High prevalence of CD3, NK, and NKT cells in the graft predicts adverse outcome after matched-related and unrelated transplantations with post transplantation cyclophosphamide

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Abstract

The predictive value of graft composition and plasma biomarkers on the outcome of allogeneic HSCT is well known for conventional GVHD prophylaxis based on calcineurin inhibitors with or without antithymocyte globulin. Currently, there is limited data whether these results could be translated to post transplantation cyclophosphamide (PTCy). The prospective extension cohort of NCT02294552 trial enrolled 79 adult patients with acute leukemia in CR. Twenty-six received matched-related bone marrow (BM) grafts with single-agent PTCy and 53 received unrelated peripheral blood stem cell graft (PBSC) with PTCy, tacrolimus, and MMF. The grafts were studied by the flow cytometry, and plasma samples were analyzed by ELISA. In the cluster and major component analysis, we determined that transplantation from donors with high content of CD3, NKT, and CD16-CD56 + subpopulations in the PBSC grafts was associated with poor immunological recovery and compromised event-free survival (50% vs. 80%, HR 2.93, p = 0.015) both due to increased relapse incidence and non-relapse mortality. The significant independent predictor of moderate and severe chronic GVHD was the high prevalence of and iNKT, Vβ11, and double-positive cells in the PBSC grafts from young donors (HR 2.75, p = 0.0483). No patterns could be identified for BM grafts and for plasma biomarkers.

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References

  1. 1.

    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.

  2. 2.

    Raiola AM, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F, et al. Unmanipulated haploidentical bone marrow transplantation and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning. Biol Blood Marrow Transplant. 2013;19:117–22.

  3. 3.

    Ruggeri A, Labopin M, Bacigalupo A, Afanasyev B, Cornelissen JJ, Elmaagacli A, et al. Post-transplant cyclophosphamide for graft-versus-host disease prophylaxis in HLA matched sibling or matched unrelated donor transplant for patients with acute leukemia, on behalf of ALWP-EBMT. J Hematol Oncol. 2018;11:40.

  4. 4.

    Luznik L, Bolaños-Meade J, Zahurak M, Chen AR, Smith BD, et al. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood. 2010;115:3224–30.

  5. 5.

    Mielcarek M, Furlong T, O’Donnell PV, Storer BE, McCune JS, Storb R, et al. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood. 2016;127:1502–8.

  6. 6.

    Kanakry CG, O’Donnell PV, Furlong T, de Lima MJ, Wei W, Medeot M, et al. Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol. 2014;32:3497–505.

  7. 7.

    Kanakry CG, Bolaños-Meade J, Kasamon YL, Zahurak M, Durakovic N, Furlong T, et al. Low immunosuppressive burden after HLA-matched related or unrelated BMT using posttransplantation cyclophosphamide. Blood. 2017;129:1389–93.

  8. 8.

    Moiseev IS, Pirogova OV, Babenko EV, Gindina TL, Darskaya EI, Morozova EV, et al. Single-agent post-transplantation cyclophosphamide versus calcineurin-based graft-versus-host disease prophylaxis in matched related bone marrow transplantation. Cell Ther Transplant (CTT). 2017;6:52–9.

  9. 9.

    Mehta RS, Saliba RM, Chen J, Rondon G, Hammerstrom AE, Alousi A, et al. Post-transplantation cyclophosphamide versus conventional graft-versus-host disease prophylaxis in mismatched unrelated donor haematopoietic cell transplantation. Br J Haematol. 2016;173:444–55.

  10. 10.

    Roscoe RA, Rybka WB, Winkelstein A, Houston AM, Kiss JE. Enumeration of CD34+ hematopoietic stem cells for reconstitution following myeloablative therapy. Cytometry. 1994;16:74–9.

  11. 11.

    Saad A, Lamb L, Wang T, Hemmer MT, Spellman S, Couriel D, et al. Impact of T-cell dose on the outcome of T-cell replete HLA matched allogeneic peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2019;S1083-8791:30291–5. https://doi.org/10.1016/j.bbmt.2019.05.007.

  12. 12.

    Waller EK, Logan BR, Harris WA, Devine SM, Porter DL, Mineishi S, et al. Improved survival after transplantation of more donor plasmacytoid dendritic or naïve T cells from unrelated-donor marrow grafts: results from BMTCTN 0201. J Clin Oncol. 2014;32:2365–72.

  13. 13.

    Reshef R, Huffman AP, Gao A, Luskin MR, Frey NV, Gill SI, et al. High graft CD8 cell dose predicts improved survival and enables better donor selection in allogeneic stem-cell transplantation with reduced-intensity conditioning. J Clin Oncol. 2015;33:2392–8.

