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

Complete substitution of cyclophosphamide by fludarabine and ATG in a busulfan-based preparative regimen for children and adolescents with β-thalassemia

Bone Marrow Transplantation volume 36, pages 383–387 (2005)Cite this article

Summary:

Children and adolescents with homozygous beta-thalassemia can be cured by transplantation of normal stem cells after eradication of the thalassemic hematopoietic system. In an attempt to achieve durable engraftment and to minimize regimen-related toxicity (RRT), we have initiated a fludarabine-based pilot protocol not containing cyclophosphamide. Between 1999 and 2004, five children with beta-thalassemia major were enrolled. Median age at transplantation was 11.5 years (range 4–14 years). Three patients received conditioning with fludarabine (30 mg/m2/day × 6), oral busulfan (3.5 mg/kg/day × 4), and ATG rabbit Fresenius (10 mg/kg/day × 4). Two children received intravenous busulfan instead of oral busulfan at a dose of 2 × 1.4 mg/kg/day × 4 days. All children were transplanted with a fresh bone marrow graft from an HLA-identical sibling. Mean cell doses given were 3.7 × 108 nucleated cells/kg BW (range 2.4–6.2 × 108/kg). Overall, 5/5 patients achieved donor engraftment and are alive and well. No GVHD exceeding grade I was observed, and 2/5 children maintained donor chimerism at 100%. One patient maintains mixed hematopoietic donor chimerism being between 94 and 97% nearly 5 years after transplant.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. Weatherall DJ, Clegg JB . Thalassemia – a global public health problem. Nat Med 1996; 2: 847–849.

    Article  CAS  Google Scholar 

  2. Hershko C, Weatherall DJ . Iron-chelating therapy. Crit Rev Clin Lab Sci 1988; 26: 303–345.

    Article  CAS  Google Scholar 

  3. Lucarelli G, Galimberti M, Polchi P et al. Marrow transplantation in patients with thalassemia responsive to iron chelation therapy. N Engl J Med 1993; 329: 840–844.

    Article  CAS  Google Scholar 

  4. Lucarelli G, Clift RA, Galimberti M et al. Marrow transplantation for patients with thalassemia: results in class 3 patients. Blood 1996; 87: 2082–2088.

    CAS  Google Scholar 

  5. Lucarelli G, Galimberti M, Polchi P et al. Bone marrow transplantation in patients with thalassemia. N Engl J Med 1990; 322: 417–421.

    Article  CAS  Google Scholar 

  6. Sodani P, Gaziev D, Polchi P et al. New approach for bone marrow transplantation in patients with class 3 thalassemia aged younger than 17 years. Blood 2004; 104: 1201–1203.

    Article  CAS  Google Scholar 

  7. McDonald GB, Slattery JT, Bouvier ME et al. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood 2003; 101: 2043–2048.

    Article  CAS  Google Scholar 

  8. Browne RK, Scheltinga DM, Pomering M, Mahony M . Testicular myxosporidiasis in anurans, with a description of Myxobolus fallax n. sp. Syst Parasitol 2002; 52: 97–110.

    Article  CAS  Google Scholar 

  9. Voorter CE, Rozemuller EH, de Bruyn-Geraets D et al. Comparison of DRB sequence-based typing using different strategies. Tissue Antigens 1997; 49: 471–476.

    Article  CAS  Google Scholar 

  10. Storb R, Deeg HJ, Whitehead J et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 1986; 314: 729–735.

    Article  CAS  Google Scholar 

  11. Przepiorka D, Weisdorf D, Martin P et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  Google Scholar 

  12. Lucarelli G, Andreani M, Angelucci E . The cure of thalassemia by bone marrow transplantation. Blood Rev 2002; 16: 81–85.

    Article  CAS  Google Scholar 

  13. Sensenbrenner LL, Owens Jr AH, Heiby JR, Jeejeebhoy HF . Comparative effects of cytotoxic agents on transplanted hematopoietic and antibody-producing cells. J Natl Cancer Inst 1973; 50: 1027–1033.

