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A combination of fludarabine, half-dose cyclophosphamide, and anti-thymocyte globulin is an effective conditioning regimen before allogeneic stem cell transplantation for aplastic anemia

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Abstract

Conditioning regimens consisting of reduced-dose cyclophosphamide (CY) and fludarabine (FDR) have been investigated for use in allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with aplastic anemia to reduce the toxicities associated with CY. However, the ideal dose of CY has not been identified. In addition, little information is available regarding donor cell chimerism after allo-HSCT with these regimens. Therefore, we retrospectively analyzed 13 patients who underwent allo-HSCT with half-dose CY (100 mg/kg in total), FDR, and anti-thymocyte globulin at total doses of 2.5–10 mg/kg at our center. All the patients except one, who died due to encephalopathy on day 20, achieved neutrophil engraftment a median of 18.5 days after HSCT with complete donor-type chimerism. Two patients who received a graft from an HLA-matched donor subsequently developed mixed chimerism (MC) associated with transfusion-dependent cytopenia. One became transfusion-independent after donor lymphocyte infusion, but continues to exhibit MC. The other regained complete donor-type chimerism after the cessation of cyclosporine, but remains transfusion-dependent. These findings suggest that a conditioning regimen with half-dose CY and FDR is effective for achieving neutrophil engraftment and complete donor-type chimerism. However, subsequent MC may be observed, especially after HLA-matched HSCT.

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References

  1. Storb R, Blume KG, O’Donnell MR, Chauncey T, Forman SJ, Deeg HJ, et al. Cyclophosphamide and antithymocyte globulin to condition patients with aplastic anemia for allogeneic marrow transplantations: the experience in four centers. Biol Blood Marrow Transpl. 2001;7:39–44.

    Article  CAS  Google Scholar 

  2. Srinivasan R, Takahashi Y, McCoy JP, Espinoza-Delgado I, Dorrance C, Igarashi T, et al. Overcoming graft rejection in heavily transfused and allo-immunised patients with bone marrow failure syndromes using fludarabine-based haematopoietic cell transplantation. Br J Haematol. 2006;133:305–14.

    Article  CAS  PubMed  Google Scholar 

  3. Bacigalupo A, Locatelli F, Lanino E, Marsh J, Socie G, Maury S, et al. Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA working party. Bone Marrow Transpl. 2005;36:947–50.

    Article  CAS  Google Scholar 

  4. Tolar J, Deeg HJ, Arai S, Horwitz M, Antin JH, McCarty JM, et al. Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose deescalation study show life-threatening adverse events at predefined cyclophosphamide dose levels. Biol Blood Marrow Transpl. 2012;18:1007–11.

    Article  CAS  Google Scholar 

  5. Maury S, Bacigalupo A, Anderlini P, Aljurf M, Marsh J, Socie G, et al. Improved outcome of patients older than 30 years receiving HLA-identical sibling hematopoietic stem cell transplantation for severe acquired aplastic anemia using fludarabine-based conditioning: a comparison with conventional conditioning regimen. Haematologica. 2009;94:1312–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Bacigalupo A, Socie G, Lanino E, Prete A, Locatelli F, Locasciulli A, et al. Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA working party. Haematologica. 2010;95:976–82.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. George B, Mathews V, Viswabandya A, Kavitha ML, Srivastava A, Chandy M. Fludarabine and cyclophosphamide based reduced intensity conditioning (RIC) regimens reduce rejection and improve outcome in Indian patients undergoing allogeneic stem cell transplantation for severe aplastic anemia. Bone Marrow Transpl. 2007;40:13–8.

    Article  CAS  Google Scholar 

  8. Resnick IB, Aker M, Shapira MY, Tsirigotis PD, Bitan M, Abdul-Hai A, et al. Allogeneic stem cell transplantation for severe acquired aplastic anaemia using a fludarabine-based preparative regimen. Br J Haematol. 2006;133:649–54.

    Article  CAS  PubMed  Google Scholar 

  9. Chan KW, Li CK, Worth LL, Chik KW, Jeha S, Shing MK, et al. A fludarabine-based conditioning regimen for severe aplastic anemia. Bone Marrow Transpl. 2001;27:125–8.

    Article  CAS  Google Scholar 

  10. Anderlini P, Acholonu SA, Okoroji GJ, Bassett RE, Shpall EJ, Qazilbash MH, et al. Fludarabine, cyclophosphamide, and antithymocyte globulin for matched related and unrelated allogeneic stem cell transplant in severe aplastic anemia. Leuk Lymph. 2011;52:137–41.

    Article  CAS  Google Scholar 

  11. Kang HJ, Lee JW, Kim H, Shin HY, Ahn HS. Successful first-line treatment with double umbilical cord blood transplantation in severe aplastic anemia. Bone Marrow Transpl. 2010;45:955–6.

    Article  CAS  Google Scholar 

  12. Antin JH, 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 of the International Bone Marrow Transplant Registry and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transpl. 2001;7:473–85.

    Article  CAS  Google Scholar 

  13. Marsh JC, Gupta V, Lim Z, Ho AY, Ireland RM, Hayden J, et al. Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia. Blood. 2011;118:2351–7.

