing at Penn Medicine?

Colin Thomas, MD: Yeah. Thanks Melanie. That's a great question. It's a question that a lot of patient's ask too, because I think if you were to Google lymphoma, it's hard not to find CAR T therapy in any, search engine search, you know, on the topic. But, so it's fair to say I, you know, CAR T therapy in B-cell, B-cell lymphoid cancers have been revolutionary.

They've had a profound impact on, survival and outcomes. You know, it really has been a paradigm shifting the past, decade or so. Utilizing this technology in T-cell lymphomas is still being explored. barriers to using CAR T therapy and T-cell lymphoma typically involve the issues of tric side and T-cell aplasia, fracture side being the process in which manufactured CAR T cells can target both the malignant T cells and their fellow CAR T cells given their shared T-cell immuno phenotypes.

And then T-cell aplasia being the prolonged period of depletion of non-malignant T cells that can occur after, well, the T cells. T-cell targeting car cells, have their off target, depletion of their non-malignant, T cells in the peripheral blood. and mind you, you know, we see B-cell aplasia after standard of care, CAR T therapy in B-cell lymphomas.

but T-cell aplasia is certainly much more problematic and dangerous with regards to infectious complications. Um, I say that all just as a, again, a prelude to, you know, what we're doing here at Penn. you we have a homegrown clinical trial here at Penn called the Viper Study. It's assessing a CD five CRISPR knockout CD five, targeting CAR T product and Relapse refractory CD five positive T-Cell Lymphoma.

it utilizes a really unique approach to circumventing the issues that I mentioned about using CAR T and t-cell lymphomas. this trial is currently enrolling patient's and, we actually have some preliminary data that was reported, this past year at ASHRM, you just last month. So pretty exciting stuff.

Melanie (Host): Dr. Thomas, would you like to share some of that preliminary data?

Colin Thomas, MD: yeah. Sure. And it's really interesting stuff, we need more patient's on the trial, You know, we need more follow-up. that's kind of the bottom line as, as just a, you know, a grain of salt that I wanted to put out there, but. but overall we're seeing a very high response rates.

so, You know, of the three patient's that actually were able to be assessed for responses early on. All three had complete responses. after getting the, the trial product, This is a CD five Knockout CAR T product, so, You know, of free patient's. Again, it's, it's a very, small patient, population.

But of the three patient's. 100% overall response rates and 100% CR rates. but again, You know, we need more follow-up. And we need more data I think it's still early to say, You know, what this means exactly, but there's certainly a high response rate, which is great to see.

the question remains, what really is the safety profile that we're seeing of this CAR T product? Are these responses gonna be enduring? Will this be a technology that we can use more so for. a bridge to an aloe or would it be a definitive therapy in itself? A lot of questions need to be answered, but again, really exciting stuff and again, the, the abstracts available for, again, this past year is ASHRM.

So, anybody needed more detail, but very interesting stuff.

Jina Chung, MD: a really, interesting clinical trial and I think it's also interesting that it doesn't cause T-cell plasia, a very, significant thing to know.

Colin Thomas, MD: Thanks Gina. Just to add that like one comment, it's, when this trial essentially manufactures these CAR T cells, it uses CRISPR knockout to knock out CD five on the CAR T cells to prevent fracture side. But it also infuses patient's with CD five knockdown non-CAR T cells, So, It actually helps preserve a certain population of T cells that won't be targeted by the CAR T cells and result in T-cell plasia.

So it's actually, You know, a really, interesting way to do that. this was done out of the lab of Marco Rua and it's been really kind of pushed forward and pioneered with, Dr. Stefan Barta, You here at Penn, you know, one of our, our T-cell lymphoma leads. But, really interesting stuff.

And of course, it's not just nodal T-cell lymphoma patient's. You know, we have. enrolled, uh, at least one of Mycosis Fungoides patient's, on the trial too. So it's, pretty interesting stuff.

Melanie (Host): Please come back and join us as you learn more. And Dr. Chung, last word to you. How would someone refer a patient directly to you for treatment or for the second opinion? And what would you like the key takeaways to be from this fascinating discussion today?

Jina Chung, MD: yeah. So if you have a patient who you are interested in getting seen for cutaneous T-cell Lymphoma by, our team, including myself, you can, contact Barbara Pratt, who's our care coordinator, and she'll help get the patient scheduled in my clinic And also. Coordinate with the outside lab to get the pathology sent here so that I can review it.

I'm a, a board-certified dermatopathologist, with an expertise in cutaneous lymphoma. So I view the cases myself And then also see the patient's in clinic or we see the patient's, together as a team. And then, uh, the clinical Pathologic correlation is so important for achieving the correct diagnosis of cutaneous T-cell lymphoma, because it can often mimic a rash, or rashes can look like cut T-cell lymphoma under the microscope.

So it's a diagnosis that can take an average of four to five biopsies and sometimes four to five years to get to the correct diagnosis. So I think that it's something that, Often you should not be afraid to seek a second opinion, and patient's should certainly feel empowered to seek a second opinion.

And we will take, indeterminate cases as well if it's, not a firmly established diagnosis, but there is concern for cutaneous lymphoma. We are happy to see those, patient's as well to try to see if we can get to the correct diagnosis. So thank you.

Melanie (Host): Thank you both so much for joining us today and really sharing your incredible expertise. This was a great discussion. Thank you again. And to refer your patient to Dr. Chung or Dr. Thomas at Penn Medicine, please call our twenty four seven provider only line at 8 7 7 9 3 7 Penn.

Or you can submit your referral via our secure online referral form by visiting our website@pennmedicine.org slash refer. I'm Melanie Cole. Thanks so much for joining us today.