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Stem cell transplantation

Killer cell immunoglobulin-like receptor ligand mismatching and outcome after haploidentical transplantation with post-transplant cyclophosphamide

Leukemia volume 33, pages 230–239 (2019)Cite this article

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Abstract

Haploidentical stem cell transplantation with T cell-replete grafts and post-transplant cyclophosphamide (PTCy) is increasingly used with encouraging outcome. Natural killer (NK) cell alloreactivity, predicted by missing killer cell immunoglobulin-like receptor (KIR) ligands in the recipient that are present in their donor improves outcome of T cell-depleted haploidentical transplants. We explored the role of KIR ligand mismatching in 444 acute leukemia patients after T cell-replete transplants with PTCy. Thirty-seven percent of all patients had KIR ligand mismatching. Patients were in first remission (CR1) (39%), second remission (CR2) (26%), or active disease (35%). Stem cell source was peripheral blood (PBSC, 46%) or bone marrow (54%). The 2-year relapse, non-relapse mortality (NRM), and survival rates were 36.0% (95% confidence interval (CI), 31.4–40.7), 23.9% (20.0–28.0), and 45.9% (40.8–51.0), respectively. Multivariate analysis identified acute myeloid leukemia compared with acute lymphoblastic leukemia (hazard ratio (HR) 0.55, P = 0.002), female gender (HR 0.72, P = 0.04), and good performance status (HR 0.71, P = 0.04) as factors associated with better survival, while advanced age (HR 1.13, P = 0.04), active disease (HR 3.38, P < 0.0001), and KIR ligand mismatching (HR 1.41, P = 0.03) as associated with worse survival. KIR ligand mismatching was associated with a trend for higher relapse but not with graft-versus-host disease or NRM. The KIR ligand-mismatching effect was more prominent in patients given PBSC. In conclusion, there is no evidence that KIR ligand mismatching results in better outcome in the PTCy setting.

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References

  1. Beatty PG, Clift RA, Mickelson EM, Nisperos BB, Flournoy N, Martin PJ, et al. Marrow transplantation from related donors other than HLA-identical siblings. N Engl J Med. 1985;313:765–71.

    Article  CAS  Google Scholar 

  2. Anasetti C, Amos D, Beatty PG, Appelbaum FR, Bensinger W, Buckner CD, et al. Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma. N Engl J Med. 1989;320:197–204.

    Article  CAS  Google Scholar 

  3. Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S, et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol. 2005;23:3447–54.

    Article  Google Scholar 

  4. Luznik L, O’Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:641–50.

    Article  CAS  Google Scholar 

  5. Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, et al. Treatment of acute leukemia with unmanipulated HLA-mismatched/haploidentical blood and bone marrow transplantation. Biol Blood Marrow Transplant. 2009;15:257–65.

    Article  CAS  Google Scholar 

  6. Passweg JR, Baldomero H, Bader P, Bonini C, Duarte RF, Dufour C, et al. Use of haploidentical stem cell transplantation continues to increase: the 2015 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2017;52:811–7.

    Article  CAS  Google Scholar 

  7. Mancusi A, Ruggeri L, Velardi A. Haploidentical hematopoietic transplantation for the cure of leukemia: from its biology to clinical translation. Blood. 2016;128:2616–23.

    Article  CAS  Google Scholar 

  8. Kanakry CG, Fuchs EJ, Luznik L. Modern approaches to HLA-haploidentical blood or marrow transplantation. Nat Rev Clin Oncol. 2016;13:10–24.

    Article  CAS  Google Scholar 

  9. Chang YJ, Luznik L, Fuchs EJ, Huang XJ. How do we choose the best donor for T-cell-replete, HLA-haploidentical transplantation? J Hematol Oncol. 2016;9:35.

    Article  Google Scholar 

  10. McCurdy SR, Fuchs EJ. Selecting the best haploidentical donor. Semin Hematol. 2016;53:246–51.

    Article  Google Scholar 

  11. Ciurea SO, Champlin RE. Donor selection in T cell-replete haploidentical hematopoietic stem cell transplantation: knowns, unknowns, and controversies. Biol Blood Marrow Transplant. 2013;19:180–4.

