EBMT 2025 | Adult TA-TMA: updating definitions and considering discontinuation of GvHD prophylaxis

So I was recently very fortunate enough to work with our group in the complement alternative pathway TMA working group at Mayo, which combined with our bone marrow transplant center, we were able to put together one of the largest transplant-associated TMA adult cohorts in the current literature. 

So within complications that can happen post-transplant, particularly post-allogeneic transplantation, when we’re speaking about adult populations, one of the largest groups of complications are some things that are called endothelial dysfunction syndromes that basically include hyperactivation and inflammation of the endothelium, ultimately leading to systemic organ damage. This includes VOD/SOS, this includes acute graft-versus-host disease, and one that has been not as well studied, just because of the incidence in adult populations, is transplant-associated TMA. 

And so the main data that we have actually comes from pediatric cohorts, given that in the pediatric cohorts, it has also been seen in autologous transplantation, particularly in patients receiving transplant for neuroblastoma. However, in adults, its incidence at our center was approximately five to six percent over almost a 20-year span. So we were able to retrospectively evaluate all of our patients that had some suggestion of TMA. And fortunately, in 2023, one of the largest kind of publications in this field came by Dr Schottler, and the new harmonizing definitions for TA-TMA across kind of both pediatric and the adult spectrum were published in an attempt to kind of enhance the possibility of future research in this area. 

And so taking that into consideration, even though this publication was definitely a relevant and very important one, one of the things that certainly has come up is that most of the data that led to those harmonizing definitions come from the pediatric experience. And so trying to kind of take that into consideration, we decided to use the harmonizing criteria and retrospectively review the patients that had TMA in our center, validating those harmonizing definitions. And so this is the second or third largest cohort of TA-TMA in general in the adult world, but specifically, it is the first that has used the updated definitions. 

And so in this setting, we were able to see that amongst patients that had what are considered high-risk criteria, we did see decreases in long-term outcomes. Nevertheless, we only noticed them across specific subtypes of those high-risk criteria. More importantly, LDH, which is one of the markers that is frequently used in the pediatric experience, was used as one of those high-risk definitions. And if a patient had more than two above the upper limit of normal of that per the referring lab, that would be considered a high-risk patient. 

We did not see any impact amongst patients that had elevated LDH in our cohort, and so that is what we are proposing is that even though the harmonizing criteria are certainly useful and should for all intents and purposes be used for definitions moving forward, they still need, as we are all aware in science, it just continues to happen, they should be adjusted as we start to learn more about specific populations. 

In our group, we are recommending from our adult perspective, not using LDH as one of the high-risk criteria for the adult patients. And then within our own group, we have adopted a strategy of considering use of complement inhibition as first-line therapy only amongst patients that have an elevated soluble C5b-9, which is one of the other risk criteria, or amongst patients that do not have a super therapeutic CNI at the time of the TMA. 

One of the things that was identified was that amongst adult patients, even though this isn’t a practice that is very frequently done in the pediatric world, in adults, because some of the drugs that are used for GvHD prophylaxis are known risk factors for TMA, one of the frequent practices amongst a lot of centers is at the time of diagnosis of TMA, that drug would be discontinued in an attempt to reduce the TMA. What we found was in our center when we did that, that actually led to an increased mortality, and that was not associated with the TMA. The TMA usually was well-controlled, but that usually resulted in a flare of GvHD, ultimately leading to the decreased outcomes. So we are recommending not discontinuing the CNI, or at least that’s what we’re doing in our group for the time being, or we are recommending in our own group, and we’re checking CNI levels to see whether or not they’re super therapeutic. If they’re super therapeutic, then consider deescalating the dose and see if that in of itself makes the TMA respond. Otherwise, then consider other strategies.

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