  14. 14.

    Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003;9:1144–50.

  15. 15.

    Locatelli F, Bauquet A, Palumbo G, Moretta F, Bertaina A. Negative depletion of α/β+ T cells and of CD19+ B lymphocytes: a novel frontier to optimize the effect of innate immunity in HLA-mismatched hematopoietic stem cell transplantation. Immunol Lett. 2013;155:21–3.

  16. 16.

    DiRienzo CG, Murphy GF, Friedman TM, Korngold R. T-cell receptor V(alpha) usage by effector CD4+Vbeta11+ T cells mediating graft-versus-host disease directed to minor histocompatibility antigens. Biol Blood Marrow Transplant. 2007;13:265–76.

  17. 17.

    Malard F, Labopin M, Chevallier P, Guillaume T, Duquesne A, Rialland F, et al. Larger number of invariant natural killer T cells in PBSC allografts correlates with improved GVHD-free and progression-free survival. Blood. 2016;127:1828–35.

  18. 18.

    Panse JP, Heimfeld S, Guthrie KA, Maris MB, Maloney DG, Baril BB, et al. Allogeneic peripheral blood stem cell graft composition affects early T-cell chimaerism and later clinical outcomes after non-myeloablative conditioning. Br J Haematol. 2005;128:659–67.

  19. 19.

    Vela-Ojeda J, García-Ruiz Esparza MA, Reyes-Maldonado E, Jiménez-Zamudio L, García-Latorre E, Moreno-Lafont M, et al. Clinical relevance of NK, NKT, and dendritic cell dose in patients receiving G-CSF-mobilized peripheral blood allogeneic stem cell transplantation. Ann Hematol. 2006;85:113–20.

  20. 20.

    Luznik L, O’Donnell PV, Fuchs EJ. Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol. 2012;39:683–93.

  21. 21.

    Mussetti A, De Philippis C, Carniti C, Bastos-Oreiro M, Gayoso J, Cieri N, et al. CD3+ graft cell count influence on chronic GVHD in haploidentical allogeneic transplantation using post-transplant cyclophosphamide. Bone Marrow Transplant. 2018;53:1522–31.

  22. 22.

    Pirogova OV, Moiseev IS, Surkova EA, Lapin SV, Bondarenko SN, Kulagin AD, et al. Profiles of pro-inflammatory cytokines in allogenic stem cell transplantation with post-transplant cyclophosphamide. Cytokine. 2017;99:148–53.

  23. 23.

    Admiraal R, Nierkens S, de Witte MA, Petersen EJ, Fleurke GJ, Verrest L, et al. Association between anti-thymocyte globulin exposure and survival outcomes in adult unrelated haemopoietic cell transplantation: a multicentre, retrospective, pharmacodynamic cohort analysis. Lancet Haematol. 2017;4:e201.

  24. 24.

    Paczesny S, Krijanovski OI, Braun TM, Choi SW, Clouthier SG, Kuick R, et al. A biomarker panel for acute graft-versus-host disease. Blood. 2009;113:273–8.

  25. 25.

    Vander Lugt MT, Braun TM, Hanash S, Ritz J, Ho VT, Antin JH, et al. ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. N Engl J Med. 2013;369:529–39.

  26. 26.

    Berger M, Signorino E, Muraro M, Quarello P, Biasin E, Nesi F, et al. Monitoring of TNFR1, IL-2Rα, HGF, CCL8, IL-8 and IL-12p70 following HSCT and their role as GVHD biomarkers in paediatric patients. Bone Marrow Transplant. 2013;48:1230–6.

  27. 27.

    Levine JE, Braun TM, Harris AC, Holler E, Taylor A, Miller H, et al. Blood and marrow transplant clinical trials network. A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study. Lancet Haematol. 2015;2:e21–9.

  28. 28.

    Moiseev IS, Pirogova OV, Alyanski AL, Babenko EV, Gindina TL, Darskaya EI, et al. Risk-adapted GVHD prophylaxis with post-transplantation cyclophosphamide in adults after related, unrelated, and haploidentical transplantations. Eur J Haematol. 2018;100:395–402.

  29. 29.

    Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–8.

  30. 30.

    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.

  31. 31.

    Wing K, Fung, Hong Gu, Liming X, et al. Assessing local influence in principal component analysiswith application to haematology study data. Stat Med. 2007;26:2730–44. https://doi.org/10.1002/sim.2747

  32. 32.

