Although post-transplant cyclophosphamide (PTCy) generated expected improvements in graft-vs-host disease (GVHD) outcomes compared with anti–T-lymphocyte globulin (ATLG), data for non-relapse mortality (NRM) and overall survival (OS) outcomes led to a surprising result in the phase 3 GRAPPA trial (NCT05153226), according to Johannes Schetelig, MD, MSc.
GRAPPA was designed to test PTCy for noninferiority compared with ATLG as GVHD prophylaxis in patients with hematologic malignancies. Data shared at the 2026 EHA Congress showed that patients treated with PTCy (n = 383) experienced lower rates of grade 2 to 4 acute GVHD (adjusted HR, 0.70; 95% CI, 0.51-0.96), any-grade chronic GVHD (adjusted HR, 0.59; 95% CI, 0.45-0.77), and severe chronic GVHD (HR, 0.71; 95% CI, 0.41-1.23) compared with patients treated with ATLG (n = 257).1
However, the 2-year NRM rate was 13% (95% CI, 9%-16%) for PTCy (n = 376) compared with 7% (95% CI, 4%-11%) for ATLG (n = 249; HR, 1.86; 95% CI, 1.09-3.17; P = .02). At a median follow-up of 2.3 years, PTCy failed the test for OS noninferiority (adjusted HR, 1.341; 95% CI, 0.999-1.801; P = .85), and superiority was nearly reached for ATLG (P = .051).
In an interview with OncLive®, Schetelig outlined the rationale for evaluating PTCy vs ATLG as GVHD prophylaxis, detailed the surprising outcomes from the trial, and explained how future approaches could improve outcomes with PTCy in this setting.2
Schetelig is head of the Stem Cell Transplantation Unit at University Hospital Carl Gustav Carus Dresden and director of clinical research at Deutsche Knochenmarkspenderdatei (DKMS) in Germany.
OncLive: What was the rationale and design of this noninferiority study of ATLG vs PTCy as GVHD prophylaxis for patients with hematologic malignancies?
Schetelig: There are 2 brands of ATG. One is called anti–T-lymphocyte globulin, and this product is produced by immunizing rabbits with the T-cell line. Then there is a second product called thymoglobulin [anti-thymocyte globulin], which is produced by immunizing rabbits with human thymocytes. I will be talking about ATLG, a product which is marketed by the company Neovii under the [trade] name Grafalon.
- PTCy (n = 383) reduced grade II to IV acute GVHD (adjusted HR, 0.70; 95% CI, 0.51-0.96) and any-grade chronic GVHD (adjusted HR, 0.59; 95% CI, 0.45-0.77) vs ATLG (n = 257).
- The 2-year NRM rate was 13% (95% CI, 9%-16%) with PTCy vs 7% (95% CI, 4%-11%) with ATLG (HR, 1.86; 95% CI, 1.09-3.17; P = .02), and PTCy failed to demonstrate OS noninferiority (adjusted HR, 1.341; 95% CI, 0.999-1.801; P = .85).
- Schetelig noted that future trials will explore reduced PTCy dosing and less post-transplant immunosuppression to improve immune reconstitution.
Together with the German Cooperative Transplant Study Group and the Study Alliance Leukemia, we launched [the] large, randomized, controlled [GRAPPA] trial comparing 2 different possibilities to form GVHD prophylaxis. One was the use of ATLG, and the second was the use of PTCy. With respect to the use of ATLG, we decided to use an intermediate dose, a cumulative dose of 30 mg/kg, administered on days –3, –2, and –1. With respect to PTCy, we stuck to the standard of administering 50 mg/kg on days 3 and 4 after transplantation [for a cumulative dose of 100 mg/kg].
We enrolled patients with myeloid blood cancers who had a matched unrelated donor, for whom a peripheral blood stem cell transplantation was planned. Those patients were randomly assigned in a 3:2 ratio between those 2 options, PTCy and ATLG. The objective of the study was to demonstrate noninferiority of PTCy compared with ATLG.
It is important to note that this study was financed and sponsored by DKMS, so we did not receive money from industry, which [shows] that we were not biased towards ATLG.
What were the key findings reported at EHA 2026?
The results of this randomized, controlled trial were a surprise. We saw what we expected, which was that PTCy was more potent at suppressing acute GVHD, mainly grade II, and chronic GVHD [of] any grade, but also moderate-to-severe and severe chronic GVHD. We saw no difference with respect to the risk of relapse.
However, we saw an increased risk of NRM after the use of PTCy, and this was due to an increased risk of infectious death in patients who did not suffer from GVHD. Altogether, this led to a 2-year OS [rate] of 75% for patients who had received ATLG and 68% for patients who had received PTCy. The NRM rate was outstandingly low after use of ATLG, at 7% at 2 years compared with 13% with the use of PTCy. This was a surprise, and this result is, from our point of view, meaningful because [GVHD] results in the PTCy arm were as expected. What was a surprise was that we saw this very low NRM rate related to less infectious death with the use of ATLG, which even gave a signal of potentially improved OS.
What are the implications of these findings? Do these findings have relevance in regions where ATLG is not approved?
We were not able to state the noninferiority of PTCy. In other words, ATLG administered at a [cumulative] dose of 30 mg/kg on days –3, –2, and –1, together with tacrolimus [Prograf] and mycophenolate mofetil [CellCept], remains standard of care for patients with matched, unrelated donors. [ATLG] is not available all around the globe; in some countries, it is not licensed, [including in the United States]. For those countries, it might be important to take results from our study to try to improve immune reconstitution after PTCy.
Although we used a cumulative dose of 100 mg/kg [for PTCy], other trials are ongoing that [are exploring] the possibility to reduce this dose. The period of neutropenia [may] be shorter, and immune reconstitution [may] be boosted. Another option is to give less post-transplant immunosuppression to patients who receive PTCy. In the future, for us, ATLG [at] 30 mg/kg will be again the control arm in a randomized, controlled trial. We are still discussing what the experimental options will be, and most likely, PTCy will be part of those options in a future trial.
References
- Stelljes M, Kunadt D, Schröder T, et al. GVHD prophylaxis including ATG remains standard of care for HLA-compatible unrelated donor hematopoietic cell transplantation: results from a large randomized controlled trial comparing ATG and PTCy. Presented at: 2026 EHA Congress; June 11-14, 2026; Stockholm, Sweden. Abstract LB5009.
- Dr Schetelig on ATLG vs PTCY as GVHD prophylaxis in hematologic malignancies. OncLive. July 22, 2026. Accessed July 22, 2026. https://www.onclive.com/view/dr-schetelig-on-atlg-vs-ptcy-as-gvhd-prophylaxis-in-hematologic-malignancies
