Impact of patient: donor HLA disparity on reduced-intensity-conditioned allogeneic stem cell transplants from HLA mismatched unrelated donors for AML: from the ALWP of the EBMT


Patients with acute myeloid leukaemia (AML) who lack a matched sibling or unrelated donor commonly undergo transplantation from a donor matched at 9/10 HLA-A, -B, -C, -DRB1, -DQB1 alleles, and it is unclear if a specific locus mismatch is preferable to any other. We therefore studied 937 patients with AML in complete remission transplanted using a reduced intensity conditioning regimen from an unrelated donor mismatched at a single allele. In a multivariate analysis, patient age, adverse karyotype and patient cytomegalovirus (CMV) seropositivity were correlated with decreased leukaemia free survival (LFS) and overall survival (OS). There was no significant difference in LFS or OS between patients transplanted from donors mismatched at HLA-A, -B, -C or -DRB1 in comparison to a HLA-DQB1 mismatched transplant. In a multivariate analysis, patients transplanted with a HLA-A mismatched donor had higher rates of acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM) than patients transplanted with a HLA-DQB1 mismatched donor. Patient CMV seropositivity was associated with an increase in NRM and acute GVHD and reduced LFS and OS, regardless of donor CMV status. For CMV seropositive patients lacking a fully matched donor, alternative GVHD and CMV prophylaxis strategies should be considered.

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  1. 1.

    Cornelissen JJ, Breems D, Putten WLJV, Gratwohl AA, Passweg JR, Pabst T, et al. Comparative analysis of the value of allogeneic hematopoietic stem-cell transplantation in acute myeloid leukemia with monosomal karyotype versus other cytogenetic risk categories. J Clin Oncol. 2012;30:2140–6.

    Article  Google Scholar 

  2. 2.

    Cornelissen JJ, van Putten WL, Verdonck LF, Theobald M, Jacky E, Daenen SM, et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood. 2007;109:3658–66.

    CAS  Article  Google Scholar 

  3. 3.

    Loke J, Malladi R, Moss P, Craddock C. The role of allogeneic stem cell transplantation in the management of acute myeloid leukaemia: a triumph of hope and experience. Br J Haematol. 2020;188:129–46.

    Article  Google Scholar 

  4. 4.

    Schlenk RF, Döhner K, Mack S, Stoppel M, Király F, Götze K, et al. Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelated donors in younger adults with high-risk acute myeloid leukemia: German-Austrian Trial AMLHD98A. J Clin Oncol. 2010;28:4642–8.

    Article  Google Scholar 

  5. 5.

    Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA. 2009;301:2349–61.

    CAS  Article  Google Scholar 

  6. 6.

    Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2009;15:1628–33.

    Article  Google Scholar 

  7. 7.

    Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, et al. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from cancer and leukemia group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. 2015;33:4167–75.

    Article  Google Scholar 

  8. 8.

    Ringdén O, Boumendil A, Labopin M, Canaani J, Beelen D, Ehninger G, et al. Outcome of allogeneic hematopoietic stem cell transplantation in patients age >69 years with acute myelogenous leukemia: on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2019;25:1975–83.

    Article  Google Scholar 

  9. 9.

    Passweg JR, Baldomero H, Basak GW, Chabannon C, Corbacioglu S, Duarte R, et al. The EBMT activity survey report 2017: a focus on allogeneic HCT for nonmalignant indications and on the use of non-HCT cell therapies. Bone Marrow Transplant. 2019;54:1575–85.

    CAS  Article  Google Scholar 

  10. 10.

    Schlenk RF, Dohner K, Mack S, Stoppel M, Kiraly F, Gotze K, et al. Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelated donors in younger adults with high-risk acute myeloid leukemia: German-Austrian trial AMLHD98A. J Clin Oncol: Off J Am Soc Clin Oncol. 2010;28:4642–8.

    Article  Google Scholar 

  11. 11.

    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;371:339–48.

    CAS  Article  Google Scholar 

  12. 12.

    Rubio MT, Savani BN, Labopin M, Polge E, Niederwieser D, Ganser A, et al. The impact of HLA-matching on reduced intensity conditioning regimen unrelated donor allogeneic stem cell transplantation for acute myeloid leukemia in patients above 50 years-a report from the EBMT acute leukemia working party. J Hematol Oncol. 2016;9:65.

    Article  Google Scholar 

  13. 13.

    Verneris MR, Lee SJ, Ahn KW, Wang HL, Battiwalla M, Inamoto Y, et al. HLA mismatch is associated with worse outcomes after unrelated donor reduced-intensity conditioning hematopoietic cell transplantation: an analysis from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2015;21:1783–9.

    Article  Google Scholar 

  14. 14.

    Ayuk F, Beelen DW, Bornhauser M, Stelljes M, Zabelina T, Finke J, et al. Relative impact of HLA matching and non-HLA donor characteristics on outcomes of allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2018;24:2558–67.

    Article  Google Scholar 

  15. 15.

    Passweg JR, Schanz U, Chalandon Y, Güngör T, Baldomero H, Heim D, et al. High-resolution HLA matching in unrelated donor transplantation in Switzerland: differential impact of class I and class II mismatches may reflect selection of nonimmunogenic or weakly immunogenic DRB1/DQB1 disparities. Bone Marrow Transplant. 2015;50:1201.

    CAS  Article  Google Scholar 

  16. 16.

    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;110:4576–83.

    CAS  Article  Google Scholar 

  17. 17.

    Mead AJ, Thomson KJ, Morris EC, Mohamedbhai S, Denovan S, Orti G, et al. HLA-mismatched unrelated donors are a viable alternate graft source for allogeneic transplantation following alemtuzumab-based reduced-intensity conditioning. Blood. 2010;115:5147–53.

