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Pediatric Transplants

Treatment of Fanconi anemia patients using fludarabine and low-dose TBI, followed by unrelated donor hematopoietic cell transplantation

Bone Marrow Transplantation volume 46, pages 539–544 (2011)Cite this article

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Abstract

A nonmyeloablative conditioning regimen consisting of fludarabine (FLU) and 2 Gy TBI has been used extensively and with substantial engraftment success without promoting excessive nonrelapse mortality in medically infirm patients requiring hematopoietic cell transplantation. In this paper, we studied this same low-toxicity regimen as a means of promoting engraftment of unrelated donor hematopoietic cell transplantation in patients with Fanconi anemia (FA). All patients tolerated the regimen well with no mucositis or other severe toxicities. Of six patients transplanted, five achieved stable mixed or full donor chimerism. Acute and chronic GVHD occurred in four and three patients, respectively. Three patients are alive and well at a median of 45.9 (range, 20.9–68.1) months after transplant. In summary, this FLU-based regimen facilitates stable engraftment of unrelated PBSCs, but is associated with significant chronic GVHD.

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References

  1. Flowers MED, Doney KC, Storb R, Deeg HJ, Sanders JE, Sullivan KM et al. Marrow transplantation for Fanconi anemia with or without leukemic transformation: an update of the Seattle experience. Bone Marrow Transplant 1992; 9: 167–173.

    CAS  PubMed  Google Scholar 

  2. Bonfim CM, de Medeiros CR, Bitencourt MA, Zanis-Neto J, Funke VA, Setubal DC et al. HLA-matched related donor hematopoietic cell transplantation in 43 patients with fanconi anemia conditioned with 60 mg/kg of cyclophosphamide. Biol Blood Marrow Transplant 2007; 13: 1455–1460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Guardiola P, Pasquini R, Dokal I, Ortega JJ, van Weel-Sipman M, Marsh JC et al. Outcome of 69 allogeneic stem cell transplantations for Fanconi anemia using HLA-matched unrelated donors: a study on behalf of the European Group for Blood and Marrow Transplantation. Blood 2000; 95: 422–429.

    CAS  PubMed  Google Scholar 

  4. Wagner JE, Eapen M, MacMillan ML, Harris RE, Pasquini R, Boulad F et al. Unrelated donor bone marrow transplantation for the treatment of Fanconi anemia. Blood 2007; 109: 2256–2262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. MacMillan ML, Auerbach AD, Davies SM, Defor TE, Gillio A, Giller R et al. Haematopoietic cell transplantation in patients with Fanconi anaemia using alternate donors: results of a total body irradiation dose escalation trial. Br J Haematol 2000; 109: 121–129.

    Article  CAS  PubMed  Google Scholar 

  6. Deeg HJ, Socié G, Schoch G, Henry-Amar M, Witherspoon RP, Devergie A 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: 386–392.

    CAS  PubMed  Google Scholar 

  7. Masserot C, Peffault de Latour R, Rocha V, Leblanc T, Rigolet A, Pascal F et al. Head and neck squamous cell carcinoma in 13 patients with Fanconi anemia after hematopoietic stem cell transplantation. Cancer 2008; 113: 3315–3322.

    Article  PubMed  Google Scholar 

  8. Motwani J, Lawson SE, Darbyshire PJ . Successful HSCT using nonradiotherapy-based conditioning regimens and alternative donors in patients with Fanconi anaemia—experience in a single UK centre. Bone Marrow Transplant 2005; 36: 405–410.

    Article  CAS  PubMed  Google Scholar 

  9. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG 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 

  10. Maris MB, Niederwieser D, Sandmaier BM, Storer B, Stuart M, Maloney D et al. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 2003; 102: 2021–2030.

    Article  CAS  PubMed  Google Scholar 

  11. Gyurkocza B, Cao TM, Storb RF, Lange T, Leisenring W, Franke GN et al. Salvage allogeneic hematopoietic cell transplantation with fludarabine and low-dose total body irradiation after rejection of first allografts. Biol Blood Marrow Transplant 2009; 15: 1314–1322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors. Transplantation 1974; 18: 295–304.

    Article  CAS  PubMed  Google Scholar 

  13. Champlin RE, Schmitz N, Horowitz MM, Chapuis B, Chopra R, Cornelissen JJ et al. Blood stem cells compared with bone marrrow as a source of hematopoietic cells for allogeneic transplantation. Blood 2000; 95: 3702–3709.

    CAS  PubMed  Google Scholar 

  14. Blaise D, Kuentz M, Fortanier C, Bourhis JH, Milpied N, Sutton L et al. Randomized trial of bone marrow versus lenograstim-primed blood cell allogeneic transplantation in patients with early-stage leukemia: a report from the Société Française de Greffe de Moelle. J Clin Oncol 2000; 18: 537–571.

