Reduced Intensity Conditioning Regimens in Combination with Total Marrow and Lymphoid Irradiation

  • Joseph RosenthalEmail author


Allogeneic hematopoietic stem cell transplantation (HCT) following myeloablative chemotherapy (MAC) has been established as a proven treatment modality in patients with hematological malignancies. Total body irradiation (TBI) as an element of MAC has been shown to have a potent antileukemic effect, but it is associated with a high rate of toxicity at the standard levels of 12–15 Gy delivered to all organs. However, its use is limited due to a high rate of life-threatening toxicities, evident particularly in older patients and in patients with preexisting morbidities. Reduced-intensity conditioning (RIC) regimens were developed in an attempt to expand the curative potential of HCT to patients who are not eligible for a fully MAC regimens. Fludarabine (FLU) and melphalan (MEL) are two of the most commonly agents used in RIC. Multiple reports have demonstrated that long-term survival and disease control can be obtained with HCT following RIC; however, patients with advanced disease at the time of transplantation have suffered significantly higher rates of relapsed leukemia. That led to an assumption that the reduction in treatment intensity associated with the use of RIC may have a negative impact on long-term leukemic control. A sound hypothesis is that technologies that may improve the antileukemic effect of treatment while maintaining a low rate of toxicities may improve outcome of RIC. Total marrow and lymphatic irradiation (TMLI) using intensity modulated radiation therapy (IMRT) enables the delivery of effective antileukemic doses to the marrow and lymphatic organ, and at the same time, delivering less lower doses to the adjacent organs, resulting in reduced toxic exposure to these organs. The chapter summarizes the experience of using helio-tomotherapy, an IMRT modality in combination with FLU/MEL, to augment the antileukemic effects of a standard RIC regimen without increasing the toxicity of the regimen.


Myeloablative conditioning (MAC) Reduced intensity conditioning (RIC) Total body irradiation (TBI) Total marrow and lymphoid irradiation (TMLI) Fludarabine (FLU) Melphalan (MEL) 


