Accredited webinar: Bridging gaps in PTLD care
Transcript: Confirming and classifying PTLD: Histology and EBV
Supported by Pierre Fabre
Nina Babel, MD, PhD.
All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
Good afternoon, everybody. It's my pleasure to welcome you on our webinar on posttransplant lymphoproliferative disorder. I am Nina Babel. I'm happy to moderate today's webinar, and PTLD remains a very challenging complication after kidney transplantation, and the reason for this is that it sits in an intersection between different disciplines – histopathology, hematology, immunology, virology – and that is pretty much the panel we brought together today. I'm delighted to be accompanied by internationally recognized experts in this area. We have today Daan Dierickx from KU Leuven in Belgium. He is a hematologist. We have Sylvain Choquet. He is also a hematologist from Pitié-Salpêtrière in Paris. And we have Susan Prockop. She is Professor of Pediatrics at Dana Farber Center and Harvard Medical School in the USA. So, that is what we're going to do today. Our agenda, we together all of us will move you through the diagnosis of PTLD, through the risk stratification, escalation, initial and second-line PTLD, and also multidisciplinary discussion and escalation and referral. And what we're going to have at the end of our webinar. I would like to have you the question all the time we present our slides to have in mind the question, "What is the right patient for the right therapy at the right time point?" And I hope at the end of our presentation you will be able to respond to this question. But let's start at the beginning and how can we confirm and classify PTLD.
So, and that is my learning objective. So, there at the end we have the PTLD diagnosis but it's not very easy. We can have suspicions that we have PTLD, for example imaging or EBV infection signs but, to be able to give the diagnosis, we have to have tissue biopsy and provide histopathological evaluation as well as EBV status. And the reason for this is we have to classify our PTLD because it can have a completely different presentation. If you look at this classification, we can distinguish between non-destructive, polymorphic, monomorphic, and Hodgkin-like diseases, and all of them have different presentation, different dignity of the disease, and they require a different therapy. That's why we need to know what is the type of the histopathology we have and whether they have EBV involvement. And the key message I would like you to take away from this slide is that the PTLD diagnosis requires a histopathology as well as EBV diagnosis to be able to move to the therapy. But, before we start with the therapy initiation, we need to bring all other pieces together, and that includes not only histopathological evaluation and EBV status. We also need to know what is disease involvement, how progressed is already the disease stage. We need to know what type of transplant we have because it's also different if I have kidney transplantation versus heart transplantation and also what type of immunosuppressive therapy we have, what is the intensity of the therapy at the end, also what is the risk of graft rejection in certain patients. And why do we need this? Because we need to consider the next step for this therapy. Now, the gold standard, the first step will be the reduction of immunosuppressive therapy, but we also need to consider are we able to do this? Can the patient or their graft survive the reduction of immunosuppressive therapy. And also, if it doesn't work, can we give the patient rituximab as the next step of therapy. Does this patient have CD20 expression of the surface of the lymphoproliferative disorder of the lymphoma? We also need to monitor EBV to know what is going on like, predictive factor. And we also need to be able to have a panel to discuss all these steps we're going to go. So, here I would like to let you know that the diagnosis is not the last step. We need also to have enough information about our patient to be able to decide what we're going to do.
