Abatacept today, TMA away: protecting the endothelium Open Access

Transplant-associated thrombotic microangiopathy (TA-TMA) and related endothelial syndromes remain among the most vexing complications of hematopoietic stem cell transplantation (HSCT), but in this issue of Blood Advances, Khandelwal et al¹ present a good solution in the form of abatacept as a dual-action agent that not only prevents acute graft-versus-host disease (GVHD) but also reduces endothelial injury syndromes in children with transfusion-dependent β-thalassemia (TDT) who are undergoing HSCT. Their retrospective study offers compelling evidence that abatacept, when added to standard calcineurin inhibitor–based GVHD prophylaxis, improves thalassemia-free survival and mitigates transplant-related toxicities.

HSCT is a curative option for TDT, but transplant-related complications remain formidable.² Decades of transfusions lead to iron overload, which catalyzes reactive oxygen species and primes the vascular endothelium for injury.³ This proinflammatory milieu, exacerbated by calcineurin inhibitors, increases susceptibility to endothelial syndromes, such as TA-TMA, sinusoidal obstruction syndrome (SOS), and posterior reversible encephalopathy syndrome.^4,5 These complications, often refractory to supportive care, drive morbidity and nonrelapse mortality. Thus, strategies that simultaneously prevent GVHD and protect the endothelium are urgently needed.

At the heart of this study lies a pivotal question: can abatacept, long recognized for its ability to prevent acute GVHD, also protect the vascular endothelium and thereby improve survival in children with transfusion-dependent thalassemia who are undergoing HSCT? Abatacept is a cytotoxic T lymphocyte–associated protein 4 and immunoglobin fusion protein that binds CD80/CD86, thereby blocking CD28-mediated T-cell costimulation. Its efficacy in acute GVHD prophylaxis is now well established.⁶ However, its potential endothelial benefits are less explored. Of note, CD80 is also expressed on neutrophils, and neutrophil extracellular traps (NETs) have been implicated in activating complement and injuring the endothelium.⁷ Khandelwal et al hypothesized that abatacept might blunt this immunologic cascade by reducing NET formation and downstream complement activation, thereby mitigating endothelial syndromes.

In this single-center, retrospective analysis, 64 children with TDT underwent HSCT using a busulfan-based conditioning regimen. Of those, 50 received abatacept on days −1, +5, +14, and +28 after transplant, whereas 14 served as controls. The results were striking; neutrophil and platelet recovery were prompt in both groups, and infection/reactivation rates were similar, indicating that attenuating T-cell costimulation did not come at the expense of graft integrity or immune reconstitution. Acute grade 2 to 4 GVHD occurred in 0% of the abatacept group vs 35% of controls. Endothelial injury syndromes were significantly lower in the abatacept cohort (16% vs 64%; P = .0009) and thalassemia-free survival was 100% as opposed to 71% in the control group. Importantly, the study explored mechanistic biomarkers. The day +14 levels of circulating double-stranded DNA, a surrogate for NETs, and soluble C5b-9, a marker of complement activation, were significantly lower in the abatacept group. These findings suggest that abatacept may reduce NETosis and downstream complement activation, offering a novel explanation for its endothelial protective effects.

The dual benefit, namely GVHD prevention and endothelial protection, positions abatacept as more than a GVHD drug. It represents a strategy of endothelial preservation, thereby reframing vascular injury as a preventable transplant complication rather than an unavoidable cost. Importantly, the drug was well tolerated with no infusion-related adverse events and did not compromise engraftment or donor chimerism. Mechanistically, the study underscores how immunologic cross talk drives transplant toxicity. By blunting T-cell activation, abatacept seems to reduce cytokine-driven neutrophil activation, dampen NET formation, and prevent complement-mediated vascular injury.⁸ These findings resonate far beyond thalassemia; they highlight how targeted immunomodulation can reduce non-GVHD complications, an observation relevant to hemoglobinopathies and malignant indications alike.

The study was retrospective, nonrandomized, and limited by a small control cohort. Baseline NET data were unavailable, and CD80/86 expression on neutrophils was not directly measured. Chronic GVHD incidence was unchanged, echoing a previous abatacept experience.⁶ However, the findings raise important next questions. Is the 4-dose schedule sufficient or could extended dosing reduce chronic GVHD or late vascular injury? Could abatacept enable reduced reliance on calcineurin inhibitors, themselves toxic to the endothelium? How does it compare with or complement posttransplant cyclophosphamide? Which patients benefit most among those with high ferritin, baseline endothelial stress, or complement susceptibility? Prospective studies with serial biomarker assessments and functional assays will be essential to confirm the link between abatacept, NET inhibition, and complement control.

This work illustrates the potential of strategic immunomodulation to transform HSCT for TDT. Rather than reacting to SOS or TA-TMA with rescue therapies, such as defibrotide or eculizumab,⁹ abatacept prophylaxis prevents the cascade from igniting. By simultaneously preventing acute GVHD and shielding the endothelium, abatacept offers a more balanced approach to transplantation. The implications are particularly profound in low- and middle-income countries where gene therapy remains out of reach and HSCT is the only curative option. Optimizing transplant safety with agents like abatacept could substantially expand access to cure.¹⁰ Prospective studies, including trials of extended dosing and comparisons with alternative prophylaxis regimens, will be essential to define its optimal role. Most importantly, this work signals a paradigm shift; endothelial protection may soon stand alongside engraftment and GVHD prevention as a central goal of transplantation.

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