GRAPPA Trial: ATLG Superior to Post-Transplant Cyclophosphamide for GvHD Prophylaxis in Unrelated Donor Stem Cell Transplants
核心洞察
The Phase III GRAPPA study shows ATLG-based GvHD prophylaxis yields 75% two-year overall survival versus 68% with PTCy (HR=1.34, p=0.051) in unrelated donor transplants.
Non-relapse mortality at two years was significantly lower with ATLG (7%) compared to PTCy (13%), driven primarily by fewer infections in the ATLG arm (HR=1.86, p=0.02).
Although PTCy reduced mild-to-moderate acute and chronic GvHD, this did not translate into a survival benefit for patients with blood cancers.
ATLG-based graft-versus-host disease (GvHD) (搜索) prophylaxis significantly reduces treatment-related mortality compared to post-transplant cyclophosphamide (PTCy) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) from unrelated donors, according to initial results from the Phase III GRAPPA study presented as a late-breaking abstract at the European Hematology Association (EHA) Congress in Stockholm.
The multicenter, randomized trial enrolled 640 patients with acute myeloid leukemia (AML) (搜索), myelodysplastic syndrome (MDS) (搜索), or myeloproliferative neoplasms (MPN) (搜索) who required allogeneic HSCT and had an available unrelated donor with no more than one mismatch at a single HLA locus. Patients were randomized in a 3:2 ratio to receive either PTCy (50 mg/kg on days +3 and +4) or ATLG (10 mg/kg on days -3, -2, and -1), with all patients additionally receiving immunosuppressive therapy with tacrolimus twice daily and mycophenolate mofetil three times daily.
Survival Outcomes Favor ATLG
The study was originally designed to demonstrate non-inferiority of PTCy to ATLG in terms of overall survival. Instead, the results pointed in the opposite direction. Two-year overall survival reached 75% in the ATLG arm compared to 68% in the PTCy arm (hazard ratio [HR]=1.34, p=0.051), representing a near-significant advantage favoring ATLG.
More strikingly, non-relapse mortality (NRM) at two years post-transplant was 7% among patients receiving ATLG versus 13% in the PTCy group (HR=1.86, p=0.02). “We observed very low treatment-related mortality in patients receiving ATLG for GvHD prophylaxis, 7% within the first 2 years. Such a good result has never before been reported from a large study involving unrelated stem cell donors. This is a new milestone,” said Prof. Dr. Johannes Schetelig, Head of the Stem Cell Transplantation Unit at University Hospital Carl Gustav Carus Dresden and Director Clinical Research at DKMS (搜索), who led the study.
The increased NRM in the PTCy arm was attributed primarily to more frequent infections. “Simply being aware of this risk can help us take more precautions and respond more quickly,” Schetelig noted.
GvHD Incidence: A Nuanced Picture
While PTCy was associated with fewer cases of acute GvHD Grades II to IV and fewer cases of chronic GvHD overall — appearing to reduce the risk of mild or moderate GvHD in particular — severe cases of acute (Grade III and IV) and chronic GvHD were comparable between both study arms. Critically, the reduction in milder GvHD with PTCy did not translate into a survival benefit.
“Despite many years of experience and numerous publications on the potential of both therapies, a direct comparison was lacking,” emphasized Schetelig, underscoring the importance of the GRAPPA data in filling a long-standing evidence gap.
Clinical Implications and Future Directions
“GvHD prophylaxis with ATLG in combination with tacrolimus and mycophenolate mofetil remains the standard of care for stem cell transplants from HLA-matched unrelated donors in countries where ATLG is available, as this regimen is highly beneficial for patients,” Schetelig summarized.
However, the findings also point to a potential role for PTCy that warrants further investigation. “The potential of PTCy to prevent chronic forms of GvHD in particular should be further explored,” Schetelig said. For centers using PTCy, an optimized dosing strategy for immunosuppression and enhanced monitoring of patients will be crucial to mitigate infection risk and associated mortality.
“These findings can be followed up with many subsequent studies, the results of which may provide even stronger guidance and concrete recommendations for action regarding the use of this prophylactic strategy in the future,” Schetelig added.
The GRAPPA study was conducted by the DKMS (搜索) Clinical Trials Unit, the research arm of the international nonprofit organization that has registered more than 13 million potential donors and facilitated over 135,000 blood stem cell donations worldwide. The results were presented by Prof. Schetelig on Saturday, June 13, at the EHA 2026 Congress in Stockholm.