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Graft Manipulation

Recipient/donor HLA and CMV matching in recipients of T-cell-depleted unrelated donor haematopoietic cell transplants

Abstract

Improving haematopoietic cell transplantation outcomes by selection of an HLA-matched unrelated donor is best practice; however, donor selection by secondary characteristics is controversial. We studied 1271 recipients with haematological malignancies who underwent T-cell-depleted allografts and had complete data on HLA-matching status for six loci (HLA-A, -B, -C, -DRB1, -DQB1, -DPB1) and clinical outcome data. Five-year overall survival was 40.6%. HLA mismatching (at HLA-A, -B, -C, -DRB1, -DQB1) relative risk (RR) 1.22, 95% confidence interval (CI) 1.2–1.5, P=0.033 for 1 mismatch and RR 1.46, 95% CI 1.1–1.9, P=0.009 for >1 mismatch) and CMV mismatching (RR 1.37, 95% CI 1.2–1.6, P<0.001) were significantly associated with inferior survival. Donors aged <30 years showed a trend towards better survival. The multivariate model for mortality, combining CMV and HLA-match status, found an RR of 1.36 (95% CI 1.1–1.7, P=0.003) for HLA matched/CMV mismatched, an RR of 1.22 (95% CI 0.99–1.5, P=0.062) for HLA mismatched/CMV matched and an RR of 1.81 (95% CI 1.4–2.3, P=<0.001) for HLA/ CMV mismatched, compared with the HLA/CMV-matched recipients. These data suggest that HLA and CMV matching status should be considered when selecting unrelated donors and that CMV matching may abrogate the effect of an HLA mismatch.

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References

  1. Ottinger H, Ferencik S, Beelen D, Lindemann M, Peceny R, Elmaagacli A et al. Hematopoietic stem cell transplantation: contrasting the outcome of transplantations from HLA-identical siblings, partially HLA-mismatched related donors and HLA-matched unrelated donors. Blood 2003; 102: 1131–1137.

    Article  CAS  Google Scholar 

  2. Lee S, Klein J, Haagenson M, Baxter-Lowe L, Confer D, Eapen M et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 2007; 110: 4576–4583.

    Article  CAS  Google Scholar 

  3. Pidala J, Lee SJ, Ahn KW, Spellman S, Wang HL, Aljurf M et al. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. Blood 2014; 124: 2596–2606.

    Article  CAS  Google Scholar 

  4. Fleischhauer K, Shaw BE, Gooley T, Malkki M, Bardy P, Bignon J-D 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: 366–374.

    Article  CAS  Google Scholar 

  5. Shaw BE, Mayor NP, Russell NH, Apperley JF, Clark RE, Cornish J et al. Diverging effects of HLA-DPB1 matching status on outcome following unrelated donor transplantation depending on disease stage and the degree of matching for other HLA alleles. Leukemia 2010; 24: 58–65.

    Article  CAS  Google Scholar 

  6. Burt C, Parker A, McQuaker G, Copland M, Brierley C, Little AM et al. In a 12-allele analysis HLA-DPB1 matching is associated with improved OS in leukaemic and myelodysplastic patients receiving myeloablative T-cell-depleted PBSCT from unrelated donors. Bone Marrow Transplant 2014; 49: 657–663.

    Article  CAS  Google Scholar 

  7. Morishima Y, Kashiwase K, Matsuo K, Azuma F, Morishima S, Onizuka M et al. Biological significance of HLA locus matching in unrelated donor bone marrow transplantation. Blood 2015; 125: 1189–1197.

    Article  CAS  Google Scholar 

  8. 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: 885–892.

    Article  CAS  Google Scholar 

  9. Kollman C, Howe C, Anasetti C, Antin J, Davies S, Filipovich A et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 2001; 98: 2043–2051.

    Article  CAS  Google Scholar 

  10. Ljungman P, Brand R, Einsele H, Frassoni F, Niederwieser D, Cordonnier C . Donor CMV serologic status and outcome of CMV-seropositive recipients after unrelated donor stem cell transplantation: an EBMT megafile analysis. Blood 2003; 102: 4255–4260.

