Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Conditioning Regimens

400 cGy TBI with fludarabine for reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation

Abstract

Fludarabine and 200 cGy TBI are commonly used for reduced-intensity conditioning preceding allogeneic hematopoietic SCT (HSCT). However, graft rejection and disease relapse are significant causes of treatment failure with this regimen. We modified this regimen by escalating the TBI dose to 400 cGy in 40 patients with hematologic malignancies. Thirty-four patients achieved complete donor T-cell chimerism at a median of 40 days following HSCT. The incidences of grades II–IV and III–IV acute GVHD were 40 and 15%, respectively, whereas that of limited and extensive chronic GVHD were 12 and 20%, respectively. Two patients rejected their grafts and 12 relapsed. The 100-day mortality was 18%, 2-year transplant-related mortality 20% and overall survival was 58% at a median follow-up of 16 months. There were no significant survival differences between patients with lymphoid compared to myeloid malignancies. A dose of 400 cGy TBI administered with fludarabine is well tolerated and further study is needed to determine whether outcomes are superior to those with 200 cGy TBI.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Niederwieser D, Maris M, Shizuru J, Petersdorf E, Hegenbart U, Sandmaier B et al. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases. Blood 2003; 101: 1620–1629.

    Article  CAS  PubMed  Google Scholar 

  2. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756–763.

    CAS  PubMed  Google Scholar 

  3. Childs R, Clave E, Contentin N, Jayasekera D, Hensel N, Leitman S et al. Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses. Blood 1999; 94: 3234–3241.

    CAS  PubMed  Google Scholar 

  4. Giralt S, Thall PF, Khouri I, Wang X, Braunshweig I, Ippolitti C 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: 631–637.

    Article  CAS  Google Scholar 

  5. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier B, Molina A, Maloney D et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390–3400.

    Article  CAS  PubMed  Google Scholar 

  6. Scott BL, Sandmaier BM, Storer B, Marris M, Sorror M, Maloney D et al. Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis. Leukemia 2006; 20: 128–135.

    Article  CAS  Google Scholar 

  7. Maris MB, Sandmaier BM, Storer B, Agura E, Wade J, Maziarz R et al. Allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning for relapsed or refractory follicular lymphoma. Blood 2005; 106: 329a (abstract no. 1130).

    Google Scholar 

  8. Sobecks RM, Ball EJ, Askar M, Theil K, Rybicki L, Thomas D et al. Influence of killer immunoglobulin-like receptor/HLA ligand matching on achievement of T-cell complete donor chimerism in related donor nonmyeloablative allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2008; 41: 709–714.

    Article  CAS  PubMed  Google Scholar 

  9. Paul P, Apgar J, Ball EJ . HLA-DRB1* intron-primed sequencing for haploid genotyping. Clin Chem 2003; 49: 692–694.

    Article  CAS  PubMed  Google Scholar 

  10. Paul P, Thomas D, Kawczak P, Good D, Cook DJ, Ball EJ . Resolution of cis-trans ambiguities between HLA-DRB1 alleles using single-strand conformation polymorphisms and sequencing. Tissue Antigens 2001; 57: 300–307.

    Article  CAS  PubMed  Google Scholar 

  11. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  PubMed  Google Scholar 

  12. Vogelsang GB . How I treat chronic graft-versus-host disease. Blood 2001; 97: 1196–1201.

    Article  CAS  PubMed  Google Scholar 

  13. Kaplan EL, Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1957; 53: 457–481.

    Article  Google Scholar 

  14. Pepe MS, Mori M . Kaplan–Meier, marginal or conditional probability curves in summarizing competing risk failure data. Stat Med 1993; 12: 737–751.

    Article  CAS  PubMed  Google Scholar 

  15. Khouri IF, Keating M, Korbling M, Przepiorka D, Anderini P, O’Brien S et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998; 16: 2817–2824.

    Article  CAS  PubMed  Google Scholar 

  16. Chakraverty R, Peggs K, Chopra R, Milligan D, Kottaridis PD, Verfuerth S et al. Limiting transplantation-related mortality following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning regimen. Blood 2002; 99: 1071–1078.

    Article  CAS  PubMed  Google Scholar 

  17. Taussig D, Davies A, Cavenagh J, Oakervee H, Syndercombe-Court D, Kelsey S et al. Durable remissions of myelodysplastic syndrome and acute myeloid leukemia after reduced-intensity allografting. J Clin Oncol 2003; 21: 3060–3065.

