The influence of the degree of compatibility of the patient and donor HLA genotype on the outcome of allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the effective methods for treating hematological diseases. High accuracy of donor-recipient pair selection based on HLA-system reduces the risk of complications after allo-HSCT. Modern typing methods allow us to study HLA loci not only in high, but also in allelic resolution.

The aim of the study was to evaluate the effect of compatibility at five HLA loci in allelic resolution and mismatches at the HLADPB1 locus of donor-recipient pairs on the outcome of allogeneic unrelated HSCT.

Material and methods. The work included 38 donor-recipient pairs; before HSCT, HLA-typing at the HLA-A, -B, -C, -DQB1, -DRB1 loci was performed in high resolution. Retrospectively, all studied donor–recipient pairs were typed by NGS technology at allelic resolution using the AllType NGS II Loci Amplification Kit (One Lambda, USA) and NGSgo-MX11-3 (GenDX, Netherlands). Statistical data processing was performed using StatTech 4.8.3 software (developer – StatTech LLC, Russia). The DPB1 T-cell Epitope (TCE) Algorithm v2.0 calculator was used to classify the type of HLA-DPB1 mismatch.

Results and discussion. When assessing the overall three-year survival for recipients compatible with donors 10/10 at allelic resolution and less than 10/10, no statistically significant differences were found (p = 0.912). Mismatch in HLA-DPB1 according to the classification did not have a statistically significant effect on the overall three-year survival (p = 0.589). The analysis revealed that the odds of developing chronic graft-versus-host disease in recipients with TCE-incompatible mismatch were higher (p = 0.045) compared with recipients whose donor was incompatible with TCE-compatible mismatch or fully compatible.

Conclusion. Non-permissive HLA-DPB1 mismatch in donor-recipient pairs is one of the predictors of the development of chronic graft-versus-host disease in recipients. The model obtained by binary logistic regression had good discriminatory ability (area under the ROC curve 0.713; 95 % confidence interval 0.513–0.912).

1. Passweg J.R., Baldomero H., Bader P., Basak G.W., Bonini C., Duarte R., Dufour C., Kröger N., Kuball J., Lankester A., … European Society for Blood and Marrow Transplantation (EBMT). Is the use of unrelated donor transplantation leveling off in Europe? The 2016 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2018;53(9):1139–1148. doi: 10.1038/s41409018-0153-1

2. Afanas’ev B.V., Zubarovskaja L.S., Aljanskij A.L., Paina O.V., Borovkova A.S., Kuzmich E.V., Bykova T.A., Deev R.V., Isaev A.A. Selection of donor of allogeneic hematopoietic stem cell transplantation. Rossiyskiy zhurnal detskoy gematologii i onkologii = Russian Journal of Pediatric Hematology and Oncology. 2016;3(3):30–36. [In Russian]. doi: 10.15789/1563-0625-HDI-2182

3. Савченко В.Г. Программное лечение заболеваний системы крови. М.: Практика, 2012. 1056 c. Savchenko V.G. Software treatment of blood system diseases. Moskow: Praktika, 2012. 1056 p. [In Russian].

4. Order of the Ministry of Health of Russian Federation № 519-n of 29.07.2022 g. «On approval of the Procedure for conducting a medical examination of a donor who has given written informed voluntary consent to the removal of his organs and (or) tissues for transplantation». [In Russian]. Available at: clck.ru/3PtqNa

5. Marsh S.G., Albert E.D., Bodmer W.F., Bontrop R.E., Dupont B., Erlich H.A., FernándezViña M., Geraghty D.E., Holdsworth R., Hurley C.K., … Trowsdale J. Nomenclature for factors of the HLA system 2010. Tissue Antigens. 2010;75(4):291–455. doi: 10.1111/j.1399-0039.2010.01466.x

6. Mayor N.P., Wang T., Lee S.J., Kuxhausen M., Vierra-Green C., Barker D.J., Auletta J., Bhatt V.R., Gadalla S.M., Gragert L., … Marsh S.G.E. Impact of previously unrecognized HLA mismatches using ultrahigh resolution typing in unrelated donor hematopoietic cell transplantation. J. Clin. Oncol. 2021;39(21):2397– 2409. doi: 10.1200/JCO.20.03643

