Allogeneic hematopoietic cell transplant (alloHCT) cures many malignant and non-malignant hematological disorders, but graft vs. host disease (GVHD) remains a common cause of transplantrelated morbidity and mortality. Acute GVHD tissue injury is often a consequence of damage associated with conditioning and further driven by donor T lymphocyte antigen recognition and cell activation. Systemic corticosteroids are the first-line treatment for acute GVHD, yet an estimated 10-50% of patients will fail to respond to corticosteroids, with a markedly shortened overall survival [1-5].

Ruxolitinib, a dual JAK1/2 inhibitor, is approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of steroid refractory acute GVHD (SR-aGVHD), and while the overall response rate (ORR) at day 28 with this agent is around 60%, complete response (CR) rates are low (34%)[6], especially for those with grade III-IV SR-aGVHD,(25%)[6, 7]. Optimizing treatment for patients with severe SR-aGVHD is a high priority to improve transplant outcomes. T-Guard, a combination of anti-CD3 and anti-CD7 antibodies conjugated to immunotoxin [8, 9], has induced CR rates of 43% in patients with severe SR-aGVHD across a series of phase 1/2 trials and expanded access protocols, including a previous phase 3 Blood and Marrow Transplant Clinical Trials Network trial (BMT CTN 1802)[10, 11]. However, BMT CTN 1802 had unexpected early deaths, potentially related to participant factors [12]. Therefore, with support from the FDA and the EMA, the BMT CTN and Xenikos, the manufacturer of T-Guard, initiated BMT CTN 2002, a phase 3 multicenter trial that randomized patients with severe (grade III/IV) SR-aGVHD to either T-Guard or ruxolitinib (N CT04934670). BMT CTN 2002 applied more rigorous exclusion criteria than BMT CTN 1802 based on potential risk factors for early mortality previously identified, such as body mass index (BMI)≥ 35, prior exposure to checkpoint inhibitors, or the presence of thrombotic microangiopathy (TMA). Other key exclusion criteria common to both studies included renal insufficiency, treatment with other systemic medications (besides steroids), and those with either uncontrolled infection, severe organ toxicity, sinusoidal obstructive syndrome, or evidence of disease relapse/minimal residual disease positivity. Notably, BMT CTN 2002 targeted patients with more severe SR-aGVHD (grade III/IV) than BMT CTN