  1. 1.
    Gale RP, Buchner T, Zhang MJ, et al. HLA-identical sibling bone marrow transplants vs chemotherapy for acute myelogenous leukemia in first remission. Leukemia. 1996;10:1687–91.PubMedGoogle Scholar
  2. 2.
    Herzig RH, Bortin MM, Barrett AJ, et al. Bone-marrow transplantation in high-risk acute lymphoblastic leukaemia in first and second remission. Lancet. 1987;1:786–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Torres A, Martinez F, Gomez P, et al. Allogeneic bone marrow transplantation versus chemotherapy in the treatment of childhood acute lymphoblastic leukemia in second complete remission. Bone Marrow Transplant. 1989;4:609–12.PubMedGoogle Scholar
  4. 4.
    Brochstein JA, Kernan NA, Groshen S, et al. Allogeneic bone marrow transplantation after hyperfractionated total-body irradiation and cyclophosphamide in children with acute leukemia. N Engl J Med. 1987;317:1618–24.PubMedCrossRefGoogle Scholar
  5. 5.
    Boulad F, Steinherz P, Reyes B, et al. Allogeneic bone marrow transplantation versus chemotherapy for the treatment of childhood acute lymphoblastic leukemia in second remission: a single-institution study. J Clin Oncol. 1999;17:197–207.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Coccia PF, Strandjord SE, Warkentin PI, et al. High-dose cytosine arabinoside and fractionated total-body irradiation: an improved preparative regimen for bone marrow transplantation of children with acute lymphoblastic leukemia in remission. Blood. 1988;71:888–93.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Bushhouse S, Ramsay NK, Pescovitz OH, Kim T, Robison LL. Growth in children following irradiation for bone marrow transplantation. Am J Pediatr Hematol Oncol. 1989;11:134–40.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Sanders JE. Endocrine problems in children after bone marrow transplant for hematologic malignancies. The long-term follow-up team. Bone Marrow Transplant. 1991;8(Suppl 1):2–4.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Liesner RJ, Leiper AD, Hann IM, Chessells JM. Late effects of intensive treatment for acute myeloid leukemia and myelodysplasia in childhood. J Clin Oncol. 1994;12:916–24.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Cohen A, van Lint MT, Uderzo C, et al. Growth in patients after allogeneic bone marrow transplant for hematological diseases in childhood. Bone Marrow Transplant. 1995;15:343–8.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Deeg HJ, Socie G, Schoch G, et al. Malignancies after marrow transplantation for aplastic anemia and fanconi anemia: a joint Seattle and Paris analysis of results in 700 patients. Blood. 1996;87:386–92.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Santos GW, Tutschka PJ, Brookmeyer R, et al. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med. 1983;309:1347–53.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Tutschka PJ, Copelan EA, Klein JP. Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen. Blood. 1987;70:1382–8.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Michel G, Socie G, Gebhard F, et al. Late effects of allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: the impact of conditioning regimen without total-body irradiation--a report from the Societe Francaise de Greffe de Moelle. J Clin Oncol. 1997;15:2238–46.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Shankar SM, Bunin NJ, Moshang T Jr. Growth in children undergoing bone marrow transplantation after busulfan and cyclophosphamide conditioning. J Pediatr Hematol Oncol. 1996;18:362–6.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Adan L, de Lanversin ML, Thalassinos C, Souberbielle JC, Fischer A, Brauner R. Growth after bone marrow transplantation in young children conditioned with chemotherapy alone. Bone Marrow Transplant. 1997;19:253–6.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Blaise D, Maraninchi D, Michallet M, et al. Long-term follow-up of a randomized trial comparing the combination of cyclophosphamide with total body irradiation or busulfan as conditioning regimen for patients receiving HLA-identical marrow grafts for acute myeloblastic leukemia in first complete remission. Blood. 2001;97:3669–71.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Ringden O, Ruutu T, Remberger M, et al. A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic bone marrow transplantation group. Blood. 1994;83:2723–30.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Davies SM, Ramsay NK, Klein JP, et al. Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia. J Clin Oncol. 2000;18:340–7.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Bunin N, Aplenc R, Kamani N, Shaw K, Cnaan A, Simms S. Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: a pediatric blood and marrow transplant consortium study. Bone Marrow Transplant. 2003;32:543–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Clift RA, Buckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood. 1990;76:1867–71.PubMedCrossRefGoogle Scholar
  22. 22.
    Clift RA, Buckner CD, Appelbaum FR, Sullivan KM, Storb R, Thomas ED. Long-term follow-up of a randomized trial of two irradiation regimens for patients receiving allogeneic marrow transplants during first remission of acute myeloid leukemia. Blood. 1998;92:1455–6.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Mulrooney DA, Dover DC, Li S, et al. Twenty years of follow-up among survivors of childhood and young adult acute myeloid leukemia: a report from the childhood cancer survivor study. Cancer. 2008;112:2071–9.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Armenian SH, Sun CL, Kawashima T, et al. Long-term health-related outcomes in survivors of childhood cancer treated with HSCT versus conventional therapy: a report from the bone marrow transplant survivor study (BMTSS) and childhood cancer survivor study (CCSS). Blood. 2011;118:1413–20.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Armenian SH, Sun CL, Shannon T, et al. Incidence and predictors of congestive heart failure after autologous hematopoietic cell transplantation. Blood. 2011;118:6023–9.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Copelan EA, Avalos BR, Ahn KW, et al. Comparison of outcomes of allogeneic transplantation for chronic myeloid leukemia with cyclophosphamide in combination with intravenous busulfan, oral busulfan, or total body irradiation. Biol Blood Marrow Transplant. 2015;21:552–8.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Michel G, Gluckman E, Esperou-Bourdeau H, et al. Allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: impact of conditioning regimen without total-body irradiation--a report from the Societe Francaise de Greffe de Moelle. J Clin Oncol. 1994;12:1217–22.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Wingard JR, Plotnick LP, Freemer CS, et al. Growth in children after bone marrow transplantation: busulfan plus cyclophosphamide versus cyclophosphamide plus total body irradiation. Blood. 1992;79:1068–73.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Copelan EA, Deeg HJ. Conditioning for allogeneic marrow transplantation in patients with lymphohematopoietic malignancies without the use of total body irradiation. Blood. 1992;80:1648–58.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Giralt S, Thall PF, Khouri I, et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood. 2001;97:631–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Wong R, Giralt SA, Martin T, et al. Reduced-intensity conditioning for unrelated donor hematopoietic stem cell transplantation as treatment for myeloid malignancies in patients older than 55 years. Blood. 2003;102:3052–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Champlin R, Khouri I, Komblau S, Molidrem J, Giralt S. Reinventing bone marrow transplantation. Nonmyeloablative preparative regimens and induction of graft-vs-malignancy effect. Oncology (Williston Park). 1999;13:621–8. discussion 31, 35-8, 41Google Scholar
