No Differences in Transplant Outcomes with Post-Transplant Cyclophosphamide in One Antigen Mismatched Unrelated Donor Compared to Matched Unrelated Donor Recipients Receiving Antithymocyte Globulin in Patients with Acute Myeloid Leukemia: A Study from the Acute Leukemia Working Party of the EBMT

Background. Antithymocyte globulin (ATG) for graft-versus-host disease (GVHD) prophylaxis in allogeneic hematopoietic cell transplantation (allo-HCT) from matched (MUD) and 9/10 human leucocyte antigen (HLA)-mismatched unrelated donors (MMUD) has for years, represented a gold standard in Europe. However, the more recent expansion of post-transplant cyclophosphamide (PTCy) has shown promising results with even superior outcomes compared to ATG in the MMUD setting, while no differences have been observed in the MUD setting. Historically, outcomes of allo-HCT from MMUD have been reported as worse compared to MUD, due to the existence of HLA mismatches. Whether the use of PTCy for MMUD may abrogate these differences deserves investigation.

Methods. We aimed to compare outcomes after allo-HCT from MUD with ATG (MUD-ATG) to those from MMUD with PTCy (MMUD-PTCy) in adults with acute myeloid leukemia (AML) in first complete remission transplanted during the period 2010-2022 and receiving peripheral blood stem cells. Patients receiving both ATG and PTCy were excluded. Only a calcineurin inhibitor (CNI) in association with either mycophenolate mofetil (MMF) or methotrexate (MTX) were included as adjuvant immunosuppressors. Propensity score matching was used to reduce or eliminate confounding effects. Each MMUD-PTCy patient was matched with three MUD-ATG patients using the nearest neighbor method. Included in the propensity score model were: Karnofsky performance status, age at allo-HCT, year of transplant, female donor to male recipient, cytogenetic risk, interval from diagnosis to transplant, intensity of the conditioning regimen. Univariable Cox analysis was performed on pair-matched data. Before matching, 5835 patients (MMUD-PTCy, n=188; MUD-ATG, n=5647) were identified. Herein we report the results after pair-matching.

Results. After pair-matching, 538 and 180 patients in MUD-ATG and MMUD-PTCy groups, respectively, were included. Median age at transplant was 54 years (range 18-77 for MUD-ATG and 20-76 for MMUD-PTCy) while median interval from diagnosis to transplant was nearly 5 months in both groups (interquartile range 4.1-6.9 for MUD-ATG and 4.4-6.7 for PTCy-MMUD). Patients in the MMUD-PTCy were transplanted more recently (2020 versus 2019 for MUD-ATG). A Karnofsky score <90 was observed in 17% (n=90 for ATG-MUD and n=30 for PTCy-MMUD) of cases in both groups. Most patients were transplanted for intermediate-risk cytogenetics AML (69% [n=327] for ATG-MUD and 70% [n=109] for MMUD-PTCy) while adverse karyotype occurred in 25% (n=119 for ATG-MUD and n=38 for PTCy-MMUD) of cases in both groups. A female donor to male recipient combination was recorded for 17% (n=89) and 19% (n=34) of cases for MUD-ATG and MMUD-PTCy groups, respectively. Ninety-nine percent of patients in the MMUD-PTCy group received a CNI+MMF as adjuvant immunosuppression (n=178), also used in 41% (n=222) of cases in the MUD-ATG group. A myeloablative conditioning regimen was used in 51% (n=264 for MUD-ATG and n=89 for MMUD-PTCy) of cases in both groups. Neutrophil engraftment at 30 days was significantly higher in the MUD-ATG group (97.5% [95% CI 95.7-98.6] versus 94.1% [95% CI 89.2-96.8] for MMUD-PTCy, HR 0.67 [SE 0.56-0.79], p<0.0001). With a median follow-up of 2 years, no differences were observed for transplant outcomes. Indeed, survival outcomes at 2 years were distributed as follows for MUD-ATG and MMUD-PTCy groups, respectively: overall survival 74.3% (95% CI 69.8-78.2) versus 69.1% (95% CI 60.9-75.9), p=0.389; leukemia-free survival 66.5% (95% CI 61.8-70.7) versus 64.9% (95% CI 56.8-71.9), p=0.511; relapse incidence 23.7% (95% CI 19.8-27.8) versus 28.5% (95% CI 21.6-35.8), p=0.110; non-relapse mortality 9.8% (7.4-12.8) versus 6.6% (95% CI 3.4-11.1), p=0.209; 180-day grade II-IV acute GVHD 24.5% (95% CI 20.9-28.3) versus 26.1% (95% CI 19.7-32.8), p=0.763; grade III-IV acute GVHD 7.9% (95% CI 5.8-10.4) versus 9.8% (95% CI 6-14.8), p=0.424; chronic GVHD of all grades 33.6% (95% CI 29.2-38.1) versus 27.4% (95% CI 20.8-34.5), p=0.556; extensive chronic GVHD 13.1% (95% CI 10.1-16.5) versus 9.1% (95% CI 5.2-14.4), p=0.209.

Conclusions. When using PTCy, transplant outcomes of MMUD transplantation are not different from those from MUD recipients receiving ATG. Use of PTCy may allow to overcome the HLA barrier abrogating the historical differences in transplant outcomes between MMUD and MUD recipients.