    Article  CAS  PubMed  Google Scholar 

  15. Burroughs LM, Storb R, Leisenring WM, Pulsipher MA, Loken MR, Torgerson TR et al. Intensive postgrafting immune suppression combined with nonmyeloablative conditioning for transplantation of HLA-identical hematopoietic cell grafts: results of a pilot study for treatment of primary immunodeficiency disorders. Bone Marrow Transplant 2007; 40: 633–642.

    Article  CAS  PubMed  Google Scholar 

  16. Rosenberg PS, Greene MH, Alter BP . Cancer incidence in persons with Fanconi anemia (erratum appears in Blood 2003 March 15; 101: 2136). Blood 2003; 101: 822–826.

    Article  CAS  PubMed  Google Scholar 

  17. Yabe H, Inoue H, Matsumoto M, Hamanoue S, Koike T, Ishiguro H et al. Allogeneic haematopoietic cell transplantation from alternative donors with a conditioning regimen of low-dose irradiation, fludarabine and cyclophosphamide in Fanconi anaemia. Br J Haematol 2006; 134: 208–212.

    Article  CAS  PubMed  Google Scholar 

  18. Tan PL, Wagner JE, Auerbach AD, Defor TE, Slungaard A, MacMillan ML . Successful engraftment without radiation after fludarabine-based regimen in Fanconi anemia patients undergoing genotypically identical donor hematopoietic cell transplantation. Pediatric Blood and Cancer 2006; 46: 630–636.

    Article  PubMed  Google Scholar 

  19. 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, post-transplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14: 641–650.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chaudhury S, Auerbach AD, Kernan NA, Small TN, Prockop SE, Scaradavou A et al. Fludarabine-based cytoreductive regimen and T-cell-depleted grafts from alternative donors for the treatment of high-risk patients with Fanconi anaemia (Review). Br J Haematol 2008; 140: 644–655.

    Article  CAS  PubMed  Google Scholar 

  21. Bitan M, Or R, Shapira MY, Aker M, Resnick IB, Ackerstein A et al. Fludarabine-based reduced intensity conditioning for stem cell transplantation of Fanconi anemia patients from fully matched related and unrelated donors. Biol Blood Marrow Transplant 2006; 12: 712–718.

    Article  CAS  PubMed  Google Scholar 

  22. de La Fuente J, Reiss S, McCloy M, Vulliamy T, Roberts IA, Rahemtulla A et al. Non-TBI stem cell transplantation protocol for Fanconi anaemia using HLA-compatible sibling and unrelated donors. Bone Marrow Transplant 2003; 32: 653–656.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the patients and families enrolled in this study. We also thank our in-patient and outpatient clinical transplant teams for the substantial care of our patients, as well as the research nurses and data managers for coordination of this trial. We appreciate the help of Helen Crawford, Bonnie Larson and Sue Carbonneau for paper preparation. MST received salary support from the Fanconi Anemia Research Fund Inc. This trial was also supported in part by NIH/NHLBI HL36444 and CA15704.

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Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA, USA

    M S Thakar, R Storb, W Leisenring, M E D Flowers, B M Sandmaier, A Woolfrey & H-P Kiem

  2. Departments of Pediatrics, Seattle, WA, USA

    M S Thakar & A Woolfrey

  3. Oregon Health Sciences University, Portland, OR, USA

    P Kurre

  4. Department of Medicine, University of Washington, Seattle, WA, USA

    R Storb, W Leisenring, M E D Flowers, B M Sandmaier & H-P Kiem

  5. Children's Memorial Hospital, Chicago, IL, USA

    M Kletzel

  6. Monroe Carell Jr Children's Hospital at Vanderbilt, Nashville, TN, USA

    H Frangoul

  7. Primary Children's Medical Center, Salt Lake City, UT, USA

    M A Pulsipher

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  1. M S Thakar
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  2. P Kurre
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  3. R Storb
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  4. M Kletzel
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  5. H Frangoul
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  6. M A Pulsipher
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  7. W Leisenring
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  8. M E D Flowers
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  9. B M Sandmaier
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  10. A Woolfrey
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  11. H-P Kiem
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Correspondence to H-P Kiem.

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Thakar, M., Kurre, P., Storb, R. et al. Treatment of Fanconi anemia patients using fludarabine and low-dose TBI, followed by unrelated donor hematopoietic cell transplantation. Bone Marrow Transplant 46, 539–544 (2011). https://doi.org/10.1038/bmt.2010.154

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