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Selective T-cell depletion targeting CD45RA as a novel approach for HLA-mismatched hematopoietic stem cell transplantation in pediatric nonmalignant hematological diseases

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Abstract

Severe aplastic anemia and congenital amegakaryocytic thrombocytopenia are rare bone marrow failure syndromes. Treatment for aplastic anemia consists of hematopoietic stem cell transplantation (HSCT) from a matched sibling donor or immunosuppressant drugs if there is no donor available. Congenital amegakaryocytic thrombocytopenia is a rare autosomal recessive disease that causes bone marrow failure and has limited treatment options, except for transfusion support and HSCT. In the absence of a suitable matched sibling donor, matched-unrelated, haploidentical, or mismatched donors may be considered. A 2-step partial T-cell-depletion strategy can remove CD45RA+ naïve T cells responsible for graft-versus-host disease (GvHD) while preserving memory T cells. Five patients underwent transplantation using this strategy with rapid neutrophil and platelet recovery. Acute and chronic GvHD ≥ grade 2 appeared in two and one patient, respectively. No severe infections were observed before day + 100. A high (60%) incidence of transplant-associated microangiopathy was observed. Three patients (60%) remain alive, with a median follow-up of 881 (range 323–1248) days. CD45RA-depleted HSCT is a novel approach for patients lacking a suitable matched donor; however, further improvements are needed.

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References

  1. Barone A, Lucarelli A, Onofrillo D, Verzegnassi F, Bonanomi S, Cesaro S, et al. Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP). Blood Cells Mol Dis. 2015;55(1):40–7.

    Article  Google Scholar 

  2. Geddis A. Congenital amegakaryocytic thrombocytopenia and thrombocytopenia with absent radii. Hem Oncol Clin North Am. 2009;23(2):321–31.

    Article  Google Scholar 

  3. Lackner A, Basu O, Bierings M, Lassay L, Schaefer U, Revesz T, et al. Haematopoietic stem cell transplantation for amegakaryocytic thrombocytopenia. Br J Haematol. 2000;109(4):773–5.

    Article  CAS  Google Scholar 

  4. Dietz A, Lucchini G, Samarasinghe S, Pulsipher M. Evolving hematopoietic stem cell transplantation strategies in severe aplastic anemia. Curr Opin Pediatr. 2016;28(1):3–11.

    Article  CAS  Google Scholar 

  5. Kumar R, Bonfim C, George B. Hematopoietic cell transplantation for aplastic anemia. Curr Opin Hematol. 2017;24(6):509–14.

    Article  Google Scholar 

  6. de Latour RP. Transplantation for bone marrow failure: current issues. Hematol Am Soc Hematol Educ Program. 2016;2016(1):90–8.

    Article  Google Scholar 

  7. Prata PH, Elkema D, Afansyev B, Bosman P, Smiers F, Diez-Martin JL, et al. Haploidentical transplantation and posttransplant cyclophosphamide for treating aplastic anemia patients: a report from the EBMT Severe Aplastic Anemia Working Party. Bone Marrow Transpl. 2019;55(6):1050–8.

    Article  Google Scholar 

  8. Lacerda J, Martins C, Carmo J, Lourenço F, Juncal C, Ismail S, et al. Haploidentical stem cell transplantation with purified CD34+ cells after a chemotherapy-alone conditioning regimen in heavily transfused severe aplastic anemia. Biol Blood Marrow Transpl. 2005;11(5):399–400.

    Article  CAS  Google Scholar 

  9. Bertaina A, Merli P, Rutella S, Pagliara D, Bernardo M, Masetti R, et al. HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders. Blood. 2014;124(5):822–6.

    Article  CAS  Google Scholar 

  10. Bleakley M, Heimfeld S, Loeb K, Jones L, Chaney C, Seropian S, et al. Outcomes of acute leukemia patients transplanted with naive T cell–depleted stem cell grafts. J Clin Invest. 2015;125(7):2677–89.

    Article  Google Scholar 

  11. Sisinni L, Gasior M, de Paz R, Querol S, Bueno D, Fernández L, et al. Unexpected high incidence of human herpesvirus-6 encephalitis after Naive T cell-depleted graft of haploidentical stem cell transplantation in pediatric patients. Biol Blood Marrow Transpl. 2018;24(11):2316–23.

    Article  Google Scholar 

  12. Glucksberg H, Storb R, Fefer A, Buckner C, Neiman P, Clift R, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors. Transplantation. 1974;18(4):295–304.

    Article  CAS  Google Scholar 

  13. Harris A, Young R, Devine S, Hogan W, Ayuk F, Bunworasate U, et al. International, multicenter standardization of acute graft-versus-host disease clinical data collection: a report from the mount sinai acute GVHD International Consortium. Biol Blood Marrow Transpl. 2016;22(1):4–10.

    Article  Google Scholar 

  14. Jagasia MH, Greinix H, Arora M, Hogan W, Ayuk F, Bunworasate U, et al. National Institutes of Health Consensus Development Project on Criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 diagnosis and staging working group report. Biol Blood Marrow Transpl. 2015;21(3):389-401.e1.

    Article  Google Scholar 

  15. Gadalla S, Cawthon R, Giri N, Alter B, Savage S. Telomere length in blood, buccal cells, and fibroblasts from patients with inherited bone marrow failure syndromes. Aging (Albany NY). 2010;2(11):867–74.