    Joseph FH, Rolph AE, Ronald LT, William CB. Multivariate data analysis, 5th ed. Pearson Education; 2003.

  33. 33.

    Santagostino A, Garbaccio G, Pistorio A, Bolis V, Camisasca G, Pagliaro P, et al. An Italian national multicenter study for the definition of reference ranges for normal values of peripheral blood lymphocyte subsets in healthy adults. Haematologica. 1999;84:499–504.

  34. 34.

    Forman SJ, Rowe JM. The myth of the second remission of acute leukemia in the adult. Blood. 2013;121:1077–82.

  35. 35.

    Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007;21:1387–94.

  36. 36.

    Klyuchnikov E, Asenova S, Kern W, Kilinc G, Ayuk F, Wiedemann B, et al. Post-transplant immune reconstitution after unrelated allogeneic stem cell transplant in patients with acute myeloid leukemia. Leuk Lymphoma. 2010;51:1450–63.

  37. 37.

    Bartelink IH, Belitser SV, Knibbe CA, Danhof M, de Pagter AJ, Egberts TC, et al. Immune reconstitution kinetics as an early predictor for mortality using various hematopoietic stem cell sources in children. Biol Blood Marrow Transplant. 2013;19:305–13.

  38. 38.

    Cutolo М, Sulli A, Pizzorni C. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis. 2001;60:729–35.

  39. 39.

    Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. 2000;47:85–118.

  40. 40.

    Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology. 2000;47:119–25.

  41. 41.

    Alter G, Teigen N, Davis BT, Addo MM, Suscovich TJ, Waring MT et al. Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection. Blood. 2005;106:3366–9.

  42. 42.

    Forconi CS, Cosgrove CP, Saikumar-Lakshmi P, Nixon CE, Foley J, Ong'echa JM et al. Poorly cytotoxic terminally differentiated CD56negCD16pos NK cells accumulate in Kenyan children with Burkitt lymphomas. Blood Adv. 2018;2:1101–14.

  43. 43.

    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;131:247–262.

  44. 44.

    Ferrara J, Deeg H, Cooke K, Ferrara J, Cooke K, Deeg H (eds.). Graft vs. host disease. Boca Raton: CRC Press;2004.

  45. 45.

    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.

  46. 46.

    Kanakry CG, Coffey DG, Towlerton AM, Vulic A, Storer BE, Chou J, et al. Origin and evolution of the T cell repertoire after posttransplantation cyclophosphamide. JCI Insight. 2016;1:e86252. epub Apr 21 2016

  47. 47.

    Kanakry CG, Bakoyannis G, Perkins SM, McCurdy SR, Vulic A, Warren EH, et al. Plasma-derived proteomic biomarkers in human leukocyte antigen-haploidentical or human leukocyte antigen-matched bone marrow transplantation using post-transplantation cyclophosphamide. Haematologica. 2017;102:932–40.

  48. 48.

    Nascimbeni M, Shin EC, Chiriboga L, Kleiner DE, Rehermann B. Peripheral CD4(+)CD8(+) T cells are differentiated effector memory cells with antiviral functions. Blood. 2004;104:478–86.

  49. 49.

    Quandt D, Rothe K, Scholz R, Baerwald CW, Wagner U. Peripheral CD4CD8 double positive T cells with a distinct helper cytokine profile are increased in rheumatoid arthritis. PLoS ONE. 2014;9:e93293.

  50. 50.

    van der Vliet HJ, von Blomberg BM, Nishi N, Reijm M, Voskuyl AE, van Bodegraven AA, et al. Circulating V(alpha24+) Vbeta11+ NKT cell numbers are decreased in a wide variety of diseases that are characterized by autoreactive tissue damage. Clin Immunol. 2001;100:144–8.

  51. 51.

    Smith E, Croca S, Waddington KE, Sofat R, Griffin M, Nicolaides A, et al. Cross-talk between iNKT cells and monocytes triggers an atheroprotective immune response in SLE patients with asymptomatic plaque. Sci Immunol. 2016;1:eaah4081.

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Acknowledgements

The study was supported by the RFBR grant 16–34–60142 mol_а_dk and RSF grant №17–75–20145. We express our deep gratitude to the unrelated donor registries’ employees who provided the extended information about the unrelated donors: Tigran Torosian and Jan Markert from DKMS, Andreas Heu from Stefan Morsch Stiftung, Malisheva Natalia from Kirov registry, and Marina Teterina from Saint-Petersburg registry. We thank Valerii Beklenischev for performing the biobanking and handling of the frozen samples and our nurses for the collection of the samples.

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Correspondence to Ivan S. Moiseev.

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