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Haploidentical CD3 or α/β T-cell depleted HSCT in advanced stage sickle cell disease

Bone Marrow Transplantation volume 54, pages 1859–1867 (2019)Cite this article

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Abstract

Despite significant improvements in the supportive care, sickle cell disease (SCD) leads to significant morbidity and mortality. Allogeneic hematopoietic stem cell transplantation (HSCT), the only curative option, is limited due to matched donor availability. This could be met with T-cell-depleted haploidentical HSCT. Twenty advanced-stage SCD patients, median age 15 years, and 9 patients, median age 14 years, were transplanted with CD3/CD19- or TCRαβ/CD19-depleted grafts and from matched sibling donors (MSDs). The conditioning consisted of ATG, thiotepa, fludarabine, and treosulfan. The median follow-up in the T-haplo-HSCT and the MSD patients was 21 (9–62) and 25 (7–60) months, respectively. The OS in the T-haplo-HSCT and MSD was 90% and 100%, respectively. In the T-haplo-HSCT group, two patient succumbed to a CMV pneumonitis and a macrophage activation syndrome (MAS). One patient in the T-haplo-HSCT group requires renal replacement therapy because of BK virus nephritis. None developed grade III–IV acute GvHD. In the T-haplo-HSCT and in the MSD, 20% and 22%, respectively, developed a mild or moderate chronic GvHD. These results demonstrate the feasibility, safety, and efficacy of T-haplo-HSCT also for adult advanced stage SCD patients.

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References

  1. Gluckman E. Allogeneic transplantation strategies including haploidentical transplantation in sickle cell disease. Hematol Am Soc Hematol Educ Program. 2013;2013:370–6. https://doi.org/10.1182/asheducation-2013.1.370

    Article  Google Scholar 

  2. Ballas SK. Self-management of sickle cell disease: a new frontier. J Natl Med Assoc. 2010;102:1042–3.

    Article  PubMed  Google Scholar 

  3. Bernaudin F, Socie G, Kuentz M, Chevret S, Duval M, Bertrand Y, et al. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007;110:2749–56. https://doi.org/10.1182/blood-2007-03-079665.

    Article  CAS  PubMed  Google Scholar 

  4. Gluckman E, Cappelli B, Bernaudin F, Labopin M, Volt F, Carreras J, et al. Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation. Blood. 2017;129:1548–56. https://doi.org/10.1182/blood-2016-10-745711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Walters MC, Patience M, Leisenring W, Eckman JR, Scott JP, Mentzer WC, et al. Bone marrow transplantation for sickle cell disease. New Engl J Med. 1996;335:369–76. https://doi.org/10.1056/NEJM199608083350601.

    Article  CAS  PubMed  Google Scholar 

  6. Justus D, Perez-Albuerne E, Dioguardi J, Jacobsohn D, Abraham A. Allogeneic donor availability for hematopoietic stem cell transplantation in children with sickle cell disease. Pedia Blood Cancer. 2015;62:1285–7. https://doi.org/10.1002/pbc.25439

    Article  CAS  Google Scholar 

  7. Gragert L, Eapen M, Williams E, Freeman J, Spellman S, Baitty R, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med. 2014;371:339–48. https://doi.org/10.1056/NEJMsa1311707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shenoy S, Eapen M, Panepinto JA, Logan BR, Wu J, Abraham A, et al. A trial of unrelated donor marrow transplantation for children with severe sickle cell disease. Blood. 2016;128:2561–7. https://doi.org/10.1182/blood-2016-05-715870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gladstone DE, Zachary A, Fuchs EJ. De-sensitization for mismatched hematopoietic stem cell transplantation (HSCT). Blood. 2011;118:1955.

    Article  Google Scholar 

  10. Bertaina A, Merli P, Rutella S, Pagliara D, Bernardo ME, Masetti R, et al. HLA-haploidentical stem cell transplantation after removal of alphabeta + T and B cells in children with nonmalignant disorders. Blood. 2014;124:822–6. https://doi.org/10.1182/blood-2014-03-563817

    Article  CAS  PubMed  Google Scholar 

  11. Lang P, Teltschik HM, Feuchtinger T, Muller I, Pfeiffer M, Schumm M, et al. Transplantation of CD3/CD19 depleted allografts from haploidentical family donors in paediatric leukaemia. Br J Haematol. 2014;165:688–98. https://doi.org/10.1111/bjh.12810

