Total Marrow/Lymphoid Irradiation in the Conditioning Regimen for Haploidentical T-Cell-Depleted Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia: The Perugia Experience

  • Cynthia AristeiEmail author
  • Simonetta Saldi
  • Antonio Pierini
  • Loredana Ruggeri
  • Sara Piccinelli
  • Gianluca Ingrosso
  • Massimo Fabrizio Martelli
  • Andrea Velardi


This chapter briefly outlines Perugia University’s experience with haploidentical hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML). It describes modifications to the conditioning regimens over time, focusing on the contribution from radiation oncology and the changes to the haploidentical graft. It reports outcomes in a subset of elderly or unfit young patients with AML who received an immunosuppressive, myeloablative, low-toxic total marrow/lymphoid irradiation (TMLI)-based conditioning regimen and a CD34+ inoculum with Treg/Tcon adoptive immunotherapy. Finally, perspectives and future directions of TMLI are illustrated.


Total marrow/lymphoid irradiation Acute myeloid leukemia Myelodisplasia Haploidentical hematopoietic stem cell transplantation T-cell depletion Adoptive immunotherapy T regulatory cells 


  1. 1.
    Aristei C, Carotti A, Palazzari E, et al. The total body irradiation schedule affects acute leukemia relapse after matched T cell-depleted hematopoietic stem cell transplantation. Int J Radiat Oncol Biol Phys. 2016;96:832–9.CrossRefGoogle Scholar
  2. 2.
    Reisner Y, Hagin D, Martelli MF. Haploidentical hematopoietic transplantation: current status and future perspectives. Blood. 2011;118:6006–17.CrossRefGoogle Scholar
  3. 3.
    Shank B, O’Reilly RJ, Cunningham I, et al. Total body irradiation for bone marrow transplantation: the Memorial Sloan-Kettering Cancer Center experience. Radiother Oncol. 1990;18(Suppl 1):68–81.CrossRefGoogle Scholar
  4. 4.
    Shank B, Andreeff M, Li D. Cell survival kinetics in peripheral blood and bone marrow during total body irradiation for marrow transplantation. Int J Radiat Oncol Biol Phys. 1983;9:1613–23.CrossRefGoogle Scholar
  5. 5.
    Terenzi A, Aristei C, Aversa F, et al. Efficacy of fludarabine as an immunosuppressor for bone marrow transplantation conditioning: preliminary results. Transplant Proc. 1996;28:3101.PubMedGoogle Scholar
  6. 6.
    Aversa F, Terenzi A, Carotti A, et al. Improved outcome with T-cell-depleted bone marrow transplantation for acute leukemia. J Clin Oncol. 1999;17:1545–50.CrossRefGoogle Scholar
  7. 7.
    Latini P, Aristei C, Aversa F, et al. Lung damage following bone marrow transplantation after hyperfractionated total body irradiation. Radiother Oncol. 1991;22:127–32.CrossRefGoogle Scholar
  8. 8.
    Aristei C, Latini P, Terenzi A, et al. Total body irradiation-based regimen in the conditioning of patients submitted to haploidentical stem cell transplantation. Radiother Oncol. 2001;58:247–9.CrossRefGoogle Scholar
  9. 9.
    Aristei C, Latini P, Falcinelli F, et al. The role of total body irradiation in the conditioning of patients receiving haploidentical stem cell transplantation. Tumori. 2001;87:402–6.CrossRefGoogle Scholar
  10. 10.
    Storb R, Raff RF, Appelbaum FR, et al. Comparison of fractionated to single-dose total body irradiation in conditioning canine littermates for DLA-identical marrow grafts. Blood. 1989;74:1139–43.CrossRefGoogle Scholar
  11. 11.
    Down JD, Tarbell NJ, Thames HD, et al. Syngeneic and allogeneic bone marrow engraftment after total body irradiation: dependence on dose, dose rate, and fractionation. Blood. 1991;77:661–9.CrossRefGoogle Scholar
  12. 12.
    Storb R, Raff RF, Appelbaum FR, et al. Fractionated versus single-dose total body irradiation at low and high dose rates to condition canine littermates for DLA-identical marrow grafts. Blood. 1994;83:3384–9.CrossRefGoogle Scholar
  13. 13.
    Terenzi A, Aristei C, Aversa F, et al. Comparison of immunosuppressive effects of single-dose and hyperfractionated total body irradiation. Transplant Proc. 1994;26:3217.PubMedGoogle Scholar
  14. 14.
    Anasetti C, Amos D, Beatty PG, 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.CrossRefGoogle Scholar
  15. 15.
    Reisner Y, Martelli MF. Bone marrow transplantation across HLA barriers by increasing the number of transplanted cells. Immunol Today. 1995;16:437–40.CrossRefGoogle Scholar
  16. 16.
    Aversa F, Tabilio A, Velardi A, et al. Treatment of high-risk acute leukemia with T-cell–depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med. 1998;339:1186–93.CrossRefGoogle Scholar
  17. 17.
    Aversa F, Terenzi A, Tabilio A, 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.CrossRefGoogle Scholar
  18. 18.
    Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097–100.CrossRefGoogle Scholar
  19. 19.
    Ruggeri L, Mancusi A, Capanni M, 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.CrossRefGoogle Scholar
  20. 20.
    Velardi A, Ruggeri L, Mancusi A, et al. Natural killer cell allorecognition of missing self in allogeneic hematopoietic transplantation: a tool for immunotherapy of leukemia. Curr Opin Immunol. 2009;21:525–30.CrossRefGoogle Scholar
  21. 21.
