Melanie Cole, MS (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. Jina 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: 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 nodes.

Host: Well, thank you both. And along those lines, then, Dr. Chung, we often refer to treatment journeys for patients, 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 patients with suspected T cell lymphoma.

Jina Chung, MD: So, we do have certain genetic phenotypes that are associated with certain cutaneous T cell lymphomas such as T follicular helper-type lymphomas, or  mycosis fungoides or Sézary syndrome, but [00:02:00] 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 lymphoma, first begins with a skin biopsy. So typically, patients 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 patients begin with.

Colin Thomas, MD: Yeah. And I completely agree with what Jina 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 [00:03:00] prognosis.

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: 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 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 [00:04:00] 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, 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: Yes, I think that we try to make it as easy as possible for the patient. We try to coordinate visits. Typically, when patients are being referred to care, they might see dermatology and oncology. And typically, we will try to obtain the outside biopsies so that they can be reviewed by our expert dermatopathologists and hematopathologists who have an expertise in cutaneous lymphoma.

Host: That's so important. And so, along those lines, Dr. Chung, briefly discuss for us the coordination of that diagnostic and therapeutic care at Penn Medicine for these cancers. Who's [00:05:00] involved and what makes it so unique about this?

Jina Chung, MD: So, we typically have 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 specimens reviewed by our 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 patients 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 patients are being followed up, we still have a very good strong team that continuously communicate with each other. So, we might see the patients on the same day on follow-up visits as well. And then, we directly communicate with each other. We also have tumor boards and cutaneous lymphoma conferences where we view the pathology together, and then we discuss complex cases.

Colin Thomas, MD: [00:06:00] Yeah, exactly. And Jina and I worked very closely together, which I think is a testament to the coordinated care effort that we have for our T cell lymphoma patients.  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 Jina is a dermopathologist too, which I think makes collaboration really nice and easy. But also, coordination with radiation oncology, of course our hem-onc team, which is what I'm part of, discussing these cases at tumor board. And we also have our more so informal T cell lymphoma, research meetings that we have that is very, again, multidisciplinary where we talk about patient cases and research projects, clinical trials, and how we can improve outcomes for our patients.

Host: Dr. Thomas, as we've spoken about the diagnostic journey, 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 [00:07:00] therapy based on subtypes? Tell us a little bit about treatment and what's happening.

Colin Thomas, MD: And if I had-- oh, boy, I could talk about this for hours too, but I know we're 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, NOS; the T follicular helper cell lymphomas, anaplastic large cell lymphoma, the extranodal 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 different chemotherapy cocktails such as CHOP, CHOEP; CHOEP, typically being reserved for younger patients, typically 60 and under; BV-CHP. The latter of which is a cocktail containing the antibody-drug [00:08:00] conjugate, brentuximab vedotin. This is a cocktail I typically reserve for patients with anaplastic large cell lymphoma. And just to mention, extranodal NK/T cell lymphoma, it's a subtype that requires a non–anthracycline-containing chemotherapy cocktail, such as asparaginase-containing regimen. And we do that just because of this inherent resistance 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, cutaneous T cell lymphomas, which are the cases which can be-- boy, I mean, these patients can be very sick. They can be very problematic to control, manage. And Jina and I work really closely with these patients. I would say, I'm sure Jina can mention more about this, but when it comes to limited stage, early stage CTCL patients, I know dermatology tends to be the quarterback, so to speak, with managing the therapies for these patients.

But when it comes to advanced stage or aggressive CTCLs or cutaneous T cell lymphomas, you know, hem-onc, like myself will typically help manage these frontline therapies. And you can use chemotherapy. But more often, we use novel therapies such as [00:09:00] romidepsin, an HDAC inhibitor; mogamulizumab, an antibody that targets CCR4; 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 patients.

Jina Chung, MD: And Colin's put it very nicely that it's such a complex treatment ladder. And as Colin said, we typically treat kind of the earlier disease patients 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 patients for radiation to our rad-onc specialist here at Penn. And then, we might also prescribe some oral therapies such as methotrexate or bexarotene, which is a retinoid. And we sometimes prescribe injectable treatments such as interferon as well.

Host: Dr. Thomas, what's the plan for treatment in relapsed or refractory disease?

Colin Thomas, MD: Yeah just to preface that question 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 a bit harder to study and establish good clinical trials.

But with that said, relapsed/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 sent would be very important for the reason of exploring what trial options that we have, you know, available for such a patients. But however, for standard of care treatment for relapse/refractory, and nodal T cell lymphomas, just to mention that for a moment, chemotherapy-based options, you know, can be used, still be explored, especially if there's reason to think they're still chemo-sensitive. Or if there are patients who have aggressive, rapidly growing disease and they're in the inpatient setting, you need something to potentially work a little bit [00:11:00] faster.

But with that said, in the relapsed/refractory setting, we tend to use non-chemo options. These include treatments like duvelisib, a PI3K inhibitor, or HDAC inhibitors such as romidepsin 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  romidepsin with duvelisib or romidepsin 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 subset of disease relapsed/refractory disease that is not curative with these therapies, with targeted therapies with more chemotherapy. And these are patients that ultimately require an allogeneic bone marrow transplant as a hope for achieving long-term remission, assuming they're eligible for such a procedure.