    Article  CAS  PubMed  Google Scholar 

  12. de la Fuente J, Dhedin N, Koyama T, Bernaudin F, Kuentz M, Karnik L, et al. Haploidentical bone marrow transplant with post-transplant cyclophosphamide plus thiotepa improves donor engraftment in patients with sickle cell anemia: results of an international learning collaborative. Biol Blood Marrow Transplant. 2018. https://doi.org/10.1016/j.bbmt.2018.11.027

    Article  PubMed  Google Scholar 

  13. Saraf SL, Oh AL, Patel PR, Sweiss K, Koshy M, Campbell-Lee S, et al. Haploidentical peripheral blood stem cell transplantation demonstrates stable engraftment in adults with sickle cell disease. Biol Blood Marrow Transplant. 2018;24:1759–65. https://doi.org/10.1016/j.bbmt.2018.03.031

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bolanos-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ, et al. HLA-haploidentical bone marrow transplantation with post-transplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood. 2012. https://doi.org/10.1182/blood-2012-07-438408.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Schumm M, Lang P, Bethge W, Faul C, Feuchtinger T, Pfeiffer M, et al. Depletion of T-cell receptor alpha/beta and CD19 positive cells from apheresis products with the CliniMACS device. Cytotherapy. 2013;15:1253–8. https://doi.org/10.1016/j.jcyt.2013.05.014

    Article  CAS  PubMed  Google Scholar 

  16. Stahl T, Bohme MU, Kroger N, Fehse B. Digital PCR to assess hematopoietic chimerism after allogeneic stem cell transplantation. Exp Hematol. 2015;43:462–8 e461. https://doi.org/10.1016/j.exphem.2015.02.006

    Article  CAS  PubMed  Google Scholar 

  17. Payne AB, Mehal JM, Chapman C, Haberling DL, Richardson LC, Bean CJ, et al. Mortality trends and causes of death in persons with sickle cell disease in the United States, 1979-2014. Blood. 2017;130(Suppl 1):865–865.

    Google Scholar 

  18. Lanzkron S, Carroll CP, Haywood C Jr. Mortality rates and age at death from sickle cell disease: U.S., 1979-2005. Public Health Rep. 2013;128:110–6.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330:1639–44. https://doi.org/10.1056/NEJM199406093302303

    Article  CAS  PubMed  Google Scholar 

  20. Quinn CT, Rogers ZR, McCavit TL, Buchanan GR. Improved survival of children and adolescents with sickle cell disease. Blood. 2010;115:3447–52. https://doi.org/10.1182/blood-2009-07-233700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Switzer GE, Bruce JG, Myaskovsky L, DiMartini A, Shellmer D, Confer DL, et al. Race and ethnicity in decisions about unrelated hematopoietic stem cell donation. Blood. 2013;121:1469–76. https://doi.org/10.1182/blood-2012-06-437343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Peters C, Schrappe M, von Stackelberg A, Schrauder A, Bader P, Ebell W, et al. Stem-cell transplantation in children with acute lymphoblastic leukemia: a prospective international multicenter trial comparing sibling donors with matched unrelated donors-The ALL-SCT-BFM-2003 trial. J Clin Oncol. 2015;33:1265–74. https://doi.org/10.1200/JCO.2014.58.9747

    Article  CAS  PubMed  Google Scholar 

  23. Cappelli B, Scigliuolo GM, Volt F, Corbacioglu S, de la Fuente J, Dhedin N, et al. Alternative donor hematopoietic stem cell transplantation for sickle cell disease in Europe. Blood. 2018;132(Suppl 1):4645–4645. https://doi.org/10.1182/blood-2018-99-111129

    Article  Google Scholar 

  24. Luznik L, Fuchs EJ. High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res. 2010;47:65–77. https://doi.org/10.1007/s12026-009-8139-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Anurathapan U, Hongeng S, Pakakasama S, Sirachainan N, Songdej D, Chuansumrit A, et al. Hematopoietic stem cell transplantation for homozygous beta-thalassemia and beta-thalassemia/hemoglobin E patients from haploidentical donors. Bone Marrow Transplant. 2016;51:813–8. https://doi.org/10.1038/bmt.2016.7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Katewa S, Kharya G, Karnik L, Kassim AA, de la Fuente J. Pre-transplantation suppression of haemopoiesis is associated with a high rate of macrophage activation syndrome in Ptcy haploidentical transplantation for haemoglobinopathies. Blood. 2017;130(Suppl 1):1931–1931.

