Matched sibling donors still provide superior survival outcomes in older patients with AML in second complete remission. a study from the global committee and the acute leukemia working party of the european society for blood and marrow transplantati

Abstract Introduction Acute myeloid leukemia (AML) is a disease of older patients, with a median age at diagnosis of 68 years. Accumulating evidence has reported the feasibility of allogeneic hematopoietic cell transplantation (allo-HCT) in older patients in first complete remission (CR1). However, the role of allo-HCT and the optimal donor for older patients with AML in CR2 remains to be explored. Methods We retrospectively analyzed data from the European Society for Blood and Marrow Transplantation (EBMT) for older patients (age≥68) with AML who underwent first allo-HCT in CR2 between 2010 and 2022. Donors included a matched sibling (MSD), a haploidentical donor (Haplo) with a T-cell replete graft, or a 10/10 matched/9/10 mismatched unrelated donor (MUD/MMUD). All the enrolled patients were divided into three groups by donor type. Results The analysis comprised 531 patients: 84 in the MSD group, 87 in the Haplo group, and 360 in the MUD/MMUD group. For the entire cohort, the median age was 70 years (IQR 69, 72) and was comparable among the three groups (P=0.66). The median donor age was older in the MSD group (65) than the Haplo (42) and MUD/MMUD (29) groups (P<0.001). Male recipients in the MSD (29.8%) and Haplo (26.4%) groups received grafts from female donors more frequently than those in the MUD/MMUD group (12.5%) (P<0.001). Peripheral blood was used more frequently as the graft source in the MUD/MMUD (97.8%) and MSD (90.5%) groups than in the Haplo group (74.7%) (P<0.001). The MUD/MMUD group had a higher proportion of D-/P- Cytomegalovirus (CMV) serostatus (28.9%) compared to the MSD (14.6%) and Haplo (14.3%) groups (P=0.001). Baseline characteristics such as patient sex, Karnofsky performance status (KPS), and risk classification were similar among the three groups. Reduced-intensity conditioning (RIC) was used for 84.9% of the entire cohort. In the Haplo group, 80.2% of patients received post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis. HCT-related cause and original disease were the major causes of death for the three cohorts. In univariate analysis, Haplo-HCT was associated with a lower 1-year overall survival (OS) (MSD 65.7%, Haplo 53.7%, MUD/MMUD 64%), leukemia-free survival (LFS) (MSD 61.6%, Haplo 46.9%, MUD/MMUD 57.3%), GVHD-free, relapse-free survival (GRFS) (MSD 46.8%, Haplo 36.3%, MUD/MMUD 46.2%), higher non-relapse mortality (NRM) (MSD 18.7%, Haplo 33.6%, MUD/MMUD 21.4%), and similar Relapse incidence (RI) (MSD 19.7%, Haplo 19.5%, MUD/MMUD 21.3%). The 180-day cumulative incidence of grade II-IV acute GVHD was higher in Haplo (27.1%) than in MSD (21.1%) or MUD/MMUD (22.6%) recipients. The incidence of grade III-IV acute GVHD was also higher in Haplo (15.5%) than in MSD (6.2%) or MUD/MMUD (7.7%) recipients. Interestingly, the 1-year cumulative incidence of overall chronic GVHD was higher in the MSD group (43.4%) than in the Haplo (21.5%) or MUD/MMUD (24.1%) recipients. In multivariate analysis, the Haplo (HR=2.28, P=0.01) and MUD/MMUD (HR=2.21, P=0.027) groups were associated with worse OS compared to the MSD group. The Haplo (HR=2.02, P=0.02) and MUD/MMUD (HR=2.11, P=0.028) groups were also associated with worse LFS, while no significant difference in GRFS was observed between the three cohorts. NRM was higher for Haplo (HR=4.8, P=0.001) and MUD/MMUD (HR=4.82, P=0.002) recipients compared to MSD recipients. Importantly, there was no significant difference among different donor types with respect to RI. Concerning GVHD, the Haplo (HR=3.01, P=0.022) and MUD/MMUD (HR=3.14, P=0.028) groups were associated with a higher risk of grade II-IV acute GVHD compared to the MSD group. The Haplo (HR=16.35, P=0.014) and MUD/MMUD (HR=12.21, P=0.038) groups were also associated with a higher risk of grade III-IV acute GVHD compared to the MSD group. There was no significant difference among the three groups in the incidence of overall and extensive chronic GVHD. Older patient age was associated with worse LFS (HR=1.92, P=0.047). Older donor age was associated with worse OS (HR=1.23, P=0.015), worse LFS (HR=1.21, P=0.02), higher NRM (HR=1.42, P=0.003), and a higher risk of grade II-IV aGVHD (HR=1.34, P=0.019). CMV serostatus other than D-/R- had a significantly lower risk of RI (HR=0.64, P=0.044). Conclusions For older AML patients in CR2, allo-HCT is feasible, and MSD-HCT remains the best option with prolonged OS and LFS compared to Haplo- and MUD/MMUD-HCT due to lower NRM and comparable RI.