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Improved survival rate in T-cell depleted haploidentical hematopoietic cell transplantation over the last 15 years at a single institution

Bone Marrow Transplantation volume 55, pages 929–938 (2020)Cite this article

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Abstract

T-cell depletion of an HLA-haploidentical (haplo) graft is often used to reduce the risk of graft-versus-host disease (GVHD), but the lack of donor T cells in the infused product may lead to graft failure, slow T-cell reconstitution, infections, and relapse. More selective T-cell depletion targeting CD45RA can effectively deplete naive T cells but preserve large numbers of memory T cells leading to robust engraftment of diverse T-cell populations and reduction of viremia in the early posttransplant period. Herein, we report the outcome of 143 pediatric and young adult hematologic malignancy patients receiving a first allogeneic hematopoietic cell transplantation (HCT) on six consecutive ex vivo T-cell depleted haploHCT protocols over the past 15 years at a single institution—including the first 50 patients on an active CD45RA-depleted haploHCT study in which patients also received NK-cells and pharmacological GvHD prophylaxis post transplant. Our data demonstrated an increase in the 3-year overall survival and event-free survival in nonchemorefractory recipients receiving CD45RA-depleted grafts (78.9% and 77.7%, respectively) compared with historic T-cell depleted haploHCT cohorts (46.7% and 42.7%, respectively, p = 0.004, and 0.003). This improvement was primarily due to a reduction in transplant related mortality without significant increase in the rates of GVHD.

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References

  1. Oliansky DM, Camitta B, Gaynon P, Nieder ML, Parsons SK, Pulsipher MA, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of pediatric acute lymphoblastic leukemia: update of the 2005 evidence-based review. ASBMT Position Statement. Biol Blood Marrow Transplant. 2012;18:979–81. https://doi.org/10.1016/j.bbmt.2012.03.011.

    Article  PubMed  Google Scholar 

  2. Oliansky DM, Rizzo JD, Aplan PD, Arceci RJ, Leone L, Ravindranath Y, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in children: an evidence-based review. Biol Blood Marrow Transplant. 2007;13:1–25. https://doi.org/10.1016/j.bbmt.2006.10.024.

    Article  PubMed  Google Scholar 

  3. Brissot E, Rialland F, Cahu X, Strullu M, Corradini N, Thomas C, et al. Improvement of overall survival after allogeneic hematopoietic stem cell transplantation for children and adolescents: a three-decade experience of a single institution. Bone Marrow Transplant. 2016;51:267–72. https://doi.org/10.1038/bmt.2015.250. e-pub ahead of print 2015/12/08

    Article  CAS  PubMed  Google Scholar 

  4. Gratwohl A, Brand R, Frassoni F, Rocha V, Niederwieser D, Reusser P, et al. Cause of death after allogeneic haematopoietic stem cell transplantation (HSCT) in early leukaemias: an EBMT analysis of lethal infectious complications and changes over calendar time. Bone Marrow Transplant. 2005;36:757–69. https://doi.org/10.1038/sj.bmt.1705140.

    Article  CAS  PubMed  Google Scholar 

  5. Holtan SG, DeFor TE, Lazaryan A, Bejanyan N, Arora M, Brunstein CG, et al. Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood. 2015;125:1333–8. https://doi.org/10.1182/blood-2014-10-609032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Solh M, Zhang X, Connor K, Brown S, Solomon SR, Morris LE, et al. Factors predicting graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation: multivariable analysis from a single center. Biol Blood Marrow Transplant. 2016;22:1403–9. https://doi.org/10.1016/j.bbmt.2016.04.006.

    Article  PubMed  Google Scholar 

  7. Kuhlen M, Willasch AM, Dalle JH, Wachowiak J, Yaniv I, Ifversen M, et al. Outcome of relapse after allogeneic HSCT in children with ALL enrolled in the ALL-SCT 2003/2007 trial. Br J Haematol. 2018;180:82–89. https://doi.org/10.1111/bjh.14965.

    Article  PubMed  Google Scholar 

  8. Avigan D, Hari P, 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 II. Autologous Transplantation-novel agents and immunomodulatory strategies. Biol Blood Marrow Transplant. 2013;19:1661–9. https://doi.org/10.1016/j.bbmt.2013.08.011.

    Article  PubMed  PubMed Central  Google Scholar 

  9. 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 

  10. Lang P, Handgretinger R. Haploidentical SCT in children: an update and future perspectives. Bone Marrow Transpl. 2008;42:S54–59. https://doi.org/10.1038/bmt.2008.285.