    Article  CAS  PubMed  Google Scholar 

  18. Hegenbart U, Niederwieser D, Sandmaier BM, Maris MB, Shizuru JA, Greinix H et al. Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors. J Clin Oncol 2006; 24: 444–453.

    Article  CAS  Google Scholar 

  19. de Lima M, Anagnostopoulos A, Munsell M, Shahjahan M, Ueno N, Ippoliti C 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: 865–872.

    Article  CAS  Google Scholar 

  20. Champlin R, Khouri I, Saliba R, Cohen A, de Lima M, Giralt S . Dose matters: Improved disease control with increased cytoreduction in nonablative BMT for late chronic and accelerated phase CML. Blood 2001; 98: 478a (abstract no. 1996).

    Article  Google Scholar 

  21. Hallemeier C, Girgis M, Blum W, Brown R, Khoury H, Devine S et al. Long-term remissions in patients with myelodysplastic syndrome and secondary acute myelogenous leukemia undergoing allogeneic transplantation following a reduced intensity conditioning regimen of 550 cGy total body irradiation and cyclophosphamide. Biol Blood Marrow Transplant. 2006; 12: 749–757.

    Article  CAS  PubMed  Google Scholar 

  22. Kahl C, Mielcarek M, Iwata M, Harkey M, Storer B, Torok-Storb B . Radiation dose determines the degree of myeloid engraftment after nonmyeloablative stem cell transplantation. Biol Blood Marrow Transplant 2004; 10: 826–833.

    Article  PubMed  Google Scholar 

  23. Weisser M, Schleuning M, Ledderose G, Rolf B, Schnittger S, Schoch C et al. Reduced-intensity conditioning using TBI (8 Gy), fludarabine, cyclophosphamide and ATG in elderly CML patients provides excellent results especially when performed in the early course of the disease. Bone Marrow Transplant 2004; 34: 1083–1088.

    Article  CAS  PubMed  Google Scholar 

  24. Stelljes M, Bornhauser M, Kroger M, Beyer J, Sauerland M, Heinecke A et al. Conditioning with 8-Gy total body irradiation and fludarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia. Blood 2005; 106: 3314–3321.

    Article  CAS  PubMed  Google Scholar 

  25. Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb HJ . Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 2005; 23: 5675–5687.

    Article  PubMed  Google Scholar 

  26. Antin J, Childs R, Filipovich AH, Giralt S, Mackinnon S, Spitzer T et al. Establishment of complete and mixed donor chimerism after allogeneic lymphohematopoietic transplantation: recommendations from a workshop at the 2001 Tandem Meetings. Biol Blood Marrow Transplant 2001; 7: 473–485.

    Article  CAS  PubMed  Google Scholar 

  27. Baron F, Baker J, Storb R, Gooley TA, Sandmaier BM, Maris MB et al. Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 2004; 104: 2254–2262.

    Article  CAS  PubMed  Google Scholar 

  28. Carvallo C, Geller N, Kurlander R, Srinivasan R, Mena O, Igarashi T et al. Prior chemotherapy and allograft CD34+ dose impact donor engraftment following nonmyeloablative allogeneic stem cell transplantation in solid tumor patients. Blood 2004; 103: 1560–1563.

    Article  CAS  PubMed  Google Scholar 

  29. Valcarcel D, Martino R, Caballero D, Mateos MV, Pérez-Simón JA, Canals C et al. Chimerism analysis following allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning. Bone Marrow Transplant 2003; 31: 387–392.

    Article  CAS  PubMed  Google Scholar 

  30. Fung H, Cohen S, Rodriguez R, Smith D, Krishnan A, Somlo G 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: 649–656.

    Article  CAS  PubMed  Google Scholar 

  31. Baron F, Storb R, Storer B, Maris M, Niederwieser D, Shizuru J et al. Factors associated with outcomes in allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning after failed myeloablative hematopoietic cell transplantation. J Clin Oncol 2006; 24: 4150–4157.

    Article  PubMed  Google Scholar 

  32. Escalón MP, Champlin RE, Saliba RM, Acholonu SA, Hosing C, Fayad L et al. Nonmyeloablative allogeneic hematopoietic transplantation: a promising salvage therapy for patients with non-Hodgkin's lymphoma whose disease has failed a prior autologous transplantation. J Clin Oncol 2004; 22: 2419–2423.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to R M Sobecks.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sobecks, R., Dean, R., Rybicki, L. et al. 400 cGy TBI with fludarabine for reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 42, 715–722 (2008). https://doi.org/10.1038/bmt.2008.248

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2008.248

Keywords

This article is cited by

Search

Quick links