Innovations for the Management of EBV+ PTLD

Jennifer Amengual, MD: Hi and welcome. Today, we'll be discussing EBV-positive post-transplant Lymphoproliferative disorder or EBV-positive PTLD, a serious complication that can arise following organ or hematopoietic stem cell transplantation. My name is Jennifer Amengual. I'm an associate professor at Columbia University Irving Medical Center, and I'm joined by two colleagues and experts in the field. I'm excited to have a chat with them. Welcome. Would you guys both please introduce yourselves?

Samuel Yamshon, MD: Hi, I'm Sam Yamshon. I'm an assistant professor of medicine at Weill Cornell Medicine, also in New York City.

Joe Schroers-Martin, MD, PhD: Great. I'm Joe Schroers-Martin. I'm an assistant professor of oncology at Stanford University in California.

Dr Amengual: Fortunately, especially in the relapse setting, there are some additional options, specifically adoptive T cell therapy, has really coming into play, and this has been important, especially for EBV-positive PTLD where EBV-specified cytotoxic T lymphocytes can be effective in treating PTLD, both in hematopoietic stem cell transplant patients and organ transplant patients. This has been studied in an international multicenter study. I can never say the name so well: tabelecleucel, this off-the-shelf EBV-specified T-cell immunotherapy that's approved, and we've certainly seen really nice responses in EBV-positive PTLD relapse after traditional frontline therapy. In those who are either EBV-positive or EBV-negative, and we typically reserve it for the EBV-negative patients who might not be a candidate for EBV-specified cytotoxic T cell, one may consider CAR-T therapy. I think this has picked up some traction. Whoever is met with lots of challenges, the duration of response tends to be quite short, and it's probably due to the persistence of these T cells in the setting of ongoing immunosuppression. So, certainly, not quite ready for all patients, I would say, but something that could be considered. And I think in this setting, thinking about EBV CTLs as potential prophylaxis and maybe other ways to really monitor early on for PTLD might be something we can consider. I was wondering Dr Schroers-Martin, maybe you can touch upon that in your experiences with that.

Dr Schroers-Martin: Sure. I totally agree that in EBV-positive disease viral control goes hand in hand with disease control. Viral concentrations in the plasma go along with disease control. I guess biologically, one other thing I wanted to point out when we were talking about risk stratification is that, in addition to virus-associated CD30 positivity, these early aggressive virally associated PTLDS also tend to be an activated B-cell phenotype, which has been associated in immunocompetent lymphoma with poor outcomes. I think that was one of the drivers behind the unsuccessful addition of ibrutinib to risk-stratified therapy. So, some things that we've been very interested in and looking at in order to try and risk stratify in lymphomas in general, many other hematologic malignancies like CML are really molecularly guided by MRD-based strategies, and in myeloma as well. Therapy is frequently driven by MRD, at least in a trial setting, and has recently been endorsed by the FDA and in a discussion of myeloma.

So MRD-based strategies looking for detectable cancer-associated molecules are under development in a lot of immunocompetent lymphomas in diffuse large B-cell lymphoma. Circulating tumor DNA levels tend to be very, very high at diagnosis. They drop very rapidly with CHOP-like chemotherapy. Achieving this sort of rapid response has been described as a favorable prognostic factor again in immunocompetent large-cell lymphomas. So, part of the thought is that, particularly in PTLD, where, much more so than in other aggressive B-cell lymphomas, a risk-adapted, imaging-adapted paradigm is already kind of part of the standard of care. Could we adopt some of these approaches here as well, where that interim molecular response, as defined in the PTLD-1 and PTLD-2 trials, is accompanied by an interim viral response and interim molecular response? So for patients like that where you see a favorable imaging response, viral and molecular response, I think at that point you could really feel reassured that you could go on to some of these gentle immunotherapy-based approaches, or vice versa, for an inadequate response thinking about escalation strategies beyond standard R-CHOP. Since this is already an established risk-directed paradigm, I think that's really intriguing.

Dr Amengual: Yeah, thanks. I think that's great. I think the ability to potentially monitor PTLD more sensitively can help us understand how much treatment to give and whether or not we should be moving on to things like EDV-directed CTLs earlier on in the treatment paradigm if one's not responding to single-agent rituximab or to chemotherapy, as you think that they might. Okay. Well I think any other clinical experiences that you'd like to share, especially maybe how cellular therapy has been being intertwined into the management of PTLD?

Dr Yamshon: Sure, I can comment on that a bit. I agree with you on several of the fronts that you use said already. One is that I think that tabelecleucel, is potentially a very effective treatment and one that I think has garnered a lot of excitement around the country. We were a participant in the clinical trials, and I guess I'll comment on what's the data that's publicly available, which was published in Blood Advances a few months ago. The response rates, and again in patients who have been refractory to many different lines of therapy previously, are exciting. We saw high rates of response and high rates of complete response with a pretty manageable safety profile. One thing that I think differs quite a bit from some of the other cellular therapies is that these are from HLA match donors.
So, one of the problems with doing CAR-T in PTLD, which we've also had some success with, but as you say, because these patients are on chronic immunosuppression, we know that there's T-cell dysfunction there because that's how EBV-positive PTLD came to be there in the first place. So, getting good, functional, strong T cells that are going to go and get rid of the lymphoma can be very difficult. The fact that the tabelecleucel is off-the-shelf and is from healthy donors, I think, is a big advantage and is also because it's specifically EBV-directed; we don't see as much of those severe cytokine release neurotoxicity in the trials, too. I do think that CAR-T is still a viable strategy. We've published on using CAR-T in solid organ transplant recipients, and there is data that it can be successful, but it's another area where it's a very hard bridge to walk. So having tabelecleucelI, I think, is fantastic.  

Dr Amengual: I agree. I think, especially in the hematopoietic stem cell transplant setting, there have been lots of data in the past about using these types of therapies early on, just in EBV reactivation, in terms of trying to prevent PTLD in allogeneic stem cell transplant patients. I'm curious, as the data matures and other studies come to fruition, to see if this is something that can hold up in solid organ transplants, as well, and really sort of learning how to monitor EBV more specifically and sensitively and try to find strategies to prevent this from happening. Maybe we touched upon rituximab a little bit; perhaps that could be a strategy for EBV-cytotoxic T cells, perhaps that could be a strategy. I think these are all things that we would look forward to learning more about as clinicians who manage a lot of PTLD.

Okay. Well, I really thank both of you for a great discussion on EBV-positive PTLD. I look forward to collaborating with you both in the future.  I think we still have so much to learn, and I think some of these new treatments that have emerged are going to pave the way for exciting times in this space.