    Article  Google Scholar 

  11. 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. https://doi.org/10.1016/j.bbmt.2008.03.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Leung W, Campana D, Yang J, Pei D, Coustan-Smith E, Gan K, et al. High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood. 2011;118:223–30. https://doi.org/10.1182/blood-2011-01-333070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Klingebiel T, Cornish J, Labopin M, Locatelli F, Darbyshire P, Handgretinger R, et al. Results and factors influencing outcome after fully haploidentical hematopoietic stem cell transplantation in children with very high-risk acute lymphoblastic leukemia: impact of center size: an analysis on behalf of the Acute Leukemia and Pediatric Disease Working Parties of the European Blood and Marrow Transplant group. Blood. 2010;115:3437–46. https://doi.org/10.1182/blood-2009-03-207001.

    Article  CAS  PubMed  Google Scholar 

  14. Yanir AD, Martinez CA, Sasa G, Leung K, Gottschalk S, Omer B, et al. Current allogeneic hematopoietic stem cell transplantation for pediatric acute lymphocytic leukemia: success, failure and future perspectives-a single-center experience, 2008 to 2016. Biol Blood Marrow Transplant. 2018;24:1424–31. https://doi.org/10.1016/j.bbmt.2018.03.001.

    Article  PubMed  Google Scholar 

  15. Federmann B, Bornhauser M, Meisner C, Kordelas L, Beelen DW, Stuhler G, et al. Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: a phase II study. Haematologica. 2012;97:1523–31. https://doi.org/10.3324/haematol.2011.059378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Vadakekolathu J, Rutella S. T-cell manipulation strategies to prevent graft-versus-host disease in haploidentical stem cell transplantation. Biomedicines 2017;5. https://doi.org/10.3390/biomedicines5020033.

  17. Bertaina A, Zecca M, Buldini B, Sacchi N, Algeri M, Saglio F, et al. Unrelated donor vs HLA-haploidentical alpha/beta T-cell- and B-cell-depleted HSCT in children with acute leukemia. Blood. 2018;132:2594–607. https://doi.org/10.1182/blood-2018-07-861575.

    Article  CAS  PubMed  Google Scholar 

  18. Huang W, Chao NJ. Memory T cells: A helpful guard for allogeneic hematopoietic stem cell transplantation without causing graft-versus-host disease. Hematol Oncol Stem Cell Ther. 2017;10:211–9. https://doi.org/10.1016/j.hemonc.2017.05.006.

    Article  CAS  PubMed  Google Scholar 

  19. Teschner D, Distler E, Wehler D, Frey M, Marandiuc D, Langeveld K, et al. Depletion of naive T cells using clinical grade magnetic CD45RA beads: a new approach for GVHD prophylaxis. Bone Marrow Transpl. 2014;49:138–44. https://doi.org/10.1038/bmt.2013.114

    Article  CAS  Google Scholar 

  20. Bleakley M, Heimfeld S, Loeb KR, Jones LA, Chaney C, Seropian S, et al. Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts. J Clin Investig. 2015. https://doi.org/10.1172/JCI81229.

  21. Sisinni L, Gasior M, de Paz R, Querol S, Bueno D, Fernandez 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 Transplant. 2018;24:2316–23. https://doi.org/10.1016/j.bbmt.2018.07.016

    Article  PubMed  Google Scholar 

  22. Shook DR, Triplett BM, Eldridge PW, Kang G, Srinivasan A, Leung W. Haploidentical stem cell transplantation augmented by CD45RA negative lymphocytes provides rapid engraftment and excellent tolerability. Pediatr Blood Cancer. 2015;62:666–73. https://doi.org/10.1002/pbc.25352.

    Article  CAS  PubMed  Google Scholar 

  23. Triplett BM, Muller B, Kang G, Li Y, Cross SJ, Moen J, et al. Selective T-cell depletion targeting CD45RA reduces viremia and enhances early T-cell recovery compared with CD3-targeted T-cell depletion. Transpl Infect Dis. 2018; 20. https://doi.org/10.1111/tid.12823.

  24. Triplett BM, Shook DR, Eldridge P, Li Y, Kang G, Dallas M, et al. Rapid memory T-cell reconstitution recapitulating CD45RA-depleted haploidentical transplant graft content in patients with hematologic malignancies. Bone Marrow Transpl. 2015;50:1012 https://doi.org/10.1038/bmt.2015.139.

