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Immunology

Incidence, risk factors and clinical outcome of leukemia relapses with loss of the mismatched HLA after partially incompatible hematopoietic stem cell transplantation

Leukemia volume 29, pages 1143–1152 (2015)Cite this article

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Abstract

Genomic loss of the mismatched human leukocyte antigen (HLA) is a recently described mechanism of leukemia immune escape and relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Here we first evaluated its incidence, risk factors and outcome in 233 consecutive transplants from partially HLA-mismatched related and unrelated donors (MMRD and MMUD, respectively). We documented 84 relapses, 23 of which with HLA loss. All the HLA loss relapses occurred after MMRD HSCT, and 20/23 in patients with acute myeloid leukemia. Upon MMRD HSCT, HLA loss variants accounted for 33% of the relapses (23/69), occurring later than their ‘classical’ counterparts (median: 307 vs 88 days, P<0.0001). Active disease at HSCT increased the risk of HLA loss (hazard ratio (HR): 10.16; confidence interval (CI): 2.65–38.92; P=0.001), whereas older patient ages had a protective role (HR: 0.16; CI: 0.05–0.46; P=0.001). A weaker association with HLA loss was observed for graft T-cell dose and occurrence of chronic graft-versus-host disease. Outcome after ‘classical’ and HLA loss relapses was similarly poor, and second transplantation from a different donor appeared to provide a slight advantage for survival. In conclusion, HLA loss is a frequent mechanism of evasion from T-cell alloreactivity and relapse in patients with myeloid malignancies transplanted from MMRDs, warranting routine screening in this transplantation setting.

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References

  1. Copelan EA . Hematopoietic stem-cell transplantation. N Engl J Med 2006; 354: 1813–1826.

    Article  CAS  PubMed  Google Scholar 

  2. Estey E, Dohner H . Acute myeloid leukaemia. Lancet 2006; 368: 1894–1907.

    Article  PubMed  Google Scholar 

  3. Kolb HJ . Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 2008; 112: 4371–4383.

    Article  CAS  PubMed  Google Scholar 

  4. Pavletic SZ, Kumar S, Mohty M, de Lima M, Foran JM, Pasquini M et al. NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: report from the Committee on the Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation. Biol Blood Marrow Transplant 2010; 16: 871–890.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363: 2091–2101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gress RE, Miller JS, Battiwalla M, Bishop MR, Giralt SA, Hardy NM et al. Proceedings from the National Cancer Institute's Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: Part I. Biology of relapse after transplantation. Biol Blood Marrow Transplant 2013; 19: 1537–1545.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Stanghellini MT et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med 2009; 361: 478–488.

    Article  CAS  PubMed  Google Scholar 

  8. Vago L, Toffalori C, Ciceri F, Fleischhauer K . Genomic loss of mismatched human leukocyte antigen and leukemia immune escape from haploidentical graft-versus-leukemia. Semin Oncol 2012; 39: 707–715.

    Article  PubMed  Google Scholar 

  9. Villalobos IB, Takahashi Y, Akatsuka Y, Muramatsu H, Nishio N, Hama A et al. Relapse of leukemia with loss of mismatched HLA resulting from uniparental disomy after haploidentical hematopoietic stem cell transplantation. Blood 2010; 115: 3158–3161.

    Article  CAS  PubMed  Google Scholar 

  10. Waterhouse M, Pfeifer D, Pantic M, Emmerich F, Bertz H, Finke J . Genome-wide profiling in AML patients relapsing after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2011; 17: 1450–1459 e1451.

    Article  CAS  PubMed  Google Scholar 

  11. Toffalori C, Cavattoni I, Deola S, Mastaglio S, Giglio F, Mazzi B et al. Genomic loss of patient-specific HLA in acute myeloid leukemia relapse after well-matched unrelated donor HSCT. Blood 2012; 119: 4813–4815.

    Article  CAS  PubMed  Google Scholar 

  12. Tamaki H, Fujioka T, Ikegame K, Yoshihara S, Kaida K, Taniguchi K et al. Different mechanisms causing loss of mismatched human leukocyte antigens in relapsing t(6;11)(q27;q23) acute myeloid leukemia after haploidentical transplantation. Eur J Haematol 2012; 89: 497–500.