    Google Scholar 

  27. Dallas MH, Triplett B, Shook DR, Hartford C, Srinivasan A, Laver J, et al. Long-term outcome and evaluation of organ function in pediatric patients undergoing haploidentical and matched related hematopoietic cell transplantation for sickle cell disease. Biol Blood Marrow Transplant. 2013;19:820–30. https://doi.org/10.1016/j.bbmt.2013.02.010.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Oevermann L, Lang P, Feuchtinger T, Schumm M, Teltschik HM, Schlegel P, et al. Immune reconstitution and strategies for rebuilding the immune system after haploidentical stem cell transplantation. Ann N Y Acad Sci. 2012;1266:161–70. https://doi.org/10.1111/j.1749-6632.2012.06606.x

    Article  CAS  PubMed  Google Scholar 

  29. Gaziev J, Isgro A, Sodani P, Paciaroni K, De Angelis G, Marziali M, et al. Haploidentical HSCT for hemoglobinopathies: improved outcomes with TCRalphabeta( + )/CD19( + )-depleted grafts. Blood Adv. 2018;2:263–70. https://doi.org/10.1182/bloodadvances.2017012005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shenoy S, Angelucci E, Arnold SD, Baker KS, Bhatia M, Bresters D, et al. Current results and future research priorities in late effects after hematopoietic stem cell transplantation for children with sickle cell disease and thalassemia: a consensus statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2017;23:552–61. https://doi.org/10.1016/j.bbmt.2017.01.009

    Article  PubMed  Google Scholar 

  31. Lang P, Feuchtinger T, Teltschik HM, Schwinger W, Schlegel P, Pfeiffer M, et al. Improved immune recovery after transplantation of TCRalphabeta/CD19-depleted allografts from haploidentical donors in pediatric patients. Bone Marrow Transplant. 2015;50(Suppl 2):S6–10. https://doi.org/10.1038/bmt.2015.87

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the patients and family members. We thank Professor Rubert Handgretinger, Department of General Pediatrics, Oncology, and Hematology, University Hospital Tuebingen, and Professor Matthias Eyrich, Department of Haematology, Oncology, and Stem Cell Transplantation, University Hospital Wuerzburg, for the always excellent preparation of T-cell-depleted peripheral stem cell grafts. We thank Ruediger Eder and Irina Fink from the Central FACS Facility, RCI, University Regensburg, for expert cell sorting.

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  1. These authors contributed equally: Juergen Foell, Johannes H Schulte

Authors and Affiliations

  1. Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Franz-Josef-Strauss-Allee 11, University Hospital of Regensburg, Regensburg, Germany

    Juergen Foell, Beatrix Pfirstinger, Anja Troeger & Selim Corbacioglu

  2. Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Charité University Hospital of Berlin, Berlin, Germany

    Johannes H Schulte, Ernst Holler & Angelika Eggert

  3. Department of Internal Medicine III, Hematology and Oncology, Franz-Josef-Strauss-Allee 11, University Hospital of Regensburg, Berlin, Germany

    Daniel Wolff, Matthias Edinger & Petra Hofmann

  4. Regensburg Center for Interventional Immunology (RCI), Franz-Josef-Strauss-Allee 11, University Hospital of Regensburg, Regensburg, Germany

    Matthias Edinger & Petra Hofmann

  5. Institute for Clinical Chemistry and Laboratory Medicine, Franz-Josef-Strauss-Allee 11, University Hospital Regensburg, Regensburg, Germany

    Charalampos Aslanidis

  6. Department of General Pediatrics, Oncology and Hematology, University of Children and Adolescents, Hoppe-Seyler-Strasse 1, Tuebingen, Germany

    Peter Lang

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Contributions

JF, JHS, AT, BP, DW, and SC reviewed the literature, analyzed the data, and wrote the manuscript. JF, JHS, AT, BP, PH, AE, CA, ME, PL, DW, EH, and SC were involved in the clinical management of the patients. All authors contributed to the intellectual content of this paper and approved the final manuscript.

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Correspondence to Selim Corbacioglu.

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Foell, J., Schulte, J.H., Pfirstinger, B. et al. Haploidentical CD3 or α/β T-cell depleted HSCT in advanced stage sickle cell disease. Bone Marrow Transplant 54, 1859–1867 (2019). https://doi.org/10.1038/s41409-019-0550-0

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