The current recommendations for acute myeloid leukemia (AML) that is treated with unrelated donor allogeneic hematopoietic cell transplantation (alloHCT) emphasize donor-recipient human leukocyte antigen (HLA) compatibility at the allele level as the most important factor in donor selection. However, according to a study published in Blood, due to the efficacy of post-transplant cyclophosphamide (PTCy) prophylaxis to prevent graft-versus-host disease (GVHD), the age of unrelated donors (UDs) is emerging as more impactful on leukemia-free survival (LFS) and overall survival (OS) than HLA in this population.
Corresponding author Jaime Sanz, MD, of the Department of Medicine at the Universidad de Valencia and of Hospital Universitari i Politècnic La Fe in Spain, and colleagues believe that “these findings could significantly influence donor selection in this setting.”
The retrospective study used the European Society for Blood and Marrow Transplantation database to analyze 1,011 adult patients (median age = 54; range = 18-77) with AML using PTCy as GVHD prophylaxis in first complete remission (83%; n=837) or second complete remission (17%; n=174) from January 2010 to December 2021. Researchers examined donor age, HLA match, cytomegalovirus (CMV) serostatus, and gender mismatch.
The primary endpoint was LFS; secondary endpoints were GVHD, disease relapse, non-relapse mortality, GVHD-free and relapse-free survival (GRFS), and OS.
No specific variable was significantly associated with severe, acute, or chronic extensive GVHD.
The study included 150 female donors matched with male recipients. In a multivariate analysis of transplant outcomes, donor-recipient gender mismatch did not significantly impact LFS (hazard ratio [HR] = 0.9; p=0.53), OS (HR=0.88; p=0.49), or GRFS (HR=1.02; p=0.87).
Furthermore, HLA compatibility demonstrated no significant difference in outcomes. Patients with 10/10 matched unrelated donors (MUD; n=621) and patients with 9/10 mismatched unrelated donors (MMUD; n=390) displayed similar LFS (HR=1.04; p=0.72), OS (HR=1.09; p=0.5), and GRFS (HR=1.14; p=0.19). Likewise, when comparing 8/8 MUD and 7/8 MMUD, outcomes showed similar LFS (HR=1.12), OS (HR=1.17), and GRFS (HR=1.19). Finally, the use of HLA-DPB1 mismatched donors had no significant influence on LFS (HR=0.72).
The findings underscore PTCy’s ability to mitigate HLA-related negative effects. In this setting, “regarding transplant outcomes, our study confirms the safety and efficacy of unrelated donor [HCT],” researchers said.
In contrast to gender and HLA compatibility, donor age significantly influenced outcomes. Donors aged 25 to 30 years had similar LFS as donors aged 18 to 24 (HR=1.18), establishing age 30 as the most discriminative cutoff for LFS. Overall, patients transplanted with donors older than 30 experienced unfavorable rates of LFS, OS, and GRFS (HR=1.4, 1.45, and 1.29, respectively), as well as increased relapse rates (HR=1.38). Additionally, donors older than 30 “had a borderline detrimental effect” on non-relapse mortality (HR=1.42), so “in this context, prioritizing donor age over HLA match or gender considerations might be warranted,” researchers said.
CMV serostatus also had a significant impact on outcomes. Nineteen percent of the overall patient population (n=189) were matched for CMV negativity, which improved LFS (HR=0.74; p=0.04). Nevertheless, researchers acknowledged that the study population was transplanted before the availability of letermovir, which has modified the impact of CMV in HCT. “Whether or not CMV serostatus is still relevant with the use of letermovir should be addressed in future studies,” researchers said.
Because the study was retrospective and reliant on registry data, researchers cited exclusion of bone marrow grafts, limited relevant molecular information, and incomplete disease, graft, and donor characteristics as limitations. Prospective studies are necessary for further validation of these results.
PTCy prophylaxis seems to have overcome adverse risks that lead to GVHD and are associated with one allele mismatched donors, leaving age as the primary determinant of transplant outcomes in this population.
Although Dr. Sanz emphasized that donor selection should be made carefully, study results suggest that clinicians “start a donor search as soon as there is indication for transplant, considering matched and 1 antigen mismatched donors, and then select the younger donor.”
Any conflicts of interest declared by the authors can be found in the original study.
Reference
Sanz J, Ciceri F, Choi G, et al. Younger unrelated donors may be preferable over HLA match in the PTCy era: a study from the ALWP of the EBMT [published online ahead of print, 2024 March 29]. Blood. doi: 10.1182/blood.2023023697.