    CAS  Article  Google Scholar 

  18. 18.

    Perez-Simon JA, Kottaridis PD, Martino R, Craddock C, Caballero D, Chopra R, et al. Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. Blood. 2002;100:3121–7.

    CAS  Article  Google Scholar 

  19. 19.

    Shaw BE, Mayor NP, Szydlo RM, Bultitude WP, Anthias C, Kirkland K, et al. Recipient/donor HLA and CMV matching in recipients of T-cell-depleted unrelated donor haematopoietic cell transplants. Bone Marrow Transplant. 2017;52:717–25.

    CAS  Article  Google Scholar 

  20. 20.

    Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant. 2005;11:945–56.

    Article  Google Scholar 

  21. 21.

    GLUCKSBERG H, STORB R, FEFER A, BUCKNER CD, NEIMAN PE, CLIFT RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18:295–304.

    CAS  Article  Google Scholar 

  22. 22.

    Ruggeri A, Labopin M, Ciceri F, Mohty M, Nagler A. Definition of GvHD-free, relapse-free survival for registry-based studies: an ALWP–EBMT analysis on patients with AML in remission. Bone Marrow Transplant. 2015;51:610.

    Article  Google Scholar 

  23. 23.

    Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81.

    Article  Google Scholar 

  24. 24.

    Kanate SK, Nagler A, Savani, B. Summary of scientific and statistical methods, study endpoints and definitions for observational and registry-based studies in hematopoietic cell transplantation. Clin Hematol Int. 2020;2:2–4.

    Google Scholar 

  25. 25.

    Yokoyama H, Kanda J, Fuji S, Kim SW, Fukuda T, Najima Y, et al. Impact of human leukocyte antigen allele mismatch in unrelated bone marrow transplantation with reduced-intensity conditioning regimen. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2017;23:300–9.

    Article  Google Scholar 

  26. 26.

    Petersdorf EW, Carrington M, O’HUigin C, Bengtsson M, De Santis D, Dubois V, et al. Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation: a retrospective cohort study. Lancet Haematol. 2020;7:e50–60.

    Article  Google Scholar 

  27. 27.

    Fürst D, Müller C, Vucinic V, Bunjes D, Herr W, Gramatzki M, et al. High-resolution HLA matching in hematopoietic stem cell transplantation: a retrospective collaborative analysis. Blood. 2013;122:3220–9.

    Article  Google Scholar 

  28. 28.

    Dehn J, Spellman S, Hurley CK, Shaw BE, Barker JN, Burns LJ, et al. Selection of unrelated donors and cord blood units for hematopoietic cell transplantation: guidelines from the NMDP/CIBMTR. Blood. 2019;134:924–34.

    CAS  Article  Google Scholar 

  29. 29.

    Petersdorf EW, Anasetti C, Martin PJ, Gooley T, Radich J, Malkki M, et al. Limits of HLA mismatching in unrelated hematopoietic cell transplantation. Blood. 2004;104:2976–80.

    CAS  Article  Google Scholar 

  30. 30.

    Broers AEC, Van Der Holt R, Van Esser JWJ, Gratama JW, Henzen-Logmans S, Kuenen-Boumeester V, et al. Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell-depleted stem cell transplantation. Blood. 2000;95:2240–5.

    CAS  Article  Google Scholar 

  31. 31.

    Cantoni N, Hirsch HH, Khanna N, Gerull S, Buser A, Bucher C, et al. Evidence for a bidirectional relationship between cytomegalovirus replication and acute graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16:1309–14.

    Article  Google Scholar 

  32. 32.

    Stevanović S, van Bergen CAM, van Luxemburg-Heijs SAP, van der Zouwen B, Jordanova ES, Kruisselbrink AB, et al. HLA class II upregulation during viral infection leads to HLA-DP–directed graft-versus-host disease after CD4+ donor lymphocyte infusion. Blood. 2013;122:1963–73.

    Article  Google Scholar 

  33. 33.

    Petersdorf EW, Gooley TA, Malkki M, Bacigalupo AP, Cesbron A, Du Toit E, et al. HLA-C expression levels define permissible mismatches in hematopoietic cell transplantation. Blood. 2014;124:3996–4003.

    CAS  Article  Google Scholar 

  34. 34.

    Fleischhauer K, Shaw BE, Gooley T, Malkki M, Bardy P, Bignon JD, et al. Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study. Lancet Oncol. 2012;13:366–74.

    CAS  Article  Google Scholar 

  35. 35.

    Savani BN, Labopin M, Kroger N, Finke J, Ehninger G, Niederwieser D, et al. Expanding transplant options to patients over 50 years. Improved outcome after reduced intensity conditioning mismatched-unrelated donor transplantation for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the EBMT. Haematologica. 2016;101:773–80.

    CAS  Article  Google Scholar 

  36. 36.

    Battipaglia G, Labopin M, Kroger N, Vitek A, Afanasyev B, Hilgendorf I, et al. Posttransplant cyclophosphamide vs antithymocyte globulin in HLA-mismatched unrelated donor transplantation. Blood. 2019;134:892–9.

    CAS  Article  Google Scholar 

  37. 37.

    Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell. Transplantation. 2017;377:2433–44.

    CAS  Google Scholar 

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Research support and clinical trials funding from CRUK, Bloodwise and Cure Leukaemia acknowledged. Core funding to the Birmingham ECMC Centre programme is gratefully acknowledged.

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Loke, J., Labopin, M., Craddock, C. et al. Impact of patient: donor HLA disparity on reduced-intensity-conditioned allogeneic stem cell transplants from HLA mismatched unrelated donors for AML: from the ALWP of the EBMT. Bone Marrow Transplant (2020).

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