Three Regimens Show Comparable Efficacy in Preventing GVHD in Haplo-PBSCT

No statistically significant differences in the incidence of grade 2 to 4 acute graft-vs-host disease (aGVHD) or GVHD-/relapse-free survival (GRFS) were seen between standard-dose antithymocyte globulin (ATG), posttransplant cyclophosphamide (PTCy), and a low-dose ATG/PTCy combination as GVHD prophylaxis in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT), according to results published in Blood.¹

The randomized, multicenter trial (NCT03608059) from 6 Chinese centers was the first phase 3 trial to directly compare these 3 graft-vs-host disease (GVHD) prophylaxis regimens. At day 100, the cumulative incidence (CI) of grade 2 to 4 aGVHD was 13.0% (95% CI, 8.6%-18.3%) in the ATG/PTCy group, 15.9% (95% CI, 9.9%-23.3%) in the ATG group, and 19.3% (95% CI, 12.5%-27.2%) in the PTCy group, a nonsignificant difference (P =.210). One-year GRFS likewise did not differ significantly among groups (72.4% vs 69.0% vs 70.6%, respectively; P =.611). However, the combination regimen was associated with significantly faster neutrophil and platelet recovery.

“The main message is that both single-agent strategies are effective in haplo-[PBSCT] for myeloid malignancies, and centers with established expertise in either platform have no strong rationale to switch,” David J. Curtis, of Monash University, concluded in a commentary published in Blood alongside the clinical trial outcomes.²

Background: An Unresolved Clinical Question

GVHD remains the principal barrier to successful haploidentical hematopoietic stem cell transplantation. In China, the Beijing protocol of standard-dose rabbit-derived ATG is widely used for its high engraftment rate and relatively low incidence of grade 2 to 4 aGVHD, but is associated with higher rates of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation. PTCy, known as the Baltimore protocol, produces lower rates of acute and chronic GVHD (cGVHD) but is linked to higher graft failure rates in bone marrow transplants, with aGVHD incidence increasing when peripheral blood stem cells are used instead.

Combination strategies pairing ATG and PTCy have been developed to offset the limitations of either single agent, but prior studies evaluating these combinations have been predominantly retrospective with heterogeneous patient cohorts and have reported conflicting results regarding whether combination therapy offers a meaningful advantage. This trial was designed as a prospective, randomized head-to-head comparison to address that uncertainty.

Trial Design and Patient Population

The trial was conducted at 6 centers in China between October 2018 and August 2023. Four hundred and seven patients with acute myeloid leukemia or high-risk myelodysplastic syndromes were randomly assigned in a 2:1:1 ratio to receive low-dose ATG/PTCy (n = 185), standard-dose ATG (n = 113), or PTCy (n = 109) for GVHD prophylaxis.

Eligible patients were aged 14 to 70 years. The ATG/PTCy group received ATG at 2.5 mg/kg per day on days −2 and −1 before transplant, cyclophosphamide 50 mg/kg on day +3, and calcineurin inhibitor plus mycophenolate mofetil (MMF). The ATG group received ATG 2.5 mg/kg per day on days −4 to −1 plus calcineurin inhibitor, MMF, and methotrexate. The PTCy group received cyclophosphamide 50 mg/kg per day on days +3 and +4 plus calcineurin inhibitor and MMF. The coprimary end points were the CI of grade 2 to 4 aGVHD by day 100 and 1-year GRFS.

Baseline characteristics, including recipient and donor age, diagnosis, and conditioning intensity, were well balanced across the 3 groups. The median age was 44.16 years, with 81.6% having acute myeloid leukemia; 64.1% received myeloablative conditioning and 35.9% received reduced-intensity conditioning.

Secondary Findings: Chronic GVHD, Survival, and Hematologic Recovery

Although overall cGVHD incidence was comparable across groups (P =.110), the 2-year CI of moderate-to-severe cGVHD was numerically lower with ATG/PTCy (17.4%) and ATG (17.3%) than with PTCy (28.3%), a difference that approached but did not reach statistical significance (P =.095). No significant differences were observed in 2-year overall survival (75.4% vs 74.9% vs 77.8%, respectively; P =.756), disease-free survival, relapse, or nonrelapse mortality among the 3 groups. Age 55 years or older was identified as an independent predictor of inferior overall survival (HR, 1.66), poorer disease-free survival (HR, 1.64), and increased nonrelapse mortality (HR, 2.51).

Hematologic recovery favored the combination regimen. At day 30, neutrophil recovery was significantly higher with ATG/PTCy (97.8%) than with ATG (95.6%) or PTCy (95.4%; P <.001). At day 90, platelet recovery followed a similar pattern, highest with ATG/PTCy (98.1%) compared with ATG (95.6%) and PTCy (97.1%; P <.001).

Viral Reactivation and Immune Reconstitution

One-year CMV reactivation incidence was similar across groups (41.5% vs 37.5% vs 36.9%; P =.676). EBV reactivation, however, differed markedly, occurring in just 9.7% of the PTCy group compared with 41.1% of the ATG/PTCy group and 54.5% of the ATG group (P <.001). Immune reconstitution analyses showed that PTCy was associated with more robust regulatory T-cell and CD4+ T-cell recovery within the first year compared with the ATG-containing regimens, while ATG and ATG/PTCy groups demonstrated higher natural killer cell counts in the early posttransplant period.

Study Limitations and Clinical Implications

The study authors noted several limitations, including a relatively small sample size that may have limited power to detect differences in the primary end points, a study population with a median age of 44 years that was younger than many contemporary haploidentical transplant cohorts, absence of quality-of-life assessments, and an exclusively Asian patient population, all of which may limit generalizability. The trial also did not test all possible ATG/PTCy dosing combinations, such as low-dose ATG combined with full-dose PTCy.

The authors concluded that although the ATG/PTCy combination did not demonstrate statistically significant advantages over either single-agent regimen in preventing aGVHD or improving survival, the comparable efficacy observed across all 3 strategies supports flexibility in tailoring GVHD prophylaxis to institutional experience and individual patient characteristics, while highlighting the faster hematologic recovery associated with the combination approach as a potential consideration in regimen selection.

In his commentary, Curtis stated that the trial “does not provide a compelling case” for the ATG/PTCy combination on its own, noting that retrospective studies of other doses of the combination have shown promising evidence of benefit,³ but a randomized trial such as this one would have to be done to compare other proposed doses of ATG/PTCy with the current standards.

REFERENCES

1. Yang J, Jia Y, Hu X, et al. A randomized trial of GVHD prophylaxis in haploidentical PBSC transplantation: ATG, PTCy, and low-dose combination therapy. Blood. 2026;147(26):3168-3178. doi: 10.1182/blood.2025032569

2. Curtis DJ. Beijing, Baltimore, or both: a randomized draw. Blood. 2026;147(26):3125-3126. doi: 10.1182/blood.2026033922

3. Law AD, Salas MQ, Lam W, et al. Reduced-intensity conditioning and dual T lymphocyte suppression with antithymocyte globulin and post-transplant cyclophosphamide as graft-versus-host disease prophylaxis in haploidentical hematopoietic stem cell transplants for hematological malignancies. Biol Blood Marrow Transpl. 2018;24(11):2259-2264. doi:10.1016/j.bbmt.2018.07.008