The findings from our retrospective analysis presented in this report support three major conclusions. First, the likelihood of overall survival and disease-free survival at 5 and 10 years following myeloablative allogeneic HCT in our patient population exceed 50%, suggesting that more than half of adult patients with AML in first complete remission are or will likely be cured with this treatment modality regardless of donor stem cell source. Second, compared with patients undergoing MRD HCT, the probability of an unfavorable outcome was somewhat higher for patients undergoing URD HCT, although chance remains a plausible explanation for this observation. And third, patients undergoing 9/10 URD HCT had, for the most part, similar outcomes with regard to overall mortality, failure for DFS, relapse, and NRM when compared to patients undergoing 10/10 URD HCT, although the risk of developing grades 3–4 GVHD and chronic extensive GVHD was suggestively higher in the 9/10 URD group.
The optimal treatment of AML patients in CR1 has been a question of great debate over the last two decades. A large number of prospective trials have been conducted with the intent to define the indications of allogeneic HCT in this clinical situation. Recent studies and meta-analyses have suggested that allogeneic HCT from a MRD donor should be considered for patients with poor-risk cytogenetics, intermediate-risk cytogenetics with the exception of the nucleophosmin-1 (NPM1)-positive/fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-negative subgroup, and favorable-risk cytogenetics if certain receptor tyrosine kinase mutations are present (4
). By comparison, the indications for allogeneic HCT using URDs are less well defined, and there is currently considerable uncertainty about the appropriate patient selection for this treatment approach.
Our results are consistent with those of recent Australian and German studies reporting statistically similar outcomes for matched URD and sibling donor HCT for adult patients with AML (26
); in both studies, however, only a minority of patients received HCT for AML in CR1 while the majority of patients had more advanced stages of AML (mostly first relapse or second complete remission). An additional prospective study from the French Society of Bone Marrow Transplantation and Cell Therapy showed similar outcomes of MRD and fully matched URD allogeneic HCT for patients with AML, chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS) (28
). While the studies by Moore et al.
and Schetelig et al.
differed with regard to the stage of disease at time of HCT (26
), and the study by Yakoub-Agha et al.
included different types and stages of diseases (28
), the combined findings from these studies and the results reported in this manuscript are nevertheless very similar.
The impact of HLA disparity on outcome of URD HCT has recently been reported in a large study from the National Marrow Donor Program (NMDP) (29
). In 3,857 myeloablative transplantations performed from 1988 to 2003 for AML, acute lymphoblastic leukemia (ALL), CML, and MDS, high-resolution DNA matching for HLA-A, -B, -C, and -DRB1 (8/8 match) was the minimum level of matching associated with the highest survival. By comparison, HCT from a donor with even a single mismatch (“7/8”) was associated with lower OS and DFS, higher treatment-related mortality, and more acute GVHD (29
). While our data did not yield a statistically significant difference in outcome between 9/10 and 10/10 URD HCT, the relatively small number of patients in each group severely limited the power to detect such a difference, and precluded measurements of locus-specific effects on clinical outcome. However, the hazard ratios for 9/10 vs. 10/10 URD HCT for the endpoints of overall mortality and failure for disease-free survival observed in our study were similar to those obtained by Lee et al.
). Together, these data suggest that while the outcome following 9/10 may be worse than that following 10/10 URD HCT, the magnitude of the difference is likely relatively small.
An important limitation of our study is its non-randomized nature, which offers the potential for the introduction of bias. Such bias could work both ways; only healthier patients are referred for URD transplants, or only those perceived to be at highest risk might be referred. To minimize this bias, we developed multivariate models to adjust for baseline differences in the various patient cohorts. A further limitation is the number of patients analyzed in this study, which limits to a degree the power that we had to detect differences. Acknowledging these limitations, our data indicate allogeneic HCT provides significant long-term survival for patients receiving grafts from matched (10 of 10 alleles) or nearly matched (9 of 10 alleles) URDs. The observation that the outcome for these patients is nearly as good as for patients for whom an HLA-identical related donor is available suggest that HCT may be advantageous over non-HCT approaches using chemotherapy alone even in the event that a suitable MRD cannot be identified. Until prospective studies are completed, this conclusion supports the rationale for the recommendation to consider matched or nearly matched URD HCT for similar indications as currently put forward for matched related donor HCT for AML patients in first complete remission.