  33. 33.
    Giralt S, Logan B, Rizzo D, et al. Reduced-intensity conditioning for unrelated donor progenitor cell transplantation: long-term follow-up of the first 285 reported to the national marrow donor program. Biol Blood Marrow Transplant. 2007;13:844–52.PubMedCrossRefGoogle Scholar
  34. 34.
    Vigouroux S, Michallet M, Porcher R, et al. Long-term outcomes after reduced-intensity conditioning allogeneic stem cell transplantation for low-grade lymphoma: a survey by the French Society of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC). Haematologica. 2007;92:627–34.PubMedCrossRefGoogle Scholar
  35. 35.
    Blaise D, Vey N, Faucher C, Mohty M. Current status of reduced-intensity-conditioning allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica. 2007;92:533–41.PubMedCrossRefGoogle Scholar
  36. 36.
    Kebriaei P, Detry MA, Giralt S, et al. Long-term follow-up of allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning for patients with chronic myeloid leukemia. Blood. 2007;110:3456–62.PubMedCrossRefGoogle Scholar
  37. 37.
    Devine SM, Sanborn R, Jessop E, et al. Fludarabine and melphalan-based conditioning for patients with advanced hematological malignancies relapsing after a previous hematopoietic stem cell transplant. Bone Marrow Transplant. 2001;28:557–62.PubMedCrossRefGoogle Scholar
  38. 38.
    Stein AS, Palmer JM, O'Donnell MR, et al. Reduced-intensity conditioning followed by peripheral blood stem cell transplantation for adult patients with high-risk acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2009;15:1407–14.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Scott BL, Pasquini MC, Logan BR, et al. Myeloablative versus reduced-intensity hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol. 2017;35:1154–61.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Choe HK, Gergis U, Mayer SA, et al. The addition of low-dose total body irradiation to fludarabine and melphalan conditioning in haplocord transplantation for high-risk hematological malignancies. Transplantation. 2017;101:e34–e8.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Gifford G, Wong K, Kerridge I, et al. Addition of low dose total body irradiation to fludarabine melphalan reduced intensity conditioning is feasible, tolerable, and may improve outcomes in patients with high-risk acute myeloid leukaemia and other high risk myeloid malignancies. Am J Hematol. 2015;90:E97–100.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe francophone du Myelome 9502 randomized trial. Blood. 2002;99:731–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Petropoulos D, Worth LL, Mullen CA, et al. Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies. Bone Marrow Transplant. 2006;37:463–7.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Leibel SA, Fuks Z, Zelefsky MJ, et al. Technological advances in external-beam radiation therapy for the treatment of localized prostate cancer. Semin Oncol. 2003;30:596–615.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Balog J, Mackie TR, Pearson D, Hui S, Paliwal B, Jeraj R. Benchmarking beam alignment for a clinical helical tomotherapy device. Med Phys. 2003;30:1118–27.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Schultheiss TE, Wong J, Liu A, Olivera G, Somlo G. Image-guided total marrow and total lymphatic irradiation using helical tomotherapy. Int J Radiat Oncol Biol Phys. 2007;67:1259–67.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Wong JY, Rosenthal J, Liu A, Schultheiss T, Forman S, Somlo G. Image-guided total-marrow irradiation using helical tomotherapy in patients with multiple myeloma and acute leukemia undergoing hematopoietic cell transplantation. Int J Radiat Oncol Biol Phys. 2009;73:273–9.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Mackie TR, Balog J, Ruchala K, et al. Tomotherapy. Semin Radiat Oncol. 1999;9:108–17.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Jensen LG, Stiller T, Wong JYC, Palmer J, Stein A, Rosenthal J. Total marrow lymphoid irradiation/fludarabine/melphalan conditioning for allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2018;24:301–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Fung HC, Cohen S, Rodriguez R, et al. Reduced-intensity allogeneic stem cell transplantation for patients whose prior autologous stem cell transplantation for hematologic malignancy failed. Biol Blood Marrow Transplant. 2003;9:649–56.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    de Lima M, Anagnostopoulos A, Munsell M, et al. Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation. Blood. 2004;104:865–72.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Ritchie DS, Morton J, Szer J, et al. Graft-versus-host disease, donor chimerism, and organ toxicity in stem cell transplantation after conditioning with fludarabine and melphalan. Biol Blood Marrow Transplant. 2003;9:435–42.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Chakraverty R, Peggs K, Chopra R, et al. Limiting transplantation-related mortality following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning regimen. Blood. 2002;99:1071–8.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Van Besien K, Devine S, Wickrema A, et al. Regimen-related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with hematologic malignancies. Bone Marrow Transplant. 2003;32:471–6.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Giralt S, Aleman A, Anagnostopoulos A, et al. Fludarabine/melphalan conditioning for allogeneic transplantation in patients with multiple myeloma. Bone Marrow Transplant. 2002;30:367–73.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Martino R, Caballero MD, Canals C, et al. Allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning: results of a prospective multicentre study. Br J Haematol. 2001;115:653–9.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Hui SK, Das RK, Thomadsen B, Henderson D. CT-based analysis of dose homogeneity in total body irradiation using lateral beam. J Appl Clin Med Phys. 2004;5:71–9.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Somlo G, Spielberger R, Frankel P, et al. Total marrow irradiation: a new ablative regimen as part of tandem autologous stem cell transplantation for patients with multiple myeloma. Clin Cancer Res. 2011;17:174–82.PubMedCrossRefGoogle Scholar
  62. 62.
    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.PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of PediatricsCity of HopeDuarteUSA

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