    Article  CAS  Google Scholar 

  11. Ljungman P, Brand R, Hoek J, de la Camara R, Cordonnier C, Einsele H et al. Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European group for blood and marrow transplantation. Clin Infect Dis 2014; 59: 473–481.

    Article  Google Scholar 

  12. Gratwohl A . The EBMT risk score. Bone Marrow Transplant 2012; 47: 749–756.

    Article  CAS  Google Scholar 

  13. Fine J, Gray R . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.

    Article  Google Scholar 

  14. R Core Team. R: A Language and Evnironment for Statistical Computing. R Foundation for Statistical Computing: Vienna, Austria, 2014. https://www.r-project.org/.

  15. Craddock C, Szydlo RM, Dazzi F, Olavarria E, Cwynarski K, Yong A et al. Cytomegalovirus seropositivity adversely influences outcome after T-depleted unrelated donor transplant in patients with chronic myeloid leukaemia: the case for tailored graft-versus-host disease prophylaxis. Br J Haematol 2001; 112: 228–236.

    Article  CAS  Google Scholar 

  16. Spencer A, Brookes PA, Kaminski E, Hows JM, Szydlo RM, van Rhee F et al. Cytotoxic T lymphocyte precursor frequency analyses in bone marrow transplantation with volunteer unrelated donors. Value in donor selection. Transplantation 1995; 59: 1302–1308.

    Article  CAS  Google Scholar 

  17. Bacigalupo A, Tedone E, Sanna MA, Moro F, Van Lint MT, Grazi G et al. CMV infections following allogeneic BMT: risk factors, early treatment and correlation with transplant related mortality. Haematologica 1992; 77: 507–513.

    CAS  PubMed  Google Scholar 

  18. Jaskula E, Bochenska J, Kocwin E, Tarnowska A, Lange A . CMV serostatus of donor-recipient pairs influences the risk of CMV infection/reactivation in HSCT patients. Bone Marrow Res 2012; 2012: 375075.

    Article  Google Scholar 

  19. Zhou W, Longmate J, Lacey SF, Palmer JM, Gallez-Hawkins G, Thao L et al. Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients. Blood 2009; 113: 6465–6476.

    Article  CAS  Google Scholar 

  20. Moins-Teisserenc H, Busson M, Scieux C, Bajzik V, Cayuela JM, Clave E et al. Patterns of cytomegalovirus reactivation are associated with distinct evolutive profiles of immune reconstitution after allogeneic hematopoietic stem cell transplantation. J Infect Dis 2008; 198: 818–826.

    Article  Google Scholar 

  21. Pietersma FL, van Dorp S, Minnema MC, Kuball J, Meijer E, Schuurman R et al. Influence of donor cytomegalovirus (CMV) status on severity of viral reactivation after allogeneic stem cell transplantation in CMV-seropositive recipients. Clin Infect Dis 2011; 52: e144–e148.

    Article  Google Scholar 

  22. Grob JP, Grundy JE, Prentice HG, Griffiths PD, Hoffbrand AV, Hughes MD et al. Immune donors can protect marrow-transplant recipients from severe cytomegalovirus infections. Lancet 1987; 1: 774–776.

    Article  CAS  Google Scholar 

  23. Sellar RS, Vargas FA, Henry JY, Verfuerth S, Charrot S, Beaton B et al. CMV promotes recipient T-cell immunity following reduced-intensity T-cell-depleted HSCT, significantly modulating chimerism status. Blood 2015; 125: 731–739.

    Article  CAS  Google Scholar 

  24. Elmaagacli AH, Steckel NK, Koldehoff M, Hegerfeldt Y, Trenschel R, Ditschkowski M et al. Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients. Blood 2011; 118: 1402–1412.

    Article  CAS  Google Scholar 

  25. Green ML, Leisenring WM, Xie H, Walter RB, Mielcarek M, Sandmaier BM et al. CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. Blood 2013; 122: 1316–1324.

    Article  CAS  Google Scholar 

  26. Ito S, Pophali P, Co W, Koklanaris EK, Superata J, Fahle GA et al. CMV reactivation is associated with a lower incidence of relapse after allo-SCT for CML. Bone Marrow Transplant 2013; 48: 1313–1316.

