Diagnostic Approaches for 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: So, Dr Schroers-Martin, can you tell us how we might go about making the diagnosis of PTLD?

Dr Schroers-Martin: Sure. So, as you pointed out, these patients are very complicated. They're usually on multiple medications; they're very immunosuppressed, they're at risk of other medical issues. So, differentiating these is really critical because an infection could present in the same way with fevers and night sweats. Other viral reactivations, as you pointed out, like CMV, could present in a similar way. In fact, you can have EBV reactivation and EBV viremia, which is just viral reactivation in the absence of lymphoma. All of this can be pretty tricky to tease apart.

So, cross-sectional imaging is really the first step and is the standard of care. Either with CT, looking for adenopathy either in the periphery or central adenopathy, or looking for extranodal disease, PET/CT is the definitive staging mechanism. Then, also looking for EBV DNA via PCR-based methods. I think we'll talk a little bit later on about the possibility of the utility of screening and longitudinal EBV surveillance by PCR, but certainly, at a time of suspected disease, looking for EBV by PCR-based methods is really a critical step.

These assays have been developed in either whole blood or in plasma. There are data that suggest that plasma is probably a little bit more specific, a little bit more specific for EBV-associated lymphomas than whole blood because whole blood contains B cells as well as circulating B lymphocytes, which can have EBV positivity. At least here at Stanford, plasma is the preferred analyte.

There's not really a specific threshold that has been associated with specifically differentiating EBV-positive PTLD from non-malignant EBV reactivation. There are data from Hopkins dating back a decade or so ago suggesting a threshold of around 5000 copies is potentially being differentiated. I don't think those thresholds have been perfectly validated, but certainly, once we get above a thousand or so, our suspicion really begins to get higher, and we begin to do these deeper searches with imaging and watching people very, very carefully.

Dr Amengual: Absolutely. That's great. Yeah, I mean, we took a retrospective look at patients with organ transplants at our institution at Columbia and looked at EBV levels in patients who had solid organ transplants, and it was interesting. So, it's a retrospective study that we hope to be publishing very soon, but we did find, sort of, a lower threshold, potentially, for when there might be an increased risk for PTLD, which was a little surprising to us. So, I agree that somewhere between like 1000 to 5000 is where we need to be a little bit more vigilant, and we hope to study this more robustly in a prospective study.

Yeah, I think, also, it's really challenging because when we make the diagnosis of PTLD, that in itself can also be a broad spectrum, where we can just see brisk mononucleosis-like findings in the pathology to something that's considered polymorphic where there's many different cells intermixed in the lymphoma and monomorphic PTLD, which is typically a diffuse large B cell lymphoma but could also range to Burkitt-like and even non-B-cell lymphoma, such as Hodgkin and T-cell lymphoma. It becomes challenging, even once we make the diagnosis, to really think about what variant it is and how to proceed from there. I'm curious how you guys consider when to intervene when you're considering EBV PTLD?

Dr Yamshon: Yeah, that's, I think, a very good question and one that you probably see a lot of variability on. One very open question is one that you brought up already, and I think the retrospective data that you had mentioned in the solid organ transplant population that you produced, that was presented at this past ASH, actually by one of our fellows, Dr Evan Orlando, and really I think it caused a stir because I think it raised the question of, should we be intervening even before we've potentially made the diagnosis? Should we give patients rituximab when we first see EBV in the first place to prevent it from becoming something that becomes more scary? I mean, I know, at the center in the hematopoietic stem cell transplant patients, we just routinely screen for EBV in everybody. I know that that practice is not necessarily standard everywhere, and certainly, I think there's, in the solid organ transplant world, there's even more variability. So, that question of, how do we screen if we see an EBV come up in the absence of these other things, do we intervene at that point? I think it is very much an open question and one that I think is really important. I'm actually kind of curious as to what your guys' practice is on that front.

Dr Schroers-Martin: I would say that on our side, in comparison to some indolent lymphomas where there's a watchful waiting paradigm in the immunocompetent population, I don't think that approach really exists as much in this disease just because it can be so devastating and it can move so fast when it goes quickly. With the question of low-level EBV viremia, I share your observations where longitudinal surveillance seems to be well established in pediatric transplants, where recipients more frequently might not have had prior EBV exposure. Similarly, in the stem cell transplant world, longitudinal surveillance seems to be more common in practice than in solid organ transplantation. Within solid organ transplantation, guidelines have been somewhat variable, and it also seems like, center to center, there's been variability in the utilization of longitudinal EBV surveillance, where some cardiac transplant centers do monitor, especially in the first 2 years, and others don't necessarily routinely.

I think, certainly, in the case of any histologic biopsy-proven diagnosis, whether of polymorphic or of DLBCL, like PTLD, intervention is required very rarely in the context of very late EBV-negative disease. I've certainly occasionally seen very indolent presentations of a kind of marginal zone-like phenotype with or without EBV occurring many years after transplantation. There's some temptation to watch and wait for those patients. But even in those patients, we frequently thought about additional rituximab or radiotherapy just because they are overall so high risk. Certainly, in the earlier post-transplant period in the first 2 years, generally, those first steps are taken as a routine of a reduction of immunosuppression, which I think we can discuss as a strategy, and then rituximab as a first line.

Dr Amengual: Yeah, I agree entirely, and I think such heterogeneity in the solid organ transplant groups, the different organs in terms of their standard operating procedures, in terms of how they monitor EBV, I think the first line for all patients is a reduction in immunosuppression, but one must really caution the risk of organ rejection. So, although immunosuppression should be reduced, stopping entirely is probably not the best option, and we should certainly proceed with treatment early. I agree with everyone else. We don't really watch and wait so much with PTLD, as the patients are fragile and can really become critically ill so quickly.

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.