    Article  CAS  Google Scholar 

  25. Perez-Martinez A, Leung W, Munoz E, Iyengar R, Ramirez M, Vicario JL, et al. KIR-HLA receptor-ligand mismatch associated with a graft-versus-tumor effect in haploidentical stem cell transplantation for pediatric metastatic solid tumors. Pediatr Blood Cancer. 2009;53:120–4. https://doi.org/10.1002/pbc.21955.

    Article  PubMed  Google Scholar 

  26. Prentice RL, Kalbfleisch JD, Peterson AV Jr., Flournoy N, Farewell VT, Breslow NE. The analysis of failure times in the presence of competing risks. Biometrics. 1978;34:541–54.

    Article  CAS  Google Scholar 

  27. Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141–54.

    Article  Google Scholar 

  28. 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. https://doi.org/10.1182/blood-2015-04-639831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yu X, Liu L, Xie Z, Dong C, Zhao L, Zhang J, et al. Bone marrow versus peripheral blood as a graft source for haploidentical donor transplantation in adults using post-transplant cyclophosphamide—a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2019;133:120–8. https://doi.org/10.1016/j.critrevonc.2018.05.017.

  30. Wang Y, Chang YJ, Chen L, Xu LP, Bian ZL, Zhang XH, et al. Low-dose post-transplant cyclophosphamide can mitigate GVHD and enhance the G-CSF/ATG induced GVHD protective activity and improve haploidentical transplant outcomes. Oncoimmunology. 2017;6:e1356152. https://doi.org/10.1080/2162402X.2017.1356152.

  31. Klein OR, Buddenbaum J, Tucker N, Chen AR, Gamper CJ, Loeb D, et al. Nonmyeloablative haploidentical bone marrow transplantation with post-transplantation cyclophosphamide for pediatric and young adult patients with high-risk hematologic malignancies. Biol Blood Marrow Transpl. 2017;23:325–32. https://doi.org/10.1016/j.bbmt.2016.11.016.

    Article  Google Scholar 

  32. Copelan OR, Sanikommu SR, Trivedi JS, Butler C, Ai J, Ragon BK, et al. Higher incidence of hemorrhagic cystitis following haploidentical related donor transplantation compared with matched related donor transplantation. Biol Blood Marrow Transplant. 2018. https://doi.org/10.1016/j.bbmt.2018.12.142.

  33. Mohyuddin GR, Roller J, Shune L, Lin T, Dias A, Ganguly S, et al. Epstein-Barr viremia and post-transplant lymphoproliferative disorders in patients undergoing haploidentical stem cell transplantation with post-transplant cyclophosphamide. Hematol Oncol Stem Cell Ther. 2018. https://doi.org/10.1016/j.hemonc.2018.11.002.

  34. Raiola AM, Dominietto A, di Grazia C, Lamparelli T, Gualandi F, Ibatici A, et al. Unmanipulated haploidentical transplants compared with other alternative donors and matched sibling grafts. Biol Blood Marrow Transpl. 2014;20:1573–9. https://doi.org/10.1016/j.bbmt.2014.05.029

    Article  Google Scholar 

  35. Or-Geva N, Reisner Y. The evolution of T-cell depletion in haploidentical stem-cell transplantation. Br J Haematol. 2016;172:667–84. https://doi.org/10.1111/bjh.13868

    Article  PubMed  Google Scholar 

  36. 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. https://doi.org/JCO.2005.09.117.

    Article  Google Scholar 

  37. Roux C, Harbi S, Devillier R, Legrand F, Furst S, Granata A, et al. Donor lymphocyte infusion after haploidentical transplantation with post-transplant cyclophosphamide. Blood. 2016;128:5863.

  38. Martelli MF, Ianni MD, Ruggeri L, Falzetti F, Carotti A, Reisner Y, et al. Next generation HLA-haploidentical HSCT. Bone Marrow Transplant. 2015;50:S63–S66. https://doi.org/10.1038/bmt.2015.98

    Article  CAS  PubMed  Google Scholar 

  39. Rujkijyanont P, Morris C, Kang G, Gan K, Hartford C, Triplett B, et al. Risk-adapted donor lymphocyte infusion based on chimerism and donor source in pediatric leukemia. Blood Cancer J. 2013;3:e137. https://doi.org/10.1038/bcj.2013.39.