7. Mayor N.P., Hayhurst J.D., Turner T.R., Szydlo R.M., Shaw B.E., Bultitude W.P., Sayno J.R., Tavarozzi F., Latham K., Anthias C., … Marsh S.G.E. Recipients receiving better HLA-matched hematopoietic cell transplantation grafts, uncovered by a novel HLA typing method, have superior survival: a retrospective study. Biol. Blood Marrow Transplant. 2019;25(3):443–450. doi: 10.1016/j.bbmt.2018.12.768

8. Zou J., Kongtim P., Oran B., Kosmoliaptsis V., Carmazzi Y., Ma J., Li L., Rondon G., Srour S., Copley H.C., … Cao K. Refined HLA-DPB1 mismatch with molecular algorithms predicts outcomes in hematopoietic stem cell transplantation. Haematologica. 2022;107(4):844–856. doi: 10.3324/haematol.2021.278993

9. Pidala J., Lee S.J., Ahn K.W., Spellman S., Wang H.L., Aljurf M., Askar M., Dehn J., FernandezViña M., Gratwohl A., … Anasetti C. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. Blood. 2014;124(16):2596–2606. doi: 10.1182/blood-2014-05-576041

10. Gagne K., Loiseau P., Dubois V., Dufosséx F., Perrier P., Dormoy A., Jollet I., Renac V., Masson D., Picard C., … Cesbron A. Is there any impact of HLA-DPB1 disparity in 10/10 HLA-matched unrelated hematopoietic SCT? Results of a French multicentric retrospective study. Bone Marrow Transplant. 2015;50(2):232–236. doi: 10.1038/bmt.2014.253

11. DPB1 T-Cell Epitope Algorithm v2.0. [Electronic resource]. Available at: http://www.ebi.ac.uk/ipd/imgt/hla/dpb.html.

12. Fleischhauer K., Ahn K.W., Wang H.L., Zito L., Crivello P., Müller C., Verneris M., Shaw B.E., Pidala J., Oudshorn M., Lee S.J., Spellman S.R. Directionality of non-permissive HLA-DPB1 T-cell epitope group mismatches does not improve clinical risk stratification in 8/8 matched unrelated donor hematopoietic cell transplantation. Bone Marrow Transplant. 2017;52(9):1280–1287. doi: 10.1038/bmt.2017.96

13. Akhmedov M., Kliasova G., Parovichnikova E.N. Infectious complications and their contributing risk factors after allogeneic hematopoietic stem cell transplantation. Gematologiya i transfuziologiya = Hematology and Transfusiology. 2022;67(1):90–107. [In Russian]. doi: 10.35754/0234-5730-2022-67-1-90-107

14. Chang J., Hsiao M., Blodget E., Akhtari M. Increased risk of 100-day and 1-year infection-related mortality and complications in haploidentical stem cell transplantation. J. Blood Med. 2019;10:135–143. doi: 10.2147/JBM.S201073

15. Dehn J., Spellman S., Hurley C.K., Shaw B.E., Barker J.N., Burns L.J., Confer D.L., Eapen M., Fernandez-Vina M., Hartzman R., … Pidala J. Selection of unrelated donors and cord blood units for hematopoietic cell transplantation: guidelines from the NMDP/ CIBMTR. Blood. 2019;134(12):924–934. doi: 10.1182/blood.2019001212

16. Fleischhauer K., Shaw B.E., Gooley T., Malkki M., Bardy P., Bignon J.D., Dubois V., Horowitz M.M., Madrigal J.A., Morishima Y., … International Histocompatibility Working Group in Hematopoietic Cell Transplantation. Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study. Lancet Oncol. 2012;13(4):366–374. doi: 10.1016/s1470-2045(12)70004-9

17. Khamaganova E.G., Khizhinskij S.P., Kuz’minova E.P., Abdraimova A.P., Leonov E.A., Gaponova T.V., Parovichnikova E.N. Optimal multilocus HLA typing in potential allogeneic hematopoietic stem cell donors. Klinicheskaya onkogematologiya = Clinical Oncohematology. 2023;16(4):399–406. [In Russian]. doi:10.21320/2500-2139-2023-16-4-399-406

18. Flowers M.E., Inamoto Y., Carpenter P.A., Lee S.J., Kiem H.P., Petersdorf E.W., Pereira S.E., Nash R.A., Mielcarek M., Fero M.L., … Martin P.J.Comparative analysis of risk factors for acute graftversus-host disease and for chronic graft-versus-host disease according to National Institutes of Health conse nsus criteria. Blood. 2011;117(11):3214–3219. doi: 10.1182/blood-2010-08-302109