Relationship Between TA-TMA Development and GVHD

Samer Khaled, MD: We’ll move on to our next segment and discuss the development of TA-TMA [transplant-associated thrombotic microangiopathy]. We discussed that a little before, and maybe we have more details about the development of TA-TMA and the relation of graft versus host disease [GVHD] development post-transplant. Christine, do you want to comment on that?

Christine Duncan, MD: Sure. I think that GVHD and TA-TMA and the overlapping of those circles is one of the most challenging things to address in TA-TMA. Some of that comes at every step of the TMA journey, if you will, in that if you have significant higher stage, higher grade GVHD, it is a lot easier to miss TA-TMA because of some of those symptoms that you can explain by other things. So, hypertension that you can explain by something else, or you need to give platelet transfusions because someone has significant GI [gastrointestinal] bleeding. In those patients, while we’re aware that TA-TMA...may pick it up later because you’re so focused, particularly in the patient with a higher stage, higher grade GVHD, on trying to treat something else.

For us it’s really the GI GVHD, probably less cutaneous, where we struggle with the diagnosis, just because of how sick those patients often are. The other challenge is that once you have it overlap and you think you’ve identified someone who has both of those things, what do you do in that case? If someone has significant graft versus host disease, how are you going to modulate your therapy, and what do you add? If you need to back down on something, is that going to put you at higher risk in different ways? If you back down, are you going to worsen their GVHD? With those questions, you then get caught in that vicious cycle.

I really do think that the GVHD/TA-TMA overlap is a significant challenge, and trying to identify things that can sensitively and specifically differentiate between the two, or point to where those two coexist, are going to be helpful. We think about things like the markers that people have shown in studies and how rapidly or slowly you can get those tests back, complement levels or your stage…or how fast you can get things like…in. Unfortunately for many of us, that is time prohibitive. You’re having to make a diagnosis and choose your treatment; by the time these studies come back, you must have done something by then.

One of the big unmet needs certainly is trying to identify tests, and identify differences up front that can help us better treat these patients; we struggle with diagnosis and we struggle with treatment. The patients struggle with outcome, especially when you have the higher stage, higher grade GVHD mixed with TA-TMA; those outcomes as we’re going to talk about a little bit later, are just miserable.

Samer Khaled, MD: Yes, I agree; in some situations what has been called steroid-refractory graft versus host disease could be actually concurrent TMA in these patients.

I want to move on to our next point of discussion about the morbidity and survival, and I want to invite Dr Hari to comment on that.

Parameswaran Hari, MD: We are definitely paying a price when a patient gets TA-TMA, there’s no doubt about that. Again, the same caveats on our incidence and how we diagnose and how we label somebody with TA-TMA apply. I generally look at the 2 big series that came out recently. One is the big Seattle series that you alluded to, Dr Khaled, by [Stephanie] Lee, [MD, MPH]. That series had an overall survival in the 50% to 60% range for people who had TA-TMA, and they reported 2 other things that I thought were notable in that series. One was that patients whose TA-TMA was missed by their providers at the time and then retrospectively diagnosed at the time of putting together the series, tended to do poorly. The second being the unprovoked TA-TMAs, perhaps the ones that were not associated with GVHD, tended to do better, and the ones associated with GVHD were the subgroup that did poorly.

If you go to the other big series with [Hiroyuki] Matsui, [MD, Kyoto University, Kyoto, Japan] that you also alluded to earlier, in that study the TA-TMA had a TRM, a treatment-related mortality, of almost 70%. Again, we are in the situation where if you have very stringent criteria whereby you call only severe patients as TA-TMA, then you’re looking at a very high nonrelapsed mortality.

The acute survival…is huge, and the long-term morbidity issues are also there, like renal injury. We know that somewhere between 5% and 10% of post-allogeneic transplant recipients, especially adults, end up on dialysis. That perhaps is from injury that happens acutely that gets worse over time. We have people who get right heart issues, pulmonary hypertension; many of those could be traced back, and this will all come to light only when we put together this prospective national series with very clear identification criteria.

Samer Khaled, MD: That’s right. Also from our center, we had a retrospective analysis, and it shows that there is a statistical significance for the nonrelapsed mortality between patients who have TMA and patients who didn’t have TMA.

Transcript edited for clarity.