Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Oct;51(10):1342-1349.
doi: 10.1038/bmt.2016.142. Epub 2016 May 23.

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

S R Marino  1 , S M Lee  2 , T A Binkowski  3 , T Wang  4   5 , M Haagenson  6 , H-L Wang  4   5 , M Maiers  7 , S Spellman  7 , K van Besien  8 , S J Lee  5   9 , T Karrison  2 , A Artz  10
Affiliations

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

S R Marino et al. Bone Marrow Transplant. 2016 Oct.

Abstract

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Adjusted estimates of overall survival (1a and 1b) and disease free survival (1c and 1d) by 12 months after transplantation according to the three (matched, high-risk and non-high-risk) groups. Training cohort (panels 1a and 1c), validation cohort (panels 1b and 1d).
Figure 1
Figure 1
Adjusted estimates of overall survival (1a and 1b) and disease free survival (1c and 1d) by 12 months after transplantation according to the three (matched, high-risk and non-high-risk) groups. Training cohort (panels 1a and 1c), validation cohort (panels 1b and 1d).
Figure 2
Figure 2
Adjusted cumulative incidence estimates of acute GvHD by day 100 after transplantation according to the three (matched, high-risk and non-high-risk) groups. Panel 2a: training cohort; panel 2b: validation cohort.
See this image and copyright information in PMC

References

    1. Gragert L, Eapen M, Williams E, Freeman J, Spellman S, Baitty R, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med. 2014;371(4):339–48. - PMC - PubMed
    1. Flomenberg N, Baxter-Lowe LA, Confer D, Fernandez-Vina M, Filipovich A, Horowitz M, et al. Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood. 2004;104(7):1923–30. - PubMed
    1. Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007;110(13):4576–83. - PubMed
    1. Woolfrey A, Klein JP, Haagenson M, Spellman S, Petersdorf E, Oudshoorn M, et al. HLA-C Antigen Mismatch Is Associated with Worse Outcome in Unrelated Donor Peripheral Blood Stem Cell Transplantation. Biol Blood Marrow Transplant. 2011;17(6):885–92. - PMC - PubMed
    1. Horan J, Wang T, Haagenson M, Spellman SR, Dehn J, Eapen M, et al. Evaluation of HLA matching in unrelated hematopoietic stem cell transplantation for nonmalignant disorders. Blood. 2012;120(14):2918–24. - PMC - PubMed