Ptcy Versus High Dose of ATG in HLA-Mismatched Unrelated Stem Cell Transplantation for Hematological Malignancies
Authors: Bordat Jonathan , Kaphan Eléonore , Robin Marie , Sicre de Fontbrune Flore , Chevillon Florian , Socie Gerard , Xhaard Alienor , Peffault de Latour Regis , Michonneau David 
Published: December 2024

Introduction:

Allogeneic hematopoietic stem cell transplantation (alloSCT) is an essential treatment for many malignant hematological diseases. Mismatched unrelated donor (MMUD) transplantation is an alternative when a matched donor is not available. However, it is associated with poorer outcomes due to increased non-relapse mortality (NRM) and graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide (PTCY) has emerged as a promising GVHD prophylaxis. Retrospective studies suggest PTCY may offer better outcomes than rabbit anti-thymocyte globulin (ATG), potentially due to lower NRM and GVHD rates. However, results are inconsistent across studies, often involving heterogeneous ATG doses. This retrospective single-center study compares the outcomes after GVHD prophylaxis with PTCY to our previous practice using high or low doses of ATG in MMUD alloSCT for hematological malignancies.

Method and results:

We retrospectively analyzed patients over 16 years who received MMUD (9/10 HLA) alloSCT for malignant hematological diseases between January 2010 and February 2024 at our center. Patients received high-dose ATG (HD group: ATG-T 10 mg/kg or ATG-F 60 mg/kg), low-dose ATG (LD group: ATG-T 5 mg/kg or ATG-F 30 mg/kg), or PTCY (PTCY 50mg/kg at day +3 and +4) as GVHD prophylaxis, along with cyclosporin and methotrexate or mycophenolate mofetil.

A total of 155 patients were included (41 in the PTCY group, 93 in the HD group, and 21 in the LD group), with median follow-ups of 15.2, 16.23, and 22.5 months, respectively. There were no differences in age (47.5, 43.5, and 50.1 years, p=0.08) or sex ratio (male: 53.7%, 66.7%, and 57.1%, p=0.37). Most patients were transplanted for acute leukemia (53.6%, 59.2%, and 66.6%, p=0.48). The proportion of patients with a high/very high Disease Risk Index (36.6%, 31.2%, and 42.8%, p=0.32) and receiving a myeloablative conditioning regimen (46.4%, 43%, and 42.9%, p=0.93) was similar among the PTCY, HD, and LD groups.

At one year, the PTCY group showed better progression-free survival (PFS: 74.8% vs 50% and 54%, p=0.02) and lower NRM (8.7% vs 34.6% and 35.7%, p=0.02) than HD and LD groups, respectively. The overall survival was improved in the PTCY group (OS: 78.4% vs 56.5% and 64.8%, p=0.05), with a benefit confirmed in multivariate analysis (HR HD group: 2.47, p&lt;0.01 and LD group: 2.41, p=0.03). There were no significant differences in the cumulative incidences of relapse (14.7% vs 25% and 6.7%, p=0.7) or GVHD-Free, Relapse-Free Survival (48.9% vs 33.0% and 28.5%, p=0.17) despite a trend toward better outcomes in the PTCY group. The day-100 incidences of grade II-IV (61.4%, 62.1%, and 52.9%, p=0.9) and grade III-IV acute GVHD (23.0% vs 38.8% and 26.0%, p=0.5) did not differ significantly. One-year chronic GVHD (59.7% vs 60.0% and 69.3%, p=0.4) and extensive chronic GVHD incidences (22.4% vs 31.6% and 48.6%, p=0.5) were not significantly different between the 3 groups. Subgroup analysis based on conditioning intensity showed that the HD group experienced poor outcomes due to higher NRM in reduced intensity regimens.

The PTCY group presented lower CMV (9.8% vs 37.7% and 33.3%; p&lt;0.01) and EBV (7.3% vs 48.4% and 33.3%, p&lt;0.01) infection rates, with no other differences in infectious complications at 2 years. Relapse was the leading cause of mortality across all groups (63.6%, 38.5%, and 30.8%) and GVHD-related deaths (28.8% and 23.1% vs 0%) were higher in the HD and LD groups compared to the PTCY group, respectively.

On peripheral blood lymphocyte immunophenotyping at day 100, patients in the PTCY group had a lower CD8/CD4 ratio than the HD and the LD groups (1.3 vs 5.1 and 4.4, p&lt;0.01) due to lower CD8+ T cell counts and better recovery of CD4+ T cells, with better preservation of memory CD4+ and CD8+ T cells.

Conclusion:

In our cohort, compared with high dose or low dose of ATG, the use of PTCY was associated with improved OS and PFS, primarily due to lower NRM. No differences in the incidence of GVHD or relapse were observed. However, the PTCY group exhibited lower infection rates and GVHD-related mortality, even if we cannot exclude the impact of more recently introduced anti-infectious prophylaxis such as letermovir. These results suggest that PTCY provides added value as GVHD prophylaxis in MMUD alloSCT.