Optimizing GVHD Prophylaxis after Reduced-Intensity Matched Donor Transplantation in AML and MDS: Insights from PTCy and ATG Strategies

Highlight

• Post-transplant cyclophosphamide (PTCy) significantly reduces severe acute GVHD (grade III-IV) compared to anti-thymocyte globulin (ATG) in reduced-intensity conditioned matched donor allo-HCT for AML/MDS.
• Both PTCy and ATG lower the incidence of extensive chronic GVHD compared to no in vivo T-cell depletion without increasing non-relapse mortality or relapse risk.
• One-year overall survival (OS), progression-free survival (PFS), and GVHD relapse-free survival (GRFS) rates were similar across GVHD prophylaxis strategies, indicating comparable long-term outcomes.
• This large registry dataset provides meaningful benchmarks and supports PTCy as a viable alternative to ATG in this transplant setting as ongoing trials mature.

Study Background

Allogeneic hematopoietic cell transplantation (allo-HCT) remains a potentially curative option for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, graft-versus-host disease (GVHD) represents a major post-transplant complication that adversely affects quality of life and survival. Reduced-intensity conditioning (RIC) regimens have made allo-HCT feasible for older or comorbid patients but maintaining a balance between graft-versus-leukemia effect and GVHD is critical.

In vivo T-cell depletion using agents such as anti-thymocyte globulin (ATG) has been widely employed to reduce GVHD risk, particularly in matched related (MRD) and matched unrelated donor (MUD) settings with peripheral blood stem cells (PBSCs). Recently, post-transplant cyclophosphamide (PTCy) has emerged as a transformative strategy largely in haploidentical transplantation to prevent GVHD. However, its role in matched donor, reduced-intensity conditioning allo-HCT remains less clearly defined.

This study sought to clarify the comparative effectiveness and safety of PTCy, ATG, their combination, or no in vivo T-cell depletion in RIC matched-donor PBSC transplantation for AML and MDS using a large international registry cohort.

Study Design

This retrospective registry analysis included 3624 adults with AML or MDS who underwent first allo-HCT after RIC from either a 10/10 HLA matched related donor (MRD) or matched unrelated donor (MUD) using peripheral blood stem cell grafts. Patients were reported to the French-Belgian-Swiss EBMT/SFGM-TC registry between 2014 and 2022.

The study population was stratified into four GVHD prophylaxis groups: no in vivo T-cell depletion (NONE, n=213), PTCy ± standard immunosuppressive agents (PTCy, n=97), ATG ± immunosuppression (ATG, n=3286), and the combination of PTCy + ATG ± immunosuppression (PTCy+ATG, n=28).

The primary endpoints included acute GVHD grade III-IV incidence, chronic GVHD (extensive), non-relapse mortality (NRM), relapse risk, and one-year overall survival (OS), progression-free survival (PFS), and GVHD relapse-free survival (GRFS). Multivariable competing-risk regression models were used to adjust for relevant covariates.

Key Findings

Compared to ATG, PTCy was associated with a statistically significant reduction in the hazard of grade III-IV acute GVHD (HR 0.44, p=0.026), indicating a strong protective effect against severe acute GVHD. Importantly, both PTCy and ATG groups demonstrated significantly lower incidences of extensive chronic GVHD compared to the no T-cell depletion group (NONE), underscoring their value in chronic GVHD prevention.

No significant differences were observed among the groups regarding non-relapse mortality or relapse rates, suggesting that the use of PTCy or ATG does not compromise post-transplant survival related to disease recurrence or treatment-related mortality.

With a median follow-up of 16.6 months, one-year outcomes were comparable across prophylaxis groups: overall survival was approximately 70%, progression-free survival was about 62%, and GVHD relapse-free survival hovered near 48%. These comparable long-term outcomes reinforce the clinical effectiveness and safety of PTCy as an alternative prophylaxis approach following RIC matched donor PBSC transplantation.

The combination of PTCy and ATG, though a smaller subset, did not demonstrate clear additional benefit and requires further study.

Expert Commentary

This large, homogeneous cohort provides compelling evidence supporting the incorporation of PTCy in matched donor RIC transplantation for AML/MDS. The reduction in severe acute GVHD is clinically relevant, as acute GVHD remains a significant cause of morbidity and mortality post-allo-HCT.

PTCy’s mechanism—selective elimination of proliferating alloreactive T cells post-transplant—differs biologically from ATG’s broad T-cell depletion, potentially explaining the differential effects observed. The similar relapse and survival outcomes between PTCy and ATG groups suggest no compromise in graft-versus-leukemia effect.

Randomized controlled trials are ongoing to confirm these registry findings and optimize dosing and combinations. Nevertheless, these data offer valuable benchmarks for clinicians considering GVHD prophylaxis options for RIC matched donor PBSC transplantation in AML and MDS.

Limitations of the study include its retrospective nature, potential confounding by center-specific practices, and relatively short median follow-up for chronic GVHD and long-term survival outcomes. The small sample size for PTCy and combination groups also merits cautious interpretation.

Conclusion

This comprehensive registry analysis supports the efficacy and safety of post-transplant cyclophosphamide as an effective alternative to anti-thymocyte globulin for GVHD prophylaxis following reduced-intensity conditioning matched related and unrelated donor peripheral blood stem cell transplantation in AML and MDS patients. Both strategies reduce chronic GVHD incidence without adversely impacting relapse or mortality. These findings provide a robust clinical benchmark that will inform practice as ongoing randomized studies mature.

Clinicians can consider PTCy confidently in this setting to optimize GVHD prevention, potentially enhancing patient outcomes and quality of life after transplant.

Reference

Coman T, Morisset S, Devillier R, D’Aveni M, Baron F, Bay JO, El-Cheikh J, Bilger K, Bulabois CE, Castilla-Llorente C, Ceballos P, Chalandon Y, Chantepie S, Joris M, Chevallier P, Alani M, Cornillon J, Daguindeau E, Forcade E, Mokeddem C, Guillerm G, Labussiere H, Lewalle P, Loschi M, Maertens J, Malard F, Malfuson JV, Maillard N, Mear JB, Nguyen-Quoc S, Pivert C, Poire X, Rubio MT, Suarez F, Turlure P, Villate A, Yakoub-Agha I, Raus N, Robin M, Huynh A, Michallet M. GVHD prophylaxis with PTCy, ATG, PTCy+ATG, or no in vivo T-cell depletion in RIC matched-donor PBSC transplantation for AML and MDS. Bone Marrow Transplant. 2026 Sep 12. doi: 10.1038/s41409-026-03033-6. Epub ahead of print. PMID: 42732012.