Transplant-Associated Thrombotic Microangiopathy - Episode 2
Parameswaran Hari, MD, reviews challenges in defining the incidence of transplant-associated thrombotic microangiopathy; an expert panel comments on the volume of autologous transplants performed in expert centers.
Samer Khaled, MD: What will be the incidence of transplant-associated TMA [thrombotic microangiopathy]? This question is very challenging in literature, and there are different reports in different papers. In 1 of the papers they cited a range from 0.5% to 70%-plus. I would like to invite Dr Hari to comment on the incidence and what the incidence is in his center.
Parameswaran Hari, MD: Thank you, Dr Khaled. And thank you, Dr Laurence, for that wonderful succinct explanation of the pathophysiology. We have a lot of challenges, as you correctly alluded to, in defining the incidence of TA-TMA [transplant-associated thrombotic microangiopathy]. I’m an adult transplanter, and in the adult population the incidence is quite different from the pediatric population; it is seen almost exclusively in allo [allogenic stem cell] transplant in adults. I can say that I have never seen or actually recognized a TA-TMA episode in an auto transplant for an adult patient.
There are some fundamental problems when you look back at the literature and try to gauge the instances from the existing literature. No. 1, the nebulousness of the diagnosis; we have criteria. In fact, the BMT CTN [Blood and Marrow Transplant Clinical Trials Network] criteria are only from 2010.
When you look at the retrospective series, if you look at all the patients from 2000 to 2020, when these transplants were being diagnosed, you’d have to say that they didn’t have criteria at that time to diagnose. Someone is going back in the charts and trying to find out.
No. 2, we don’t have an ICD [International Classification of Diseases] code, and there are efforts to double up an ICD code for this condition, but it didn’t really exist until 2020.
The third problem is that the criteria for diagnosis, even now, are multiple. In fact, it depends on whether you really want injury to happen and then make a diagnosis, or do you want early diagnosis. The more stringent the criteria you apply, the less the incidence will seem like.
From my own experience, I would say that the incidence is somewhere in the 10% range for TA-TMA that is of clinical consequence. If you look at everyone who has schistocytes at a certain level in a high-power field after transplant, it’s much higher because they are all events that lead to schistocytosis.
In the setting of calcineurin-mediated injury and GVHD [graft-vs-host disease] and other events—allogenic transplant, extremes of age, etc—the actual consequence of that schistocytosis—hemolysis and high LDH [lactate dehydrogenase], proteinuria, hypertension—is that complex that we call TA-TMA of clinical significance, which is probably in the 10% range. Obviously, there is a difference between people who get retransplanted. Second transplants seem to be experiencing these at a higher incidence, so in that setting it’s probably closer to 20% in that setting.
I am comfortable with a rate of around 10%, or 7% to 10% for first transplants, then maybe 15% to 20% for second transplants.
Jeffrey Laurence, MD: I can also talk to that in terms of the Weill Cornell Medicine experience. When we reviewed our first 100 allo transplants in adults, we had 20 TMAs; that would be an incidence of 20%. When we stopped the calcineurin or mTOR inhibitors, these patients were on and replaced them with higher doses of prednisone CellCept [mycophenolic acid], and mycophenolate, half of them went away. We went from an incidence of 20% to 10%. Those are the ones that persisted after withdrawing the CNIs [calcineurin inhibitors] or the mTOR inhibitors, making certain that they had no infections because a couple of them had chronic infections. I agree that at least in the adult setting, it’s 10%.
Christine may want to comment because I do understand that in Dr Sonata Jodele’s series they were upward of about 30%.
Parameswaran Hari, MD: Right.
Christine Duncan, MD: When I think about the difference between the adult and pediatric populations and the incidence, 1 of the questions that comes to mind is: Is it a difference in the patients, is it a difference in the treatment, or is it a difference in the providers? The answer may be somewhere in between, because we think 1 of the issues that’s come up with exactly what we’ve already heard is about how you are screening and how you are looking for this.
One of the issues in pediatrics that may lend to a higher incidence can actually be the screening criteria that we use.
Samer Khaled, MD: If I may go back and ask: How frequent do we see the TA-TMA in autologous transplant or postautologous transplant? Maybe I’ll start with Dr Hari.
Parameswaran Hari, MD: I do a lot of auto transplants too for myeloma and things like that, and I can say that I’ve never seen 1. At least I’ve not recognized 1 or had 1 of clinical consequence. That’s pretty strange compared with the pediatric experience. The question is: Is it because of the multiple hits required that are 1 or 2 hits that doesn’t happen in an auto transplant in an adult with a more mature endothelium?
Samer Khaled, MD: Jeff, do you see any TA-TMA in autologous transplant?
Jeffrey Laurence, MD: I’ve never seen it here at Cornell.
Samer Khaled, MD: At City of Hope we had a protocol for an autologous transplant for scleroderma, and I saw a couple of cases on that protocol. As Dr Hari mentioned, for myeloma, it is very rare. I can recall maybe 1 or 2 cases that I’ve seen over the last 12 years; it’s very rare in autologous. That’s probably related to the hits that precipitated the diagnosis.
Transcript Edited for Clarity