    Article  Google Scholar 

  16. Arias-Salgado EG, Galvez E, Planas-Cerezales L, Pintado-Berninchez L, Vallespin E, Martínez P, et al. Genetic analyses of aplastic anemia and idiopathic pulmonary fibrosis patients with short telomeres, possible implication of DNA-repair genes. Orphanet J Rare Dis. 2019;14(1):82.

    Article  Google Scholar 

  17. Dezern AE, Zahurak M, Symons H, Cooke K, Jones RJ, Brodsky RA. Alternative donor transplantation with high-dose post-transplantation cyclophosphamide for refractory severe aplastic anemia. Biol Blood Marrow Transpl. 2017;23(3):498–504.

    Article  CAS  Google Scholar 

  18. Esteves I, Bonfim C, Pasquini R, Funke V, Pereira N, Rocha V, et al. Haploidentical BMT and post-transplant Cy for severe aplastic anemia: a multicenter retrospective study. Bone Marrow Transpl. 2015;50(5):685–9.

    Article  CAS  Google Scholar 

  19. Xu LP, Zhang XH, Wang FR, Mo X, Han T, Han W, et al. Haploidentical transplantation for pediatric patients with acquired severe aplastic anemia. Bone Marrow Transpl. 2016;52(3):381–7.

    Article  Google Scholar 

  20. Arpacı F, Tezcan I, Kuzhan O, Yalman N, Uçkan D, Kürekçi A, et al. G-CSF-mobilized haploidentical peripheral blood stem cell transplantation in children with poor prognostic nonmalignant disorders. Am J Hematol. 2008;83(2):133–6.

    Article  Google Scholar 

  21. Im HJ, Koh K-N, Seo J. Haploidentical hematopoietic stem cell transplantation in children and adolescents with acquired severe aplastic anemia. Korean J Pediatr. 2015;58(6):199.

    Article  Google Scholar 

  22. Jodele S, Davies SM, Lane A, Khoury J, Dandoy C, Goebel J, et al. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014;124(4):645–53.

    Article  CAS  Google Scholar 

  23. Sanz J, Moscardó F, Montoro J, Cano J, Guerreiro M, Dasi MA, et al. Partial T cell-depleted peripheral blood stem cell transplantation from HLA-identical sibling donors for patients with severe aplastic anemia. Biol Blood Marrow Transpl. 2020;26(1):83–7.

    Article  CAS  Google Scholar 

  24. Dvorak CC, Higham C, Shimano KA. Transplant-associated thrombotic microangiopathy in pediatric hematopoietic cell transplant recipients: a practical approach to diagnosis and management. Front Pediatr. 2019;7:133.

    Article  Google Scholar 

  25. Maschan M, Blagov S, Shelikhova L, Shekhovtsova Z, Balashov D, Starichkova J, et al. Low-dose donor memory T-cell infusion after TCR alpha/beta depleted unrelated and haploidentical transplantation: results of a pilot trial. Bone Marrow Transpl. 2017;53(3):264–73.

    Article  Google Scholar 

  26. Mamcarz E, Madden R, Qudeimat A, Srinivasan A, Talleur A, Sharma A, et al. Improved survival rate in T-cell depleted haploidentical hematopoietic cell transplantation over the last 15 years at a single institution. Bone Marrow Transpl. 2019;55(5):929–38.

    Article  Google Scholar 

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Funding

This work was supported in part by the National Health Service of Spain, Instituto de Salud Carlos III (ISCIII), FONDOS FEDER Grant (FIS) PI18/01301 and the CRIS Cancer Foundation (http://criscancer.org).

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Authors and Affiliations

  1. Hematology Department, La Paz University Hospital, Paseo De La Castellana 261, 28046, Madrid, Spain

    Mercedes Gasior Kabat, Raquel De Paz, Antonio Marcos, Ana Belén Romero, Aida Constanzo & Víctor Jiménez-Yuste

  2. Pediatric Onco-Hematology Department, La Paz University Hospital, Madrid, Spain

    David Bueno, Luisa Sisinni, Yasmina Mozo, Blanca Rosich & Antonio Pérez-Martínez

  3. Foundation for Biomedical Research CSIC/UAM, IDIPaz, CIBER on Rare Diseases, La Paz University Hospital, Madrid, Spain

    Rosario Perona & Elena G. Arias-Salgado

Authors
  1. Mercedes Gasior Kabat
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  2. David Bueno
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  3. Luisa Sisinni
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  4. Raquel De Paz
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  5. Yasmina Mozo
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  6. Rosario Perona
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  7. Elena G. Arias-Salgado
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  8. Blanca Rosich
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  9. Antonio Marcos
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  10. Ana Belén Romero
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  11. Aida Constanzo
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  12. Víctor Jiménez-Yuste
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  13. Antonio Pérez-Martínez
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Correspondence to Mercedes Gasior Kabat.

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Gasior Kabat, M., Bueno, D., Sisinni, L. et al. Selective T-cell depletion targeting CD45RA as a novel approach for HLA-mismatched hematopoietic stem cell transplantation in pediatric nonmalignant hematological diseases. Int J Hematol 114, 116–123 (2021). https://doi.org/10.1007/s12185-021-03138-2

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  • DOI: https://doi.org/10.1007/s12185-021-03138-2

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