Transplant-Associated Thrombotic Microangiopathy - Episode 6
Jeffrey Laurence, MD, reviews the risk factors for developing transplant-associated thrombotic microangiopathy, and the panel discusses how risk affects their decision to change or modify treatment regimens.
Samer Khaled, MD: Thank you. We’ll move on to the next point and talk about the different risk factors for developing TA-TMA [transplant-associated thrombotic microangiopathy]. In literature there are different identified risk factors, pre-transplant and post-transplant. In a couple of recent papers, one from Japan, talks about the specific pre- and post-transplant risk factors.
The most common between both are graft-versus-host disease [GVHD], which is the highest risk for developing TA-TMA. In one study it showed that older age and previous transplant exposure, as well as some of the infections like bacteria, viral infections, and invasive fungal infection, all increase the risk of developing TA-TMA.
As mentioned, post-transplant risk factors that are grade 3 and 4 can increase by 20-fold the risk of developing of TA-TMA. Jeff, do you want to comment on risk factors?
Jeffrey Laurence, MD: We published a review in 2016 of several series that looked at pre-risk factors. The big ones from the more current reviews, as you mentioned, are infections; particularly adenovirus, cytomegalovirus and Aspergillus; having had a previous allogeneic transplant; and advanced age. Other risk factors that were also mentioned, typically in one study but not seen in another, was that female sex seem to be associated with a higher risk, the degree of your HLA mismatch, and then in one study a high level of anti–HLA-DP antibodies, as pre-risk factors.
Samer Khaled, MD: Dr Laurence, you mentioned that the complement gene polymorphisms did not contribute in your adult series, correct?
Jeffrey Laurence, MD: Right. In the one pediatric paper in Blood, it talked about a genetic fingerprint in children that was dramatic. However, we did not see it in any of our adult patients who developed a TMA persisting, and other series that I know of.
Admittedly, we’re not talking about hundreds of patients with TMA; we’re talking about each series maybe having 10 or 20. There was really no evidence that genetics helps you in the adult population, and that says 2 things. 1) As is also true for atypical HUS [hemolytic uremic syndrome], another similar complement-mediated TMA, about 70% of patients have an identifiable complement or regulatory factor mutation, but 30% do not. Is it because we’re not smart enough in the sense that our gene pool isn’t large enough to know all the mutations that are now considered polymorphisms, but really in the appropriate setting should be considered as real risk factors? Or 2) It is just that the body is overwhelmed with activated complement, certainly in the setting of some of these other pre-transplant risk factors? Even in the absence of any mutation in any complement regulator, you’re going to be in trouble because it overwhelms your existing innate ability to regulate it.
Samer Khaled, MD: I mentioned before about graft-versus-host disease prophylaxis, and in our center, for example, we find that the tacrolimus and sirolimus increase the risk of TMA. Do you have similar experiences, or do you consider changing the graft-versus-host disease prophylaxis in high-risk patients to a different, non-sirolimus or non-calcineurin inhibitor–based regimen? Christine, maybe?
Christine Duncan, MD: Yes, that’s a really interesting question, whether someone is high risk and so you preemptively make that change? I think one of the easier things to do if you’re not sure what to do with someone you think has TA-TMA, is to change it once you’ve made that diagnosis, or to come down on your levels, or to run the goals lower. We don’t preemptively change it because of risk, because we’re still more aware and anxious about the GVHD risk than we are about that TA-TMA risk going in. Once you have TA-TMA, then we’re certainly comfortable changing or modifying, and also it depends on the severity of the illness. Sometimes, we do a lot of things at once; you change the calcineurin inhibitor, you do other things to try to figure that piece out. However, we haven’t preemptively chosen different regimens up front because of a risk or what we think is a higher risk for GVHD in a patient.
Samer Khaled, MD: Hari?
Parameswaran Hari, MD: The only place that I could say, and I was racking my brain as Christine was answering, to think where I change it. I do try to do a non-CNI [calcineurin inhibitor] regimen in the second-transplant setting. When I’m doing a second allogeneic transplant of a patient I almost always just do…by choice…with very limited CNI use. You can get away with limited CNI or no CNI at all if you have a matched second transplant with…as GVHD prophylaxis.
Samer Khaled, MD: We also have experience with a busulfan and tacro/siro [tacrolimus/sirolimus] that had a very high incidence of TA-TMA. Whenever we need to use a busulfan-based regimen, then we try to avoid the sirolimus and the graft-versus-host disease prophylaxis for that reason.
Transcript Edited for Clarity