Editor's Note: At the 2026 European Hematology Association (EHA) Annual Meeting, Professor Johannes Schetelig from the Technical University Dresden and the German Bone Marrow Donor Center (DKMS) presented a highly anticipated Late-breaking Abstract. This study is a large-scale randomized controlled trial (RCT) designed to compare Anti-T Lymphocyte Globulin (ATLG) and Post-Transplant Cyclophosphamide (PTCy) "head-to-head" for the prophylaxis of Graft-versus-Host Disease (GVHD) in HLA-matched or partially matched unrelated donor hematopoietic cell transplantation (HCT). 01 Research Background: Searching for the “Gold Standard” of GVHD Prophylaxis
Graft-versus-Host Disease (GVHD) is a major complication following allogeneic hematopoietic cell transplantation. Currently, both ATLG and PTCy have been proven effective in preventing GVHD in HLA-matched related or unrelated donor transplants across various studies. However, direct randomized controlled trials comparing these two strategies have long been lacking. Previous retrospective comparisons were limited by the heterogeneity of Anti-Thymocyte Globulin (ATG) brands, dosages, administration timing, and post-transplant immunosuppression regimens. Based on this, Professor Schetelig’s team initiated this large RCT, funded by DKMS without industrial background, to determine whether PTCy provides a survival benefit compared to ATLG.
02 Trial Design: Rigorous Randomization and Non-inferiority Testing
The study included patients with myeloid malignancies scheduled for peripheral blood stem cell transplantation from HLA-matched (10/10) or partially matched (9/10) unrelated donors. • Control Group (ATLG Group): Used a moderate dose of ATLG (30 mg/kg, administered over 3 days: D-3 to D-1). • Experimental Group (PTCy Group): Followed the BMT CTN 1703 study protocol, with cyclophosphamide administered on days 3 and 4 post-transplant. • Basal Immunosuppression Regimen: Both groups received a combination of Tacrolimus and Mycophenolate Mofetil (MMF) to ensure the rigor of the trial design. • Study Endpoints: The primary endpoint was a non-inferiority comparison of Overall Survival (OS) (non-inferiority margin of 5%). Patients were randomized in a 3:2 ratio (PTCy group: ATLG group). During nearly three years of follow-up, 776 patients were screened, and 640 patients were ultimately enrolled and randomized. The median age of patients was 63 years. Most patients were rated as high or very high risk according to the Disease Risk Index (DRI), with the most common disease being primary or secondary Acute Myeloid Leukemia (AML).
03 Clinical Outcomes: PTCy Failed to Meet the OS Non-inferiority Endpoint
The study results showed that the PTCy regimen failed to reach the predefined non-inferiority for the primary survival indicator: • Overall Survival (OS): The 2-year OS rate was 75% for the ATLG group and only 68% for the PTCy group. • Non-inferiority Analysis: The PTCy group failed to demonstrate non-inferiority in OS compared to the ATLG group. In further exploratory superiority testing, the ATLG group showed a superior survival trend (P=0.051). • Non-Relapse Mortality (NRM): This was the key factor leading to the OS difference between the two groups. The 2-year NRM in the ATLG group was extremely low at 7%, while the PTCy group was 13%, a difference that was statistically significant.
04 GVHD Control and Relapse Risk: The Balancing Act of Defense and Offense
Regarding GVHD control, PTCy demonstrated strong efficacy, but this did not translate into an advantage in composite survival indicators: • Acute GVHD (aGVHD): There was no significant difference between the two groups in the incidence of Grade 3-4 aGVHD. However, for Grade 2 aGVHD, the incidence in the ATLG group was higher than in the PTCy group. • Chronic GVHD (cGVHD): The ATLG group had a significantly higher incidence of both all-grade and severe cGVHD compared to the PTCy group. • Relapse Risk: The relapse rates for both groups were essentially equal, with a 2-year relapse rate of approximately 20%. • Composite Endpoint (GRFS): The 2-year GVHD-free/Relapse-free Survival (GRFS) was 48% in the PTCy group and 40% in the ATLG group, with no statistically significant difference between the two.
05 Safety and Complications: Challenges of Infection and Delayed Engraftment
Through a competing risk analysis of causes of death, the study found that the higher mortality in the PTCy group was primarily due to infections. • Infection-related Mortality: Within 2 years post-transplant, the infection mortality rate in the PTCy group was 7.7%, significantly higher than the 3.1% in the ATLG group. This risk difference persisted even beyond 6 months post-transplant. • Hematopoietic Reconstruction: Although G-CSF was used more frequently in the PTCy group to stimulate engraftment, neutrophil engraftment was still delayed by 4 days compared to the ATLG group. • Mucositis and Hospitalization: The PTCy group had a higher incidence of Grade 3-5 oral mucositis. Furthermore, the median hospital stay from transplant to discharge was 26 days in the PTCy group, 4 days longer than the ATLG group (22 days). • Immune Reconstitution Characteristics: Supplementary examinations showed that patients in the PTCy group exhibited higher CD4+ counts, while those in the ATLG group showed higher CD8+ counts, consistent with previous retrospective findings.
Expert Conclusion and Clinical Outlook
Professor Johannes Schetelig concluded: As the largest randomized controlled clinical trial to date exploring the head-to-head comparison of ATG and PTCy, this study provides high-level evidence-based medical data. The data clearly indicate that for HLA-matched unrelated donor transplants, a GVHD prophylaxis regimen based on ATLG 30mg combined with Tacrolimus and MMF remains the current Standard of Care, due to its extremely low non-relapse mortality (2-year NRM 7%) and superior overall survival (2-year OS 75%).
Although PTCy is highly effective in preventing acute and chronic GVHD, the resulting serious infection risks, longer aplasia periods, and higher incidence of mucositis limit the ultimate survival benefit for patients. Future research should explore how to improve immune reconstitution after PTCy or consider reducing the dose of cyclophosphamide (e.g., to below 50 mg/kg) to mitigate toxicity. However, until new evidence emerges, the standard status of ATG remains solid.