    Article  CAS  PubMed  Google Scholar 

  14. Hoelle W, Beck JF, Dueckers G, Kreyenberg H, Lang P, Gruhn B, et al. Clinical relevance of serial quantitative analysis of hematopoietic chimerism after allogeneic stem cell transplantation in children for severe aplastic anemia. Bone Marrow Transpl. 2004;33:219–23.

    Article  CAS  Google Scholar 

  15. Hill RS, Petersen FB, Storb R, Appelbaum FR, Doney K, Dahlberg S, et al. Mixed hematologic chimerism after allogeneic marrow transplantation for severe aplastic anemia is associated with a higher risk of graft rejection and a lessened incidence of acute graft-versus-host disease. Blood. 1986;67:811–6.

    CAS  PubMed  Google Scholar 

  16. Ozyurek E, Cowan MJ, Koerper MA, Baxter-Lowe LA, Dvorak CC, Horn BN. Increasing mixed chimerism and the risk of graft loss in children undergoing allogeneic hematopoietic stem cell transplantation for non-malignant disorders. Bone Marrow Transpl. 2008;42:83–91.

    Article  CAS  Google Scholar 

  17. Huss R, Deeg HJ, Gooley T, Bryant E, Leisenring W, Clift R, et al. Effect of mixed chimerism on graft-versus-host disease, disease recurrence and survival after HLA-identical marrow transplantation for aplastic anemia or chronic myelogenous leukemia. Bone Marrow Transpl. 1996;18:767–76.

    CAS  Google Scholar 

  18. Yoshida N, Yagasaki H, Yabe H, Kikuchi A, Kobayashi R, Takahashi Y, et al. Donor-type aplasia after bone marrow transplantation in children with aplastic anemia: a nationwide retrospective study. Blood (ASH annual meeting abstracts). 2012;120:959.

    Google Scholar 

  19. Terasako K, Sato K, Sato M, Kimura S, Nakasone H, Okuda S, et al. The effect of different ATG preparations on immune recovery after allogeneic hematopoietic stem cell transplantation for severe aplastic anemia. Hematology. 2010;15:165–9.

    Article  CAS  PubMed  Google Scholar 

  20. Oshima K, Kanda Y, Nakasone H, Arai S, Nishimoto N, Sato H, et al. Decreased incidence of acute graft-versus-host disease by continuous infusion of cyclosporine with a higher target blood level. Am J Hematol. 2008;83:226–32.

    Article  CAS  PubMed  Google Scholar 

  21. Kanda Y, Mineishi S, Saito T, Saito A, Yamada S, Ohnishi M, et al. Long-term low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transpl. 2001;28:689–92.

    Article  CAS  Google Scholar 

  22. Asano-Mori Y, Kanda Y, Oshima K, Kako S, Shinohara A, Nakasone H, et al. Long-term ultra-low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation. Am J Hematol. 2008;83:472–6.

    Article  CAS  PubMed  Google Scholar 

  23. Kanda Y, Mineishi S, Saito T, Saito A, Ohnishi M, Niiya H, et al. Response-oriented preemptive therapy against cytomegalovirus disease with low-dose ganciclovir: a prospective evaluation. Transplantation. 2002;73:568–72.

    Article  CAS  PubMed  Google Scholar 

  24. Thiede C, Florek M, Bornhauser M, Ritter M, Mohr B, Brendel C, et al. Rapid quantification of mixed chimerism using multiplex amplification of short tandem repeat markers and fluorescence detection. Bone Marrow Transpl. 1999;23:1055–60.

    Article  CAS  Google Scholar 

  25. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48:452–8.

    Article  CAS  Google Scholar 

  26. Kanda Y, Oshima K, Kako S, Fukuda T, Uchida N, Miyamura K, et al. In vivo T-cell depletion with alemtuzumab in allogeneic hematopoietic stem cell transplantation: combined results of two studies on aplastic anemia and HLA-mismatched haploidentical transplantation. Am J Hematol. 2013;88:294–300.

    Article  CAS  PubMed  Google Scholar 

  27. Gandhi S, Kulasekararaj AG, Mufti GJ, Marsh JC. Allogeneic stem cell transplantation using alemtuzumab-containing regimens in severe aplastic anemia. Int J Hematol. 2013;97:573–80.

    Article  CAS  PubMed  Google Scholar 

  28. Al-Zahrani H, Nassar A, Al-Mohareb F, Al-Sharif F, Mohamed S, Al-Anazi K, et al. Fludarabine-based conditioning chemotherapy for allogeneic hematopoietic stem cell transplantation in acquired severe aplastic anemia. Biol Blood Marrow Transpl. 2011;17:717–22.

    Article  CAS  Google Scholar 

  29. Curtis RE, Travis LB, Rowlings PA, Socie G, Kingma DW, Banks PM, et al. Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study. Blood. 1999;94:2208–16.

    CAS  PubMed  Google Scholar 

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Correspondence to Yoshinobu Kanda.

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Ashizawa, M., Akahoshi, Y., Nakano, H. et al. A combination of fludarabine, half-dose cyclophosphamide, and anti-thymocyte globulin is an effective conditioning regimen before allogeneic stem cell transplantation for aplastic anemia. Int J Hematol 99, 311–317 (2014). https://doi.org/10.1007/s12185-014-1501-6

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  • DOI: https://doi.org/10.1007/s12185-014-1501-6

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