    Hoffmann P, Ermann J, Edinger M, et al. Donor-type CD4(1)CD25(1) regulatory T cells suppress lethal acute graft versus-host disease after allogeneic bone marrow transplantation. J Exp Med. 2002;196:389–99.CrossRefGoogle Scholar
  22. 22.
    Nguyen VH, Shashidhar S, Chang DS, et al. The impact of regulatory T cells on T-cell immunity following hematopoietic cell transplantation. Blood. 2008;111:945–53.CrossRefGoogle Scholar
  23. 23.
    Trenado A, Charlotte F, Fisson S, et al. Recipient type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus host disease while maintaining graft-versus leukemia. J Clin Invest. 2003;112:1688–96.CrossRefGoogle Scholar
  24. 24.
    Edinger M, Hoffmann P, Ermann J, et al. CD41CD251 regulatory T cells preserve graft versus-tumor activity while inhibiting graft-versus host disease after bone marrow transplantation. Nat Med. 2003;9:1144–50.CrossRefGoogle Scholar
  25. 25.
    Di Ianni M, Falzetti F, Carotti A, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117:3921–8.CrossRefGoogle Scholar
  26. 26.
    Martelli MF, Di Ianni M, Ruggeri L, et al. HLA-haploidentical transplantation with regulatory and conventional T cell adoptive immunotherapy prevents acute leukemia relapse. Blood. 2014;124:638–44.CrossRefGoogle Scholar
  27. 27.
    Surveillance, Epidemiology, and End Results (SEER) Program. Population Estimates Used in NCI’s SEER∗Stat Software. Bethesda, MD: SEER Program, National Cancer Institute; 2015. Accessed 08 April 2019.
  28. 28.
    Wong JY, Liu A, Schultheiss T, et al. Targeted total marrow irradiation using three-dimensional image-guided tomographic intensity-modulated radiation therapy: an alternative to standard total body irradiation. Biol Blood Marrow Transplant. 2006;12:306–15.CrossRefGoogle Scholar
  29. 29.
    Rosenthal J, Wong J, Stein A, et al. Phase 1/2 trial of total marrow and lymph node irradiation to augment reduced-intensity transplantation for advanced hematologic malignancies. Blood. 2011;117:309–15.CrossRefGoogle Scholar
  30. 30.
    Hui SK, Kapatoes J, Fowler J, et al. Feasibility study of helical tomotherapy for total body or total marrow irradiation. Med Phys. 2005;32:3214–24.CrossRefGoogle Scholar
  31. 31.
    Hui SK, Verneris MR, Higgins P, et al. Helical tomotherapy targeting total bone marrow - first clinical experience at the University of Minnesota. Acta Oncol. 2007;46:250–5.CrossRefGoogle Scholar
  32. 32.
    Wong JY, Forman S, Somlo G, et al. Dose escalation of total marrow irradiation with concurrent chemotherapy in patients with advanced acute leukemia undergoing allogeneic hematopoietic cell transplantation. Int J Radiat Oncol Biol Phys. 2013;85:148–56.CrossRefGoogle Scholar
  33. 33.
    Stein A, Palmer J, Tsai NC, et al. Phase I trial of total marrow and lymphoid irradiation transplantation conditioning in patients with relapsed/refractory acute leukemia. Biol Blood Marrow Transplant. 2017;23:618–24.CrossRefGoogle Scholar
  34. 34.
    Jensen LG, Stiller T, Wong JYC, et al. Total marrow lymphoid irradiation/fludarabine/melphalan conditioning for allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2018;24:301–7.CrossRefGoogle Scholar
  35. 35.
    Hui S, Brunstein C, Takahashi Y, et al. Dose escalation of total marrow irradiation in high-risk patients undergoing allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2017;23:1110–6.CrossRefGoogle Scholar
  36. 36.
    Sorror ML, Storb RF, Sandmaier BM, et al. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol. 2014;32:3249–56.CrossRefGoogle Scholar
  37. 37.
    Gupta V, Tallman MS, He W, et al. Comparable survival after HLA-well-matched unrelated or matched sibling donor transplantation for acute myeloid leukemia in first remission with unfavorable cytogenetics at diagnosis. Blood. 2010;116:1839–48.CrossRefGoogle Scholar
  38. 38.
    Bashey A, Zhang X, Sizemore C, 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.CrossRefGoogle Scholar
  39. 39.
    Scaradavou A, Brunstein CG, Eapen M, et al. Double unit grafts successfully extend the application of umbilical cord blood transplantation in adults with acute leukemia. Blood. 2013;121:752–8.CrossRefGoogle Scholar
  40. 40.
    Di Bartolomeo P, Santarone S, De Angelis G, et al. Haploidentical unmanipulated, G-CSFprimed bone marrow transplantation for patients with high risk hematological malignancies. Blood. 2013;121:849–57.CrossRefGoogle Scholar
  41. 41.
    Stefan O, Ciurea M-JZ, Bacigalupo AA. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015;126:1033–40.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Cynthia Aristei
    • 1
    Email author
  • Simonetta Saldi
    • 2
  • Antonio Pierini
    • 3
  • Loredana Ruggeri
    • 4
  • Sara Piccinelli
    • 3
  • Gianluca Ingrosso
    • 1
  • Massimo Fabrizio Martelli
    • 3
  • Andrea Velardi
    • 3
  1. 1.Radiation Oncology Section, Department of Surgical and Biomedical ScienceUniversity of Perugia and Perugia General HospitalPerugiaItaly
  2. 2.Radiation Oncology SectionPerugia General HospitalPerugiaItaly
  3. 3.Hematology and Clinical Immunology Section, Department of MedicineUniversity of PerugiaPerugiaItaly
  4. 4.Hematology and Clinical Immunology SectionPerugia General HospitalPerugiaItaly

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