For patients with acute myeloid leukemia (AML) in their first complete remission, the prospect of an allogeneic transplantation comes with the task of graft selection to achieve optimal clinical outcomes. In older patients, matched sibling donor (MSD) grafts have the attendant disadvantage of coming from older donors, whereas mismatched alternatives are likely to come from young donors, begging the question, to what extent can the well-validated benefit of donor youth compensate for imperfect HLA compatibility? In this issue of Blood Advances, Poire et al approached this question by comparing outcomes between older MSD and younger haploidentical donor transplants in older adults with AML in their first remission.1 

They retrospectively analyzed registry data from 600 transplant centers that contributed to the European Society for Blood and Marrow Transplantation and had a cohort of 1247 patients with AML who were older than 60 years of age and who were transplanted in first complete remission with either an MSD ≥60 years of age or a haploidentical donor ≤40 years of age. The age gap between donors of these 2 cohorts makes this effectively a comparison between matched sibling and haploidentical adult children donors. Importantly, all haploidentical transplants, which occurred between 2012 and 2022, received graft-versus-host disease (GVHD) prophylaxis with posttransplant cyclophosphamide, reflecting contemporary practices in HLA-mismatched transplantation.2 The cohorts were relatively well matched with an average patient age of 65 years, secondary AML in ∼15%, intermediate- and adverse-risk cytogenetics in ∼70% and ∼30%, respectively, and myeloablative conditioning in ∼20%. Haploidentical recipients were more likely to receive bone marrow grafts (20% vs 3%), had slightly fewer female donors to male recipients (33% vs 21%), and overall a shorter follow-up (24 months vs 37 months) than MSD recipients.

The authors observed that the haploidentical and MSD recipients had similar overall survival and leukemia-free survival. The haploidentical cohort had a significantly reduced incidence of relapse (20.1% vs 28.6%) but a near doubling of nonrelapse mortality (24.4% vs 14.7%) when compared with the MSD cohort. Haploidentical transplant was also associated with a higher risk for grade 2 to 4 acute GVHD but not severe (grade 3 to 4) acute GVHD nor with excess chronic GVHD. Thus, in the posttransplant cyclophosphamide era, the cost of the young haploidentical graft may not be from severe GVHD but other treatment-related complications, such as infection and graft failure. This highlights both the success of cyclophosphamide in nullifying the deleterious effects of large HLA mismatches and its associated delayed engraftment, increased risk for bacterial infections, and end-organ toxicity.3,4 In the multivariate analysis, it was noted that, in addition to donor age and disease characteristics (ie, secondary AML or adverse cytogenetics), peripheral blood grafts were also associated with reduced relapse, nonrelapse mortality, and improved overall survival.

The study by Poire et al should help clinicians to make informed decisions about donor selection for older patients with AML. The noninferior survival of young haploidentical transplants in the posttransplant cyclophosphamide era means it is a defensible option in this population, particularly when urgency makes a search for unrelated donors infeasible. However, the higher rates of nonrelapse mortality will compel transplant physicians to seek out older MSDs first until the treatment-associated harms of haploidentical transplant can be more clearly outweighed by superior leukemia control.

This study should be contextualized into a broader field of retrospective analyses of graft selection in older adults. In patients with myelodysplastic syndrome who are 50 years and older, transplants from younger matched unrelated donors (MUD) are associated with improved relapse rates and disease-free survival despite a higher incidence of GVHD when compared with older MSDs.5 Similar results have been reported in B-cell acute lymphoblastic leukemia, although not in AML.6-8 When comparing MSD in older adults with AML with various other donors, it is notable that HLA-matched MUDs and umbilical cord blood transplants led to the lowest risk for leukemic relapse, including in patients who are not in remission at transplant.9,10 Taken cumulatively, these studies lead to the conclusion that, for older individuals with AML in remission, a younger MUD is emerging as a first choice for transplant, an older MSD as second, and a younger haploidentical donor as third option. More studies are needed on the role of umbilical cord transplant in this setting.

Any reduction in relapse after haploidentical transplant, as observed here, is likely attributable to the graft-versus-leukemia effect. HLA-reactive T cells mount a potent antileukemic immune response, in addition to dangerous graft-versus-host effects.11 In parallel, natural killer cell alloreactivity enables the disinhibition of donor killer inhibitor receptors upon encountering major histocompatibility complex–mismatched recipient cells, thereby unleashing antitumor effects with less GVHD.12 These benefits are counterbalanced by the risk for engraftment failure associated with anti-HLA donor-specific antibodies, as well as unique mechanisms of immune escape and relapse via HLA allele loss.13,14 Interestingly, the authors’ observation of reduced relapse with haploidentical recipients did not translate into improvements in the leukemia-free survival, underscoring the impact of higher nonrelapse mortality in this group, which may itself be obscuring a certain proportion of patients otherwise destined for relapse.

Ultimately, practical exigencies are the clinical reality in transplantation. Siblings are only rarely HLA matched and have a high incidence of exclusionary preexisting health conditions in this age bracket. HLA-matched unrelated donor transplants, although favored for their minor histocompatibility mismatch and lower relapse rates, are disadvantaged by the time required for registry searches, donor evaluation, and coordination. Now, the young and healthy haploidentical transplant comes of age as an attractive alternative to more traditional transplant methods and is associated with comparable clinical outcomes.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

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