Abstract
Recently, a less toxic regimen comprising reduced cyclophosphamide (Cy), fludarabine, and anti-thymocyte globulin (ATG) (Cy-Flu-ATG) was used to condition high-risk patients scheduled for allogeneic hematopoietic cell transplantation (alloHSCT) instead of standard Cy-ATG in patients with severe aplastic anemia (AA). We performed a randomized phase III study to compare the regimen-related toxicities (RRTs) of two different conditioning regimens: Cy-ATG vs. Cy-Flu-ATG. Patients in the Cy-ATG arm received Cy at 200 mg/kg. Those in the Cy-Flu-ATG arm received fludarabine (Flu) at 150 mg/m2 and Cy at 100 mg/kg. A total of 83 patients (40 in the Cy-ATG and 43 in the Cy-Flu-ATG) were enrolled. Seventy-nine patients had AA and four had MDS. All predefined RRTs were significantly lower in patients of the Cy-Flu-ATG arm (23.3 vs. 55.0 %; p = 0.003). Infection with identified causative organism and sinusoidal obstruction syndrome, hematuria, febrile episodes, and death from any cause tended to be more frequent in Cy-ATG arm but did not differ significantly between arms. There was no difference in neutrophil engraftment failure (2.5 vs. 2.33 %; p = 0.959), acute graft-versus-host disease (GvHD) (15.0 vs. 23.3 %; p = 0.388), and chronic GvHD (16.7 vs. 16.2 %; p = 0.961) between Cy-ATG and Cy-Flu-ATG arms. The 4-year survival rate did not differ between the Cy-ATG and Cy-Flu-ATG arms. Preconditioning with Cy-Flu-ATG was superior to that afforded by Cy-ATG in terms of reducing RRT levels without increasing engraftment failure. (ClinicalTrials.gov number: NCT01145976)
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References
Ades L, Mary JY, Robin M, Ferry C, Porcher R, Esperou H, Ribaud P, Devergie A, Traineau R, Gluckman E, Socie G (2004) Long-term outcome after bone marrow transplantation for severe aplastic anemia. Blood 103:2490–2497
Anderlini P, Acholonu SA, Okoroji GJ, Bassett RE, Shpall EJ, Qazilbash MH, Popat UR, Worth LL, Giralt SA, Champlin RE (2011) Fludarabine, cyclophosphamide, and antithymocyte globulin for matched related and unrelated allogeneic stem cell transplant in severe aplastic anemia. Leuk Lymphoma 52:137–141
Armitage JO (1994) Bone marrow transplantation. N Engl J Med 330:827–838
Bacigalupo A, Locatelli F, Lanino E, Marsh J, Socie G, Maury S, Prete A, Locasciulli A, Cesaro S, Passweg J (2005) 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 Transplant 36:947–950
Cleland BD, Pokorny CS (1993) Cyclophosphamide related hepatotoxicity. Australian and New Zealand journal of medicine 23:408
Deeg HJ, Seidel K, Casper J, Anasetti C, Davies S, Gajeweski JL, Territo M, Ramsay N, Harris RE, Catro-Malaspina H, Collins R, Champlin R, Schoch G, King R, Howe C (1999) Marrow transplantation from unrelated donors for patients with severe aplastic anemia who have failed immunosuppressive therapy. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant 5:243–252
DeLeve LD (1996) Cellular target of cyclophosphamide toxicity in the murine liver: role of glutathione and site of metabolic activation. Hepatology 24:830–837
Goldberg JW, Lidsky MD (1985) Cyclophosphamide-associated hepatotoxicity. South Med J 78:222–223
Goligher EC, Cserti-Gazdewich C, Balter M, Gupta V, Brandwein JE (2009) Acute lung injury during antithymocyte globulin therapy for aplastic anemia. Can Respir J 16:e3–5
Kang HJ, Shin HY, Choi HS, Ahn HS (2004) Fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen for unrelated bone marrow transplantation in severe aplastic anemia. Bone Marrow Transplant 34:939–943
Kim H, Kim BS, Kim DH, Hyun MS, Kim SH, Bae SH, Choi JH, Sohn SK, Shin HJ, Won JH, Yoon SS, Jo DY, Joo YD, Park JH, Lee KH, Transplantation oboTKSoBaM (2011 Jan 8. [Epub ahead of print]) Comparison between matched related and alternative donors of allogeneic hematopoietic stem cells transplanted into Adult patients with acquired aplastic anemia: multivariate and propensity score-matched analysis. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant
Kojima S, Matsuyama T, Kato S, Kigasawa H, Kobayashi R, Kikuta A, Sakamaki H, Ikuta K, Tsuchida M, Hoshi Y, Morishima Y, Kodera Y (2002) Outcome of 154 patients with severe aplastic anemia who received transplants from unrelated donors: the Japan Marrow Donor Program. Blood 100:799–803
Lee JH, Lee JS, Kim WK, Chi HS, Lee KH (2001) Cyclophosphamide and antithymocyte globulin conditioning may be sufficient for Korean patients with early stage severe aplastic anemia transplanted with marrow from donors other than HLA-identical siblings. Haematologica 86:434–435
Lee JH, Lee KH, Choi SJ, Min YJ, Kim JG, Kim S, Lee JS, Kim SH, Park CJ, Chi HS, Kim WK (2000) Veno-occlusive disease of the liver after allogeneic bone marrow transplantation for severe aplastic anemia. Bone Marrow Transplant 26:657–662
Lee JW, Cho BS, Lee SE, Eom KS, Kim YJ, Kim HJ, Lee S, Min CK, Cho SG, Min WS, Park CW (2011) The outcome of unrelated hematopoietic stem cell transplants with total body irradiation (800cGy) and cyclophosphamide (120 mg/kg) in Adult patients with acquired severe aplastic anemia. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant 17:101–108
Maury S, Bacigalupo A, Anderlini P, Aljurf M, Marsh J, Socie G, Oneto R, Passweg JR (2009) 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 94:1312–1315
McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, Hardin BJ, Shulman HM, Clift RA (1993) Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 118:255–267
Modzelewski JR Jr, Daeschner C, Joshi VV, Mullick FG, Ishak KG (1994) Veno-occlusive disease of the liver induced by low-dose cyclophosphamide. Modern Pathol: Off J U S Can Acad Pathol, Inc 7:967–972
Oberoi S, Bansal D, Sharma RR, Gautam V, Marwaha N, Marwaha RK (2011) Antithymocyte globulin-induced acute lung injury during transplantation for aplastic anemia. J Pediatr Hematol Oncol 33:150–152
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED (1995) 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 15:825–828
Seber A, Shu XO, Defor T, Sencer S, Ramsay N (1999) Risk factors for severe hemorrhagic cystitis following BMT. Bone Marrow Transplant 23:35–40
Slattery JT, Kalhorn TF, McDonald GB, Lambert K, Buckner CD, Bensinger WI, Anasetti C, Appelbaum FR (1996) Conditioning regimen-dependent disposition of cyclophosphamide and hydroxycyclophosphamide in human marrow transplantation patients. J Clin Oncol: Off J Am Soc Clin Oncol 14:1484–1494
Storb R, Etzioni R, Anasetti C, Appelbaum FR, Buckner CD, Bensinger W, Bryant E, Clift R, Deeg HJ, Doney K et al (1994) Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia. Blood 84:941–949
Storb R, Leisenring W, Anasetti C, Appelbaum FR, Buckner CD, Bensinger WI, Chauncey T, Clift RA, Deeg HJ, Doney KC, Flowers ME, Hansen JA, Martin PJ, Sanders JE, Sullivan KM, Witherspoon RP (1997) Long-term follow-up of allogeneic marrow transplants in patients with aplastic anemia conditioned by cyclophosphamide combined with antithymocyte globulin. Blood 89:3890–3891
Acknowledgments
We thank all members of the Cooperative Study Group A for Hematology and Ye Eun Jang and Mi Young Kim for assistance. This work was supported by Priority Research Center Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2010-0029621).
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Kim, H., Lee, JH., Joo, YD. et al. A randomized comparison of cyclophosphamide vs. reduced dose cyclophosphamide plus fludarabine for allogeneic hematopoietic cell transplantation in patients with aplastic anemia and hypoplastic myelodysplastic syndrome. Ann Hematol 91, 1459–1469 (2012). https://doi.org/10.1007/s00277-012-1462-x
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DOI: https://doi.org/10.1007/s00277-012-1462-x