Separation of Gvl Effects from GvHD with Ptcy-Based Gvhd Prophylaxis in Mmud Transplantation: A Study from the ALWP of the EBMT

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-HCT^1,2. However, recent studies in patients receiving grafts from HLA-haploidentical donors with post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis failed to observe such an association^3,4, 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<0.001 and P<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<0.001) leading to worse LFS (HR=2.24, P<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<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:

1. 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).

2. 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).

3. 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).

4. 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).

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