Separation of Gvl Effects from GvHD with Ptcy-Based Gvhd Prophylaxis in Mmud Transplantation: A Study from the ALWP of the EBMT
Authors: Baron Frederic , Ferhat Berland Allain Thibeault , Labopin Myriam , Eder Matthias , Rambaldi Alessandro , Castilla-Llorente Cristina , Wolfgang Blau Igor , Bonifazi Francesca , Schroeder Thomas , Kröger Nicolaus , Blaise Didier , Dreger Peter , Gedde-Dahl Tobias , Sanz Jaime , Mohty Mohamad , Ciceri Fabio 
Published: December 2024

Background: The efficacy of allogeneic hematopoietic stem cell transplantation (allo-HCT) in patients with acute myeloid leukemia (AML) depends on immune-mediated graft-versus-leukemia (GvL) effects. GvL effects have been closely linked to graft-versus-host disease (GVHD), and many studies have observed a significant association between GVHD occurrence and lower incidence of AML relapse after allo-HCT1,2. However, recent studies in patients receiving grafts from HLA-haploidentical donors with post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis failed to observe such an association3,4, suggesting that PTCy might separate GvL effects from GVHD. In order to determine whether the separation of GvL effects from GVHD observed in PTCy-based HLA-haploidentical transplantation is indeed due to PTCy, we compared the impact of GVHD occurrence on AML relapse in a large cohort of AML patients receiving peripheral blood stem cells (PBSC) from 9/10 HLA-mismatched unrelated donor (UD 9/10) and either antithymocyte-globulin (ATG)-based or PTCy-based GVHD prophylaxis. Methods: Inclusion criteria consisted of adult AML patients, PBSC from UD 9/10, PTCy-based or ATG-based GVHD prophylaxis (no combination or alemtuzumab), first allo-HSCT between 2015 and 2022, and no ex vivo T-cell depletion. The impact of GVHD on transplantation outcomes was assessed using multivariate Cox models in which grade II-IV acute and chronic GVHD were handled as time-dependent variables. Results: Data from a total of 1989 patients given ATG-based (n=1560) or PTCy-based (n=429) GVHD prophylaxis were included. Two-year relapse incidence was 29.5% (95% CI: 27.1-31.9%) in ATG patients versus 26.8% (95% CI: 22.2-31.6%) in PTCy patients (P=0.25 in multivariate analysis (MVA)). Two-year non-relapse mortality (NRM) and leukemia-free survival (LFS) were 23.2% (95%CI: 21-25.4%) and 47.3% (95% CI: 44.7-49.9%) in ATG patients versus 11.8% (95%CI: 8.7-15.3%) and 61.4% (95% CI: 56.1-66.4%) in PTCy patients (P&lt;0.001 and P&lt;0.001 respectively, in MVA). The incidences of grade II-IV acute at day 180 (30% versus 29%) and of chronic GVHD at 2 years (30% versus 30%) were comparable in ATG and PTCy patients. Among the former, occurrence of grade II-IV acute GVHD was associated with a lower risk of AML relapse (HR=0.79, P=0.028), higher NRM (HR=1.41, P=0.002) and comparable LFS (HR=1.05, P=0.5) confirming an association between GVHD and GvL effects in that setting. In contrast, chronic GVHD was not associated with a lower relapse incidence (HR=1.43, P=0.06) but was strongly associated with NRM (HR=3.16, P&lt;0.001) leading to worse LFS (HR=2.24, P&lt;0.001). Among PTCy patients, neither grade II-IV acute GVHD (HR=0.9, P=0.68) nor chronic GVHD (HR=0.58, P=0.37) were associated with relapse incidence. Chronic GVHD, however, correlated with higher NRM (HR=5.0, P&lt;0.001) but comparable LFS (HR=1.53, P=0.22). Conclusions: This study is in line with the hypothesis of a separation of GvL effects from GVHD by the use of PTCy-based GVHD prophylaxis. In contrast, among ATG patients, grade II-IV acute GVHD occurrence was associated with a lower risk of relapse. Finally, this large study demonstrated, with the limitation of a retrospective analysis, better outcomes with PTCy-based than with ATG-based GVHD prophylaxis in patients given PBSC from UD 9/10.
References: Baron, F. et al. Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation. Leukemia26, 2462-2468 (2012). Gyurkocza, B. et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol.28, 2859-2867 (2010). Shimoni, A. et al. The association of graft-versus-leukemia effect and graft-versus host disease in haploidentical transplantation with post-transplant cyclophosphamide for AML. Bone Marrow Transplant.57, 384-390 (2022). Baron, F. et al. GVHD occurrence does not reduce AML relapse following PTCy-based haploidentical transplantation: a study from the ALWP of the EBMT. J. Hematol. Oncol.16, 10 (2023).