    Article  CAS  Google Scholar 

  27. Admiraal R, Chiesa R, Lindemans CA, Nierkens S, Bierings MB, Versluijs AB et al. Leukemia-free survival in myeloid leukemia, but not in lymphoid leukemia, is predicted by early CD4+ reconstitution following unrelated cord blood transplantation in children: a multicenter retrospective cohort analysis. Bone Marrow Transplant. 2016; 51: 1376–1378.

    Article  CAS  Google Scholar 

  28. Thomson KJ, Mackinnon S, Peggs KS . CMV-specific cellular therapy for acute myeloid leukemia? Blood 2012; 119: 1088–1090author reply 90–9.

    Article  CAS  Google Scholar 

  29. Busca A, Passera R, Pini M, Zallio F, Dellacasa C, Audisio E et al. The use of ATG abrogates the antileukemic effect of cytomegalovirus reactivation in patients with acute myeloid leukemia receiving grafts from unrelated donors. Am J Hematol 2015; 90: E117–E121.

    Article  CAS  Google Scholar 

  30. Mariotti J, Maura F, Spina F, Roncari L, Dodero A, Farina L et al. Impact of cytomegalovirus replication and cytomegalovirus serostatus on the outcome of patients with B cell lymphoma after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2014; 20: 885–890.

    Article  Google Scholar 

  31. Moscardo F, Sanz J, Carbonell F, Sanz MA, Larrea L, Montesinos P et al. Effect of CD8(+) cell content on umbilical cord blood transplantation in adults with hematological malignancies. Biol Blood Marrow Transplant 2014; 20: 1744–1750.

    Article  Google Scholar 

  32. Ganepola S, Gentilini C, Hilbers U, Lange T, Rieger K, Hofmann J et al. Patients at high risk for CMV infection and disease show delayed CD8+ T-cell immune recovery after allogeneic stem cell transplantation. Bone Marrow Transplant 2007; 39: 293–299.

    Article  CAS  Google Scholar 

  33. Avetisyan G, Aschan J, Hagglund H, Ringden O, Ljungman P . Evaluation of intervention strategy based on CMV-specific immune responses after allogeneic SCT. Bone Marrow Transplant 2007; 40: 865–869.

    Article  CAS  Google Scholar 

  34. Shaw B, Gooley T, Malkki M, Madrigal J, Begovich A, Horowitz M et al. The importance of HLA-DPB1 in unrelated donor hematopoietic cell transplantation. Blood 2007; 110: 4560–4566.

    Article  CAS  Google Scholar 

  35. Chakraverty R, Orti G, Roughton M, Shen J, Fielding A, Kottaridis P et al. Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution. Blood 2010; 116: 3080–3088.

    Article  CAS  Google Scholar 

  36. Jardine L, Publicover A, Bigley V, Hale G, Pearce K, Dickinson A et al. A comparative study of reduced dose alemtuzumab in matched unrelated donor and related donor reduced intensity transplants. Br J Haematol 2015; 168: 874–881.

    Article  CAS  Google Scholar 

  37. Kollman C, Spellman SR, Zhang MJ, Hassebroek A, Anasetti C, Antin JH et al. The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy. Blood 2016; 127: 260–267.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank all the transplant centre data managers and co-ordinators who provided clinical data or research samples for this study.

Author contributions

BES, NPM, SM and JAM designed the study, collected and curated the samples and data, performed the analysis and wrote the paper. BES, NPM and WPB performed the laboratory typing. RMS performed the statistical analysis. KK and JS collected and contributed the clinical data. BES, CA, AC, SM, DIM, AP, MNP, NHR and KT contributed patient data and samples. All of the authors contributed to the writing and review of the manuscript.

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Correspondence to B E Shaw.

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Shaw, B., Mayor, N., Szydlo, R. et al. Recipient/donor HLA and CMV matching in recipients of T-cell-depleted unrelated donor haematopoietic cell transplants. Bone Marrow Transplant 52, 717–725 (2017). https://doi.org/10.1038/bmt.2016.352

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