MIDAS touch on TA-TMA: golden gains through active screening Free

In this issue of Blood, Vasu and colleagues¹ report the results of the first prospective multicenter study on active screening for transplant-associated thrombotic microangiopathy (TA-TMA) in adult patients undergoing allogeneic hematopoietic stem cell transplant (HCT). The incidence of severe TA-TMA was higher than previously reported, and only severe TA-TMA had a significant impact on overall survival (OS) and nonrelapse mortality (NRM).

Thrombotic microangiopathies consist of a group of disorders characterized by endothelial injury, leading to microangiopathic hemolytic anemia, consumptive thrombocytopenia, and microvascular thrombosis, ultimately resulting in ischemic organ damage. This group of disorders includes primary syndromes, such as atypical hemolytic uremic syndrome (aHUS), as well as various secondary forms. TA-TMA falls into the latter category and typically arises in susceptible individuals following HCT. Although some cases follow a self-limiting course, more than one-half of patients progress to multiorgan dysfunction, often with a high mortality rate. Renal insufficiency is the most common organ manifestation of TA-TMA, although other organs, such as the central nervous system and gastrointestinal tract, may also be involved. Several factors can contribute to the development of TA-TMA after HCT, including toxicity from conditioning regimens and prior therapy, immunosuppressive strategies for graft-versus-host disease (GVHD) prophylaxis, bacterial or viral infections, and GVHD itself.^2,3 Currently, no approved therapies exist for the treatment of TA-TMA.

TA-TMA belongs to a broader spectrum of endothelial injury syndromes associated with HCT, which also includes conditions such as engraftment syndrome and hepatic sinusoidal obstruction syndrome.³ The clinical overlap among these disorders, along with the numerous diagnostic criteria proposed in the literature, makes an accurate and early identification of TA-TMA challenging. Moreover, the lack of consensus on prognostic indicators further complicates disease characterization. In response, international transplant societies have sought to standardize both diagnostic and prognostic criteria for TA-TMA, aiming to facilitate harmonization across centers and multi-institutional studies that can more accurately assess its incidence, clinical course, and outcomes.² 

Vasu and the MIDAS (MIcroangiopathy, endothelial Damage in Adults undergoing Stem cell transplantation) consortium are the first to report results from a prospective observational study in adult HCT that specifically evaluates the incidence, risk factors, and mortality of TA-TMA using the newly harmonized diagnostic criteria. Patients undergoing their first HCT at 3 centers (Ohio State University, Moffitt, and Roswell Park Comprehensive Cancer Centers) were prospectively screened through weekly clinical and laboratory assessments up to day +100 post-HCT. TA-TMA diagnoses made by the participating centers were independently reviewed and adjudicated by 3 blinded reviewers. Severe TA-TMA was defined by the presence of at least 1 of the following: lactate dehydrogenase (LDH) >2× upper limit of normal, proteinuria, or end-organ dysfunction excluding isolated kidney injury.

Consistent with findings from other prospective pediatric studies,⁴ the incidence of severe TA-TMA in this adult cohort was higher than that reported in retrospective analyses.^5,6 The cumulative incidence at day +100 was 21.8% using the harmonized criteria, without significant differences between the 3 centers. The authors also found considerable variability in case identification based on the diagnostic grading criteria used (see figure). Patients in the MIDAS cohort with severe TA-TMA had significantly worse OS (57.5%) and NRM (42.1%) at +180 days compared with patients with nonsevere or no TA-TMA. In multivariate analysis, elevated pre-HCT serum creatinine was the main factor independently associated with the development of severe TA-TMA. Interestingly, complement activation measured at various time points using soluble terminal complement C5b-9 (sC5b-9), which has been included in some TA-TMA definitions,² was not associated with the presence or severity of TA-TMA in this study.

The limitations of this study include the relatively small sample size, with 239 patients included in the analysis, as well as substantial intergroup differences in key transplant-related variables, such as conditioning intensity and GVHD prophylaxis strategies employed among the 3 centers. Most patients received peripheral blood as graft source and reduced intensity as conditioning regimen. Furthermore, a notable limitation of this study is the lack of analysis on the potential correlation between TA-TMA and acute GVHD, despite the well-established interconnection between these 2 transplant complications in the existing literature.^6,7 

These findings, however, are important in raising awareness about this potentially severe complication of HCT and in pointing out the need for future multi-institutional research focused on a more accurate diagnosis and management of TA-TMA. By systematically employing readily available and inexpensive clinical and laboratory parameters (anemia, thrombocytopenia, elevated LDH, presence of schistocytes, proteinuria, and arterial hypertension), the authors were able to clearly identify a subgroup of patients with substantially worse transplant outcomes. This highlights the critical need to implement active screening programs for TA-TMA across transplant centers, along with the urgent need for investigating prophylactic interventions and effective therapeutic strategies for these high-risk individuals. Moreover, the comparable outcomes observed between patients with nonsevere TA-TMA and those without the complication highlight the need for a refined classification that integrates pre-HCT variables, such as baseline serum creatinine, and novel endothelial biomarkers to better guide clinical decision-making.⁷ This approach would enable more precise identification of at-risk recipients and help differentiate severe TA-TMA from other conditions, such as aHUS.

Classical complement pathway inhibition strategies using eculizumab, a monoclonal antibody that specifically targets complement protein C5, have shown promise in the management of TA-TMA, but almost exclusively in pediatric populations.^4,8 In this study, the absence of a correlation between sC5b-9 levels and TA-TMA in the context of adult HCT further supports this observation. However, it is known that endothelial injury can directly activate the lectin pathway of complement, which subsequently triggers the terminal lytic cascade gated by C5. In adult patients with TA-TMA, inhibition of this complement pathway using narsoplimab, a mannan-binding lectin-associated serine protease-2 inhibitor, has yielded encouraging results and is currently accessible through an expanded access program.^9,10 Nonetheless, since endothelial dysfunction appears to represent a continuum of vascular injury rather than a discrete condition, adopting a broader perspective on vascular endothelial syndromes and their underlying pathophysiology is essential.³ Advancing this understanding will be key to developing new predictive biomarkers and exploring alternative, and potentially more effective, therapeutic approaches for adult patients with TA-TMA.

Conflict-of-interest disclosure: The authors declare no competing financial interests.