Treatment Strategies 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: Dr Yamshon, in terms of treatment, where do you go after radio-reducing immunosuppression, and at what point do you then trigger giving the rituximab?

Dr Yamshon: Yeah, I think that that's an important question, and I do think that there's some variability in that. Also, I think that, as you say, the reduction of the immunosuppression piece can be effective and is often effective, but it is a very tough rope to walk because you want to preserve either their organ or their stem cell graft; you've gone through all the trouble of—especially for solid organ transplants. Many of these patients have been on a waitlist for, say, a heart or a kidney, for some of them upwards of a decade. So, that organ is worth more than its weight in gold. You have to be very, very, very careful about the reduction of immunosuppression.

I tend to be very cautious about the amount that, in consultation with the transplanter, but I tend to be very cautious about the amount. Then, if I'm not seeing an effect relatively quickly, I'm very quick to pull the trigger on something else because, like I said, I think it's a very tough path to follow where you don't have a lot of margin for error. Generally speaking, if I don't see a reduction in immunosuppression, I mean, in theory, I like to see total resolution, and if I see less than that, I generally do almost always end up pulling the trigger on something else.

Dr Amengual: I would say probably what's most acceptable right now is sort of a sequential risk-stratified approach to treatment for PTLD, where we start with single-agent rituximab and give it weekly times four and then re-image or rest stage with the PET scan. What's been published is that if patients have even a partial response or stable disease, they can go on to receive just additional rituximab consolidation, and if not, then they can be escalated to combination chemotherapy, most commonly R chop.

Interestingly, these studies really don't incorporate the biology of disease. They don't incorporate bulk disease, and risk is really more clinical in nature, thinking about the type of organ transplant and whether or not they achieved a complete remission. So, patients with high-risk disease, which I think is quite a large percent of the patients with PTLD, tend to actually have a pretty poor outcome and could be as low as overall survival could be as low as 59, 60% in these patients.

We've been thinking about different strategies for treating this. We've used, at our institution, sort of low-dose adjusted EPOCH chemotherapy, which is infusional. This is kind of based on the theory that these patients have T-cell dysfunction very similarly to HIV-related diffuse large B-cell lymphoma. In that patient population, our CHOP does not always work well for a number of reasons. Potentially, it's more toxic given in a bolus fashion, sort of misses the dividing cells when just given in a bolus fashion. Then, also, with EPOCH, you can really sort of titrate the doses up and down based on any toxicities or cytopenias or underlying organ dysfunction with which many of these patients have and can easily be adjusted for any drug-drug interactions that are frequent in both populations. We've had some nice experiences with that and hope to publish some retrospective data and look at this prospectively.

There've been a lot of other studies sort of looking to incorporate novel agents into these treatment strategies. I think one of the most common is brentuximab vedotin, which is an antibody-drug conjugate with monomethyl auristatin E—which targets CD30—which is often present in EBV positive lymphomas in general. There have been some nice studies looking at brentuximab vedotin plus rituximab. However, they were associated with some toxicity. So, one would really need to use this cautiously. There's some thought that perhaps daratumumab, which is a monoclonal antibody to CD38 at 138, could have some activity in lymphomas that have that expression, especially plasmablastic type PTLD, which we see.  Most recently, I think there was a study looking at adding ibrutinib in combination to the sequential strategy, which really did not show any improvement in outcomes in patients with 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.