Identification of high-risk amino-acid substitutions in hematopoietic cell transplantation: a challenging task

Bone Marrow Transplant. 2016 Oct;51(10):1342-1349. doi: 10.1038/bmt.2016.142. Epub 2016 May 23.


Allogeneic hematopoietic cell transplantation (HCT) offers the potential to cure hematologic malignancies. In the absence of an HLA-matched donor, HLA mismatched unrelated donors may be used, although risks of GvHD and treatment-related mortality (TRM) are higher. Identification and avoidance of amino-acid substitution and position types (AASPT) conferring higher risks of TRM and GvHD would potentially improve the success of transplantation from single HLA mismatched unrelated donors. Using random forest and logistic regression analyses, we identified 19 AASPT associated with greater risks for at least one adverse transplant outcome: grade III-IV acute GvHD, TRM, lower disease-free survival or worse overall survival relative to HLA-matched unrelated donors and to other AASPT. When tested in an independent validation cohort of 3530 patients, none of the AASPT from the training set were validated as high risk, however. Review of the literature shows that failure to validate original observations is the rule and not the exception in immunobiology and emphasizes the importance of independent validation before clinical application. Our current data do not support avoiding any specific class I AASPT for unrelated donors. Additional studies should be performed to fully understand the role of AASPT in HCT outcomes.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Amino Acid Substitution*
  • Child
  • Child, Preschool
  • Hematopoietic Stem Cell Transplantation / adverse effects
  • Hematopoietic Stem Cell Transplantation / methods*
  • Histocompatibility / genetics
  • Humans
  • Infant
  • Logistic Models
  • Middle Aged
  • Risk Assessment
  • Treatment Outcome
  • Unrelated Donors*
  • Unsupervised Machine Learning
  • Young Adult