  40. Locatelli F, Merli P, Li Pira G, Bertaina V, Lucarelli B, Brescia LP, et al. Clinical outcome after adoptive infusion of BPX-501 cells (donor T cells transduced with iC9 suicide gene) in children given alpha/beta T-cell depleted HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT): preliminary results of a phase I–II Trial. Blood. 2015;126:1931. https://doi.org/10.1182/blood.V126.23.1931.1931

  41. Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117:3921–8. https://doi.org/10.1182/blood-2010-10-311894

    Article  CAS  PubMed  Google Scholar 

  42. 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:S6–10. https://doi.org/10.1038/bmt.2015.87

    Article  CAS  PubMed  Google Scholar 

  43. Maschan M, Shelikhova L, Ilushina M, Kurnikova E, Boyakova E, Balashov D, et al. TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia. Bone Marrow Transplant. 2016;51:668–74. https://doi.org/10.1038/bmt.2015.343.

    Article  CAS  PubMed  Google Scholar 

  44. Zvyagin IV, Mamedov IZ, Tatarinova OV, Komech EA, Kurnikova EE, Boyakova EV, et al. Tracking T-cell immune reconstitution after TCRalphabeta/CD19-depleted hematopoietic cells transplantation in children. Leukemia. 2017;31:1145–53. https://doi.org/10.1038/leu.2016.321.

    Article  CAS  PubMed  Google Scholar 

  45. Locatelli F, Merli P, Pagliara D, Li Pira G, Falco M, Pende D, et al. Outcome of children with acute leukemia given HLA-haploidentical HSCT after alphabeta T-cell and B-cell depletion. Blood. 2017;130:677–85. https://doi.org/10.1182/blood-2017-04-779769

    Article  CAS  PubMed  Google Scholar 

  46. Upadhyayula S, Michaels MG. Ganciclovir, Foscarnet, and Cidofovir: Antiviral Drugs Not Just for Cytomegalovirus. J Pediatr Infect Dis Soc. 2013;2:286–90. https://doi.org/10.1093/jpids/pit048.

    Article  Google Scholar 

  47. Symeonidis N, Jakubowski A, Pierre-Louis S, Jaffe D, Pamer E, Sepkowitz K, et al. Invasive adenoviral infections in T-cell-depleted allogeneic hematopoietic stem cell transplantation: high mortality in the era of cidofovir. Transpl Infect Dis. 2007;9:108–13. https://doi.org/10.1111/j.1399-3062.2006.00184.x.

    Article  CAS  PubMed  Google Scholar 

  48. Chan WK, Suwannasaen D, Throm RE, Li Y, Eldridge PW, Houston J, et al. Chimeric antigen receptor-redirected CD45RA-negative T cells have potent antileukemia and pathogen memory response without graft-versus-host activity. Leukemia. 2015;29:387–95. https://doi.org/10.1038/leu.2014.174.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank our colleagues for data collection and clinical management. Our thanks also go out to the many patients and families who participated in the transplantation and cellular therapy research program. We would like to recognize additional Principle Investigators of the historic T-cell depleted haploidentical donor therapeutic transplant trials initiated at this institution: Rupert Handgretinger, Eli Benaim, and Greg Hale. This work is supported in part by the National Institutes of Health Cancer Center Support (CORE) grant P30 CA021765, and the American Lebanese Syrian Associated Charities (ALSAC).

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Authors and Affiliations

  1. Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Ewelina Mamcarz, Renee Madden, Amr Qudeimat, Ashok Srinivasan, Aimee Talleur, Akshay Sharma, Ali Suliman, Wing Leung, Stephen Gottschalk & Brandon M. Triplett

  2. Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Gabriela Maron

  3. Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Anusha Sunkara & Guolian Kang

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  1. Ewelina Mamcarz
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Contributions

Contribution: BMT and WL designed the therapeutic trial. BMT and SG analyzed and interpreted data, BMT and EM wrote the paper; EM, RM, AQ, ASr, AT, ASh, ASul, GM, WL, SG, and BMT provided patient information and data for analysis, contributed to interpretation of the data; GK and ASun provided statistical analysis; and all authors contributed to the revisions of the draft and approval of the final paper.

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Correspondence to Brandon M. Triplett.

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Conflict of interest

WL is currently an employee of Miltenyi Biotech, all efforts contributing to this work except for final paper review occurred prior to this employment. BMT received travel support from Miltenyi Biotech to present previously published work at EBMT annual meeting 2018. The other authors have no financial relationships or other conflicts of interest to disclose relevant to this paper. No author received an honorarium, grant, or other form of payment to produce the paper.

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Mamcarz, E., Madden, R., Qudeimat, 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 Transplant 55, 929–938 (2020). https://doi.org/10.1038/s41409-019-0750-7

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