    Article  PubMed  Google Scholar 

  13. Dubois V, Sloan-Bena F, Cesbron A, Hepkema BG, Gagne K, Gimelli S et al. Pretransplant HLA mistyping in diagnostic samples of acute myeloid leukemia patients due to acquired uniparental disomy. Leukemia 2012; 26: 2079–2085.

    Article  CAS  PubMed  Google Scholar 

  14. Smith AG, Fan W, Regen L, Warnock S, Sprague M, Williams R et al. Somatic mutations in the HLA genes of patients with hematological malignancy. Tissue Antigens 2012; 79: 359–366.

    Article  CAS  PubMed  Google Scholar 

  15. Coppage M, Iqbal A, Ahmad A, Becker MW . Leukemia specific loss of heterozygosity of MHC in a CLL patient: disease state impacts timing of confirmatory typing. Hum Immunol 2013; 74: 41–44.

    Article  CAS  PubMed  Google Scholar 

  16. Masuda K, Hiraki A, Fujii N, Watanabe T, Tanaka M, Matsue K et al. Loss or down-regulation of HLA class I expression at the allelic level in freshly isolated leukemic blasts. Cancer Sci 2007; 98: 102–108.

    Article  CAS  PubMed  Google Scholar 

  17. Gupta M, Raghavan M, Gale RE, Chelala C, Allen C, Molloy G et al. Novel regions of acquired uniparental disomy discovered in acute myeloid leukemia. Genes Chromosomes Cancer 2008; 47: 729–739.

    Article  CAS  PubMed  Google Scholar 

  18. Raghavan M, Smith LL, Lillington DM, Chaplin T, Kakkas I, Molloy G et al. Segmental uniparental disomy is a commonly acquired genetic event in relapsed acute myeloid leukemia. Blood 2008; 112: 814–821.

    Article  CAS  PubMed  Google Scholar 

  19. van Rood JJ, Roelen DL, Claas FH . The effect of noninherited maternal antigens in allogeneic transplantation. Semin Hematol 2005; 42: 104–111.

    Article  CAS  PubMed  Google Scholar 

  20. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2100.

    Article  CAS  PubMed  Google Scholar 

  21. Apperley J, Carreras E, Gluckman E, Masszi T ESH-EBMT Handbook on Haematopoietic Stem Cell Transplantation Forum Service Editore Genova, Italy, 2012.

  22. Mazzi B, Clerici TD, Zanussi M, Lupo Stanghellini MT, Vago L, Sironi E et al. Genomic typing for patient-specific human leukocyte antigen-alleles is an efficient tool for relapse detection of high-risk hematopoietic malignancies after stem cell transplantation from alternative donors. Leukemia 2008; 22: 2119–2122.

    Article  CAS  PubMed  Google Scholar 

  23. Ciceri F, Bonini C, Stanghellini MT, Bondanza A, Traversari C, Salomoni M et al. Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study. Lancet Oncol 2009; 10: 489–500.

    Article  PubMed  Google Scholar 

  24. Peccatori J, Forcina A, Clerici D, Crocchiolo R, Vago L, Stanghellini MT et al. Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors. Leukemia 2014; e-pub ahead of print 4 June 2014; doi:10.1038/leu.2014.180.

    Article  PubMed  Google Scholar 

  25. Luznik L, O'Donnell PV, Fuchs EJ . Posttransplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol 2012; 39: 683–693.

    Article  CAS  PubMed  Google Scholar 

  26. Wang Y, Liu DH, Liu KY, Xu LP, Zhang XH, Han W et al. Long-term follow-up of haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of leukemia: nine years of experience at a single center. Cancer 2013; 119: 978–985.

    Article  PubMed  Google Scholar 

  27. Di Bartolomeo P, Santarone S, De Angelis G, Picardi A, Cudillo L, Cerretti R et al. Haploidentical, unmanipulated, G-CSF-primed bone marrow transplantation for patients with high-risk hematologic malignancies. Blood 2013; 121: 849–857.