    Article  CAS  Google Scholar 

  14. Fried W, Kedo A, Barone J . Effects of cyclophosphamide and of busulfan on spleen colony-forming units and on hematopoietic stroma. Cancer Res 1977; 37: 1205–1209.

    CAS  Google Scholar 

  15. Thomas ED, Buckner CD, Rudolph RH et al. Allogeneic marrow grafting for hematologic malignancy using HL-A matched donor-recipient sibling pairs. Blood 1971; 38: 267–287.

    CAS  PubMed  Google Scholar 

  16. 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: 1347–1353.

    Article  CAS  Google Scholar 

  17. Bearman SI . Veno-occlusive disease of the liver. Curr Opin Oncol 2000; 12: 103–109.

    Article  CAS  Google Scholar 

  18. Keating MJ, O'Brien S, Lerner S et al. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood 1998; 92: 1165–1171.

    CAS  Google Scholar 

  19. Chun HG, Leyland-Jones B, Cheson BD . Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies. J Clin Oncol 1991; 9: 175–188.

    Article  CAS  Google Scholar 

  20. Kashyap A, Wingard J, Cagnoni P et al. Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality. Biol Blood Marrow Transplant 2002; 8: 493–500.

    Article  CAS  Google Scholar 

  21. Gandhi V, Plunkett W . Cellular and clinical pharmacology of fludarabine. Clin Pharmacokinet 2002; 41: 93–103.

    Article  CAS  Google Scholar 

  22. de Lima M, Couriel D, Thall PF et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood 2004; 104: 857–864.

    Article  CAS  Google Scholar 

  23. Andersson BS, Kashyap A, Gian V et al. Conditioning therapy with intravenous busulfan and cyclophosphamide (IV BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: a phase II study. Biol Blood Marrow Transplant 2002; 8: 145–154.

    Article  CAS  Google Scholar 

  24. Iannone R, Casella JF, Fuchs EJ et al. Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia. Biol Blood Marrow Transplant 2003; 9: 519–528.

    Article  Google Scholar 

  25. Horan JT, Liesveld JL, Fenton P et al. Hematopoietic stem cell transplantation for multiply transfused patients with sickle cell disease and thalassemia after low-dose total body irradiation, fludarabine, and rabbit anti-thymocyte globulin. Bone Marrow Transplant 2005; 35: 171–177.

    Article  CAS  Google Scholar 

  26. Hongeng S, Chuansumrit A, Hathirat P et al. Full chimerism in nonmyeloablative stem cell transplantation in a beta-thalassemia major patient (class 3 Lucarelli). Bone Marrow Transplant 2002; 30: 409–410.

    Article  CAS  Google Scholar 

  27. Storb R, Floersheim GL, Weiden PL et al. Effect of prior blood transfusions on marrow grafts: abrogation of sensitization by procarbazine and antithymocyte serum. J Immunol 1974; 112: 1508–1516.

    CAS  PubMed  Google Scholar 

  28. Storb R, Etzioni R, Anasetti C et al. Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia. Blood 1994; 84: 941–949.

    CAS  Google Scholar 

  29. Slavin S, Nagler A, Naparstek E 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  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pediatric Hematology-Oncolgy, Hannover Medical University, Hannover, Germany

    M Sauer, C Bettoni, M Lauten, A Ghosh, K Rehe, L Grigull, A Beilken, K Welte & K W Sykora

Authors
  1. M Sauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Bettoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Lauten
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Ghosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Rehe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L Grigull
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Beilken
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Welte
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K W Sykora
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Sauer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sauer, M., Bettoni, C., Lauten, M. et al. Complete substitution of cyclophosphamide by fludarabine and ATG in a busulfan-based preparative regimen for children and adolescents with β-thalassemia. Bone Marrow Transplant 36, 383–387 (2005). https://doi.org/10.1038/sj.bmt.1705082

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705082

Keywords

This article is cited by

Search

Advanced search

Quick links