But, we also have challenges on the way, and the challenge is, as I told you, the presentation of PTLD is very heterogeneous and sometimes the patient presents with unusual symptoms, what we have to think about the possibility the clinical picture we have now could be a PTLD. Another challenge we can have, PTLD presentation in tissue that we cannot access very easily. Think about CNS lymphoma or maybe technically not available, they cannot do it in the heart or it's not very easy, and also what we also would like to know is we know that the earlier we diagnose PTLD the better is a prognosis. That's why we would like to have kind of surrogate markers or biomarkers that allow us to provide an early type of diagnosis of PTLD. And one of the markers could be EBV. EBV serology is a risk factor if you look before transplantation, the mismatch donor-positive recipient-negative brings a high risk for PTLD development but also in follow-up EBV PCR would be a marker for this and also cell-free DNA is also a marker that showed in the last time early in August this year a study from Netherlands showed that is very good predictive marker for progress of PTLD. So, I would like to close my part of the presentation, and I would like to start our panel discussion and maybe pass one first question to Daan. Daan, my question would be, what information beyond the histological subtype is essential when establishing an initial PTLD management plan, and what are the key challenges in achieving timely diagnosis and accurate classification of PTLD? –Yeah, thank you very much, Nina. So I think the histological subtype is as we already told is essential and, in particular, we need to know the CD20 staining because I think everyone agrees that rituximab is now part of the first-line therapy in all CD20-positive subtypes. The EBV also needs to be known. Maybe not that important for the first line, but also to plan escalation if there is no sufficient response to treatment and you want to go to second-line treatment, which includes EBV-directed therapies. For rare subtypes like all the non-DLBCL monomorphic subtypes, it's also important because there the standard of care is totally different compared to the polymorphic and to the monomorphic diffuse large B-cell lymphoma. So, as you told that the tissue is the most essential at this point, which is also the answer for the quiz question I think if I'm not wrong, but maybe that's a room for discussion. –Okay thank you so much. The second question goes to Sylvain. Sylvain, what do you think, how does EBV status influence risk assessment monitoring and prognosing and early management decision in PTLD, and do you see any limitations in routine practice for these? –Sorry, in terms of monitoring for incidents or once you've established the diagnosis I missed that part? –In establishing the diagnosis, after I have the diagnosis. –There's two aspects. First one is sometimes it's difficult to be sure that it is a pathological tissue we have in the biopsy, and in this consideration the EBV positivity is a good argument for a pathological situation and tumor, but this is a question directly for the anatomical pathologist.
For the clinicians in first-line, the EBV status of the tumor is in fact not important. We have several prospective studies showing that the EBV status for the first line give the same prognosis in word of overall survival and relapse risk but it will be totally different for the second line because at this time we will have new treatment specifically directed against EBV. So, this is the first line, it's not problem for us. Second line it will be really important to know. So, at the beginning we do not know how long it will take to see if the patient respond or not or if he is directly refractory to the treatments. So, we need since the beginning the status of EBV because we will have time just to think in case of relapse or refractory status to use specific treatments. And I will say also that sometimes difficult to have for primary CNS PTLD, sometimes difficult to have a clear biopsy. And so, in this case, if you compare the EBV viral load in the CSF and at the same time in the blood, if it is far more important in CSF, it's a good argument for the PTLD treatments. –Okay. Thank you so much. Susan, may I ask you also a question? How do delays in diagnosis or definitive classification affect treatment selection, escalation planning, and access to appropriate therapeutics across the PTLD pathway? –So, I think the first thing that's very important to distinguish is patients who have EBV PTLD after hematopoietic transplant versus after solid organ transplant, and that pathway can be very different. And so I think it's important to really distinguish those two separately. I think the incidence of, for instance a Burkitt-like or alternative histopathology in the setting of hematopoietic-transplant PTLD is much less common even though it's rare across the board. It's much less common after hematopoietic transplant than after solid organ transplant.
So, as Sylvain was saying, I think for the initial therapy, especially in the hematopoietic-transplant setting, rituximab alone is going to be your initial therapy and then, when you see response to that, is when you tend to pivot. I think from the perspective of taking the time that you have while you're using single-agent rituximab to potentially have more assessments is the place where I think there is sometimes time that you can be doing something to prepare if the patient doesn't respond. And so that's a time that, for instance, we look at the serial PCR monitoring as an indication of response after initiation of rituximab. We've demonstrated in hematopoietic-transplant recipients that if you see early complete clearance of the viremia, that's a very good sign that you're responding from the PTLD as well. And so, in the hematopoietic transplant setting, if somebody is not responding in terms of their PCR to initiation with single-agent rituximab, we start to think about whether there are additional therapies that they should be eligible for and start to think about the timeline for getting those therapies, and specifically tabelecleucel or other potential cellular therapies would be sort of how we would think about being prepared for that pivot. And then as Sylvain has talked about sort of in the solid organ transplant setting, if you're prepared to initiate multi-agent chemotherapy, or if you've already assessed that a patient is ineligible for chemotherapy, then again thinking about what your timeline to pivot to tabelecleucel could be important. –Okay, thank you so much. With that, I will close this panel discussion.
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