    Article  Google Scholar 

  12. Wang Y, Chang YJ, Xu LP, Liu KY, Liu DH, Zhang XH, et al. Who is the best donor for a related HLA haplotype-mismatched transplant? Blood. 2014;124:843–50.

    Article  CAS  Google Scholar 

  13. 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;295:2097–100.

    Article  CAS  Google Scholar 

  14. Ruggeri L, Mancusi A, Capanni M, Urbani E, Carotti A, Aloisi T, et al. Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood. 2007;110:433–40.

    Article  CAS  Google Scholar 

  15. Babor F, Fischer JC, Uhrberg M. The role of KIR genes and ligands in leukemia surveillance. Front Immunol. 2013;4:27.

    Article  Google Scholar 

  16. Handgretinger R, Lang P, André MC. Exploitation of natural killer cells for the treatment of acute leukemia. Blood. 2016;127:3341–9.

    Article  CAS  Google Scholar 

  17. Russo A, Oliveira G, Berglund S, Greco R, Gambacorta V, Cieri N, et al. NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: dynamics and clinical implications. Blood. 2018;131:247–62.

    Article  CAS  Google Scholar 

  18. Huang XJ, Zhao XY, Liu DH, Liu KY, Xu LP. Deleterious effects of KIR ligand incompatibility on clinical outcomes in haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion. Leukemia. 2007;21:848–51.

    Article  CAS  Google Scholar 

  19. Zhao XY, Chang YJ, Zhao XS, Xu LP, Zhang XH, Liu KY, et al. Recipient expression of ligands for donor inhibitory KIRs enhances NK cell function to control leukemic relapse after haploidentical transplantation. Eur J Immunol. 2015;45:2396–408.

    Article  CAS  Google Scholar 

  20. Zhao XY, Chang YJ, Huang XJ. Conflicting impact of alloreactive NK cells on transplantation outcomes after haploidentical transplantation: do the reconstitution kinetics of natural killer cells create these differences? Biol Blood Marrow Transplant. 2011;17:1436–42.

    Article  Google Scholar 

  21. Symons HJ, Leffell MS, Rossiter ND, Zahurak M, Jones RJ, Fuchs EJ. Improved survival with inhibitory killer immunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors after nonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol Blood Marrow Transplant. 2010;16:533–42.

    Article  Google Scholar 

  22. 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. 2009;15:1628–33.

    Article  Google Scholar 

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

    Article  Google Scholar 

  24. Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18:695–706.

    Article  CAS  Google Scholar 

  25. Ciurea SO, Zhang MJ, Bacigalupo AA, Bashey A, Appelbaum FR, Aljitawi OS, et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015;126:1033–40.

    Article  CAS  Google Scholar 

  26. Bashey A, Zhang X, Sizemore CA, Manion K, Brown S, Holland HK, et al. T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation. J Clin Oncol. 2013;31:1310–6.

    Article  CAS  Google Scholar 

  27. Di Stasi A, Milton DR, Poon LM, Hamdi A, Rondon G, Chen J, et al. Similar transplantation outcomes for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors. Biol Blood Marrow Transplant. 2014;20:1975–81.

    Article  Google Scholar 

  28. Piemontese S, Ciceri F, Labopin M, Arcese W, Kyrcz-Krzemien S, Santarone S, et al. A comparison between allogeneic stem cell transplantation from unmanipulated haploidentical and unrelated donors in acute leukemia. J Hematol Oncol. 2017;10:24.

    Article  Google Scholar 

  29. Kasamon YL, Luznik L, Leffell MS, Kowalski J, Tsai HL, Bolaños-Meade J, et al. Nonmyeloablative HLA-haploidentical bone marrow transplantation with high-dose posttransplantation cyclophosphamide: effect of HLA disparity on outcome. Biol Blood Marrow Transplant. 2010;16:482–9.

    Article  CAS  Google Scholar 

  30. Lorentino F, Labopin M, Fleischhauer K, Ciceri F, Mueller CR, Ruggeri A, et al. The impact of HLA matching on outcomes of unmanipulated haploidentical HSCT is modulated by GVHD prophylaxis. Blood Adv. 2017;1:669–80.