    Article  CAS  PubMed  Google Scholar 

  28. Schmid C, Schleuning M, Schwerdtfeger R, Hertenstein B, Mischak-Weissinger E, Bunjes D et al. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood 2006; 108: 1092–1099.

    Article  CAS  PubMed  Google Scholar 

  29. Passweg JR, Baldomero H, Gratwohl A, Bregni M, Cesaro S, Dreger P et al. The EBMT activity survey: 1990-2010. Bone Marrow Transplant 2012; 47: 906–923.

    Article  CAS  PubMed  Google Scholar 

  30. Petersdorf EW . Optimal HLA matching in hematopoietic cell transplantation. Curr Opin Immunol 2008; 20: 588–593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE et al. Age and acute myeloid leukemia. Blood 2006; 107: 3481–3485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rao AV, Valk PJ, Metzeler KH, Acharya CR, Tuchman SA, Stevenson MM et al. Age-specific differences in oncogenic pathway dysregulation and anthracycline sensitivity in patients with acute myeloid leukemia. J Clin Oncol 2009; 27: 5580–5586.

    Article  CAS  PubMed  Google Scholar 

  33. Schneider F, Hoster E, Schneider S, Dufour A, Benthaus T, Kakadia PM et al. Age-dependent frequencies of NPM1 mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML). Ann Hematol 2012; 91: 9–18.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Italian Ministry of Health, by the Italian Ministry of University and Research, by the Cariplo Foundation, by the Associazione Italiana per la Ricerca sul Cancro (Investigator Grant to KF and Start-Up Grant to LV), by the Conquer Cancer Foundation and by the European Commission. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Author Contributions

LaC, RC, KF, FC and LV designed the study. LaC, RC and AS performed the statistical analysis. CT, BM, FS, LoC, EZ, KF and LV performed the experiments and analyzed the data for the immunogenetic studies. LaC, RG, MTLS, AA, MGC, SM, MM, CC, MB, JP, FC and LV contributed to patient clinical care and data collection. ClB and ChB provided scientific advice and supervision. LaC, FC and LV wrote the manuscript. All authors have approved the final version of the manuscript.

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Author notes

  1. F Ciceri and L Vago: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Regenerative Medicine, Hematology and Bone Marrow Transplantation Unit, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy

    L Crucitti, R Greco, M T Lupo Stanghellini, A Assanelli, M G Carrabba, S Marktel, M Marcatti, C Corti, M Bernardi, J Peccatori, F Ciceri & L Vago

  2. Humanitas Cancer Center, Rozzano, Italy

    R Crocchiolo

  3. Division of Regenerative Medicine, Unit of Molecular and Functional Immunogenetics, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milano, Italy

    C Toffalori, B Mazzi, L Chiesa, E Zino, K Fleischhauer & L Vago

  4. Department of Health Sciences, Section of Biostatistics, University of Genova, Genova, Italy

    A Signori

  5. San Raffaele Flow Cytometry Resource, Analytical Cytology Technical Applications Laboratory, IRCCS San Raffaele Scientific Institute, Milano, Italy

    F Sizzano

  6. Università ‘Vita-Salute San Raffaele’, Milano, Italy

    C Bordignon

  7. MolMed SpA, Milano, Italy

    C Bordignon

  8. Division of Immunology, Experimental Hematology Unit, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milano, Italy

    C Bonini

  9. Institute for Experimental Cellular Therapy, University of Essen, Essen, Germany

    K Fleischhauer

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  1. L Crucitti
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Corresponding author

Correspondence to F Ciceri.

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Competing interests

Professor Claudio Bordignon is an employee of MolMed SpA, Milano, Italy. Dr Chiara Bonini is a scientific consultant of MolMed SpA, Milano, Italy. The remaining authors declare no conflict of interest.

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Crucitti, L., Crocchiolo, R., Toffalori, C. et al. Incidence, risk factors and clinical outcome of leukemia relapses with loss of the mismatched HLA after partially incompatible hematopoietic stem cell transplantation. Leukemia 29, 1143–1152 (2015). https://doi.org/10.1038/leu.2014.314

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