I think truly trying to bridge someone to a transplant, I'll typically try to be a bit more aggressive and use a doublet therapy like  duvelisib with romidepsin, again, to try to maximize our efficacy and our chances of trying to get to an [00:12:00] allo again, if they are an allo candidate.

Jina Chung, MD: Yeah, CTCL is very hard to treat because it's often not a curable lymphoma unless you go to a transplant, as Dr. Thomas mentioned. So, we often have treatment-refractory disease. And that typically does require escalation of therapy. So sometimes when we have patients who progress or are refractory on skin-directed therapy, we might progress to oral agents like  bexarotene, and methotrexate, interferon. We might also add on treatments like extracorporeal photopheresis, which we also have here at Penn. And it really does require coordination of care with oncology. I can't stress this enough that this is a multidisciplinary team approach.

Colin Thomas, MD: We have a toolbox of different medicines to use different systemic therapies. I know, Jina, you mentioned some. Really, trying to figure out a good sequence of what medicines to use first and then later on, you really want to think about at their diagnosis, any systemic therapy you use for, an advanced-stage aggressive CTCL, aggressive mycosis fungoides, it's fair to say these treatments are not going to be curative. Romidepsin, for example, or mogamulizumab, they can work well in a lot of patients, 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. 

I kind of wanted to close on this comment, clinical trials, of which Jina and I are part of many, here at Penn. It's one of the benefits of such an amazing cancer center here, especially in the T cell space. We have a lot of clinical trial options for our patients, which we hope will contribute to the therapies that can improve outcomes and help our patients in need.

Host: 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: So, sometimes our patients come from very far away and that requires us to coordinate with local providers. So, I have patients who see a local dermatologist, and then follow up with me via telemedicine visit and then send me [00:15:00] photos. And I stay in close communication with the local dermatologist. And sometimes patients might choose to get treatments locally such as phototherapy or infusion-based treatments 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, we try our best to try to coordinate visits, between dermatology, oncology and radiation oncology, so that the patients are not burdened by too many trips.

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. 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: [00:16:10] Yeah. Thanks, Melanie. That's a question that a lot of patients ask too, because I think if you were to Google lymphoma, it's hard not to find CAR T therapy. 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 shift in the past decade or so. But 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 fratricide and T cell aplasia. Fratricide 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 immunophenotypes. And then, T cell aplasia being the prolonged period of off-target depletion of non-malignant T cells in the peripheral blood. And mind you, we see B-cell aplasia after standard of [00:17:00] care CAR T therapy in B-cell lymphomas. But T cell aplasia is certainly much more problematic and dangerous with regards to infectious complications.

I say that all just as a prelude to, what we're doing here at Penn. We have a homegrown clinical trial here called the VIPER Study. It's assessing a CD5 CRISPR knockout, CD5-targeting CAR T product in relapsed/refractory CD5 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 patients. And we actually have some preliminary data that was reported this past year at ASH, just last month.

And it's really interesting stuff. Of the three patients that actually were able to be assessed for responses early on, all three had complete responses after getting the trial product, this CD5 knockout CAR T [00:18:00] product. So it's a very small patient population. But of the three patients, 100% overall response rates and 100% CR rates.

But again, we need more follow-up. And we need more data. I think it's still early to say 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 going to be enduring? Will this be a technology that we can use more so for a bridge to an allo or would it be a definitive therapy in itself? It needs more detail, but very interesting stuff.

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

Colin Thomas, MD: Just to add that one comment, this trial uses CRISPR knockout to knock out CD5 on the CAR T cells to prevent fratricide. But it also infuses patients with CD5 knockdown non-CAR [00:19:00] T cells. So, it helps preserve a certain population of T cells that won't be targeted and result in T cell aplasia. So, it's actually a really interesting way to do that. This was done out of the lab of Marco Ruella, and it's been pushed forward and pioneered with Dr. Stefan Barta here at Penn, one of our T cell lymphoma leads. But really interesting stuff. And of course, it's not just nodal T cell lymphoma patients. We have enrolled at least one mycosis fungoides patient on the trial too.

Host: 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, at Barbara.Pratt@pennmedicine.upenn.edu. And she'll help get the patient scheduled in my clinic and also coordinate with the outside lab [00:20:00] to get the pathology sent here so that I can review it.

I'm a board-certified dermatopathologist with an expertise in cutaneous lymphoma. So, I view the cases myself and then also see the patients in clinic or we see the patients together as a team. And then, 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 cutaneous 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 patients 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 patients as well to try to see if we can get to the correct diagnosis.

Host: Thank you both so much for joining us today [00:21:00] and really sharing your incredible expertise. This was a great discussion. And to refer your patient to Dr. Chung or Dr. Thomas at Penn Medicine, please call our 24/7 provider-only line at 877-937-PENN. Or you can submit your referral via our secure online referral form by visiting our website at pennmedicine.org/refer. I'm Melanie Cole.