    Article  CAS  Google Scholar 

  31. Mancusi A, Ruggeri L, Urbani E, Pierini A, Massei MS, Carotti A, et al. Haploidentical hematopoietic transplantation from KIR ligand-mismatched donors with activating KIRs reduces non-relapse mortality. Blood. 2015;125:3173–82.

    Article  CAS  Google Scholar 

  32. Bishara A, De Santis D, Witt CC, Brautbar C, Christiansen FT, Or R, et al. The beneficial role of inhibitory KIR genes of HLA class I NK epitopes in haploidentically mismatched stem cell allografts may be masked by residual donor-alloreactive T cells causing GVHD. Tissue Antigens. 2004;63:204–11.

    Article  CAS  Google Scholar 

  33. Cooley S, McCullar V, Wangen R, Bergemann TL, Spellman S, Weisdorf DJ, et al. KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation. Blood. 2005;106:4370–6.

    Article  CAS  Google Scholar 

  34. Haas P, Loiseau P, Tamouza R, Cayuela JM, Moins-Teisserenc H, Busson M, et al. NK cell education is shaped by donor HLA genotype after unrelated allogeneic hematopoietic stem cell transplantation. Blood. 2011;117:1021–9.

    Article  CAS  Google Scholar 

  35. Kanakry CG, Ganguly S, Luznik L. Situational aldehyde dehydrogenase expression by regulatory T cells may explain the contextual duality of cyclophosphamide as both a pro-inflammatory and tolerogenic agent. Oncoimmunology. 2015;4:e974393.

    Article  Google Scholar 

  36. Verneris MR. Natural killer cells and regulatory T cells: how to manipulate a graft for optimal GVL. Hematology Am Soc Hematol Educ Program 2013; 335–41.

  37. Santoro N, Ruggeri A, Labopin M, Bacigalupo A, Ciceri F, Gülbaş Z, et al. Unmanipulated haploidentical stem cell transplantation in adults with acute lymphoblastic leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT. J Hematol Oncol. 2017;10:113.

    Article  Google Scholar 

Download references

Acknowledgements

We would like to thank all investigators and data managers in the EBMT participating centers for their dedicated patient care.

Author information

Authors and Affiliations

  1. Division of Hematology, Chaim Sheba Medical Center, Tel-Hashomer and Sackler Medical School, Tel-Aviv University, Tel-Aviv, Israel

    Avichai Shimoni & Arnon Nagler

  2. Acute Leukemia Working Party Office, Paris, France

    Myriam Labopin & Arnon Nagler

  3. Hematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, Milan, Italy

    Francesca Lorentino & Fabio Ciceri

  4. Department of Haematology II, Ospedale San Martino, Genova, Italy

    Maria Teresa Van Lint

  5. Stem Cell Transplant Unit, Medical Park Hospitals, Antalya, Turkey

    Yener Koc

  6. Bone Marrow Transplantation Department, Anadolu Medical Center Hospital, Kocaeli, Turkey

    Zafer Gülbas

  7. Department of Internal Medicine III, LMU Munich Campus Grosshadern, Munich, Germany

    Johanna Tischer

  8. S.S.C.V.D. Trapianto di Cellule Staminali A.O.U. Citta della Salute e della Scienza di Torino, Torino, Italy

    Benedetto Bruno

  9. Programme de Transplantation and Therapie Cellulaire, Centre de Recherche en Cancérologie de Marseille, Institut Paoli Calmettes, Marseille, France

    Didier Blaise

  10. Ospedale San Gerardo, Clinica Ematologica dell’Universita Milano-Biocca, Monza, Italy

    Pietro Pioltelli

  11. First State Pavlov Medical University of St. Petersburg, Raisa Gorbacheva Memorial Research, Institute for Paediatric Oncology, Hematology and Transplantation, St Petersburg, Russia

    Boris Afanasyev

  12. Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, Paris, France

    Mohamad Mohty

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  1. Avichai Shimoni
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Correspondence to Avichai Shimoni.

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Shimoni, A., Labopin, M., Lorentino, F. et al. Killer cell immunoglobulin-like receptor ligand mismatching and outcome after haploidentical transplantation with post-transplant cyclophosphamide. Leukemia 33, 230–239 (2019). https://doi.org/10.1038/s41375-018-0170-5

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