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:

Aplastic Anemia

Comparable outcomes between younger (⩽40 years) and older (>40 years) adult patients with severe aplastic anemia after HLA-matched sibling stem cell transplantation using fludarabine-based conditioning

Bone Marrow Transplantation volume 51, pages 1456–1463 (2016)Cite this article

Subjects

Abstract

Allogeneic stem cell transplantation from HLA-matched siblings (MSD-SCT) for elderly patients with severe aplastic anemia (SAA) is not a widely accepted first-line treatment. Recently, fludarabine, lower-dose cyclophosphamide and antithymocyte globulin conditioning (Flu/lower-dose Cy/ATG) with lower toxicities has been investigated. To determine whether this regimen can overcome the negative effects of age, we analyzed 117 adult patients with SAA who received MSD-SCT using Flu/lower-dose Cy/ATG, and compared outcomes between 63 younger age group (YAG; ⩽40 years) and 54 older age group (OAG; >40 years) patients. No primary graft failure was observed. Neutrophil engraftment was significantly faster in the YAG compared with the OAG (12 vs 13 days; P=0.04). The incidences of acute grade II–IV (9.5% vs 9.3% at day 100; P=0.42) and chronic GVHD (8.1% vs 9.5% at 5 years; P=0.80), secondary graft failure (20.8% vs 7.9% at 5 years; P=0.11) and transplant-related mortality (5.4% and 11.1% at 5 years; P=0.91) were not significantly different between the YAG and OAG. In addition, failure-free (73.7% vs 81.0% at 5 years; P=0.73) and overall survival rates (93.7% vs 88.9% at 5 years; P=0.20) were comparable. Our results suggest that MSD-SCT using Flu/lower-dose Cy/ATG may be a feasible first-line treatment even in older patients with SAA.

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Shin SH, Lee SE, Lee JW . Recent advances in treatment of aplastic anemia. Korean J Intern Med 2014; 29: 713–726.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Marsh JC, Ball SE, Cavenagh J, Darbyshire P, Dokal I, Gordon-Smith EC et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol 2009; 147: 43–70.

    Article  CAS  PubMed  Google Scholar 

  3. Scheinberg P, Young NS . How I treat acquired aplastic anemia. Blood 2012; 120: 1185–1196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Young NS . Current concepts in the pathophysiology and treatment of aplastic anemia. Hematology Am Soc Hematol Educ Program 2013; 2013: 76–81.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Doney K, Leisenring W, Storb R, Appelbaum FR . Primary treatment of acquired aplastic anemia: outcomes with bone marrow transplantation and immunosuppressive therapy. Seattle Bone Marrow Transplant Team. Ann Intern Med 1997; 126: 107–115.

    Article  CAS  PubMed  Google Scholar 

  6. Gupta V, Eapen M, Brazauskas R, Carreras J, Aljurf M, Gale RP et al. Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors. Haematologica 2010; 95: 2119–2125.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bacigalupo A, Brand R, Oneto R, Bruno B, Socie G, Passweg J et al. Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy—The European Group for Blood and Marrow Transplantation experience. Semin Hematol 2000; 37: 69–80.

    Article  CAS  PubMed  Google Scholar 

  8. Bacigalupo A, Socie G, Hamladji RM, Aljurf M, Maschan A, Kyrcz-Krzemien S et al. Current outcome of HLA identical sibling versus unrelated donor transplants in severe aplastic anemia: an EBMT analysis. Haematologica 2015; 100: 696–702.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Sangiolo D, Storb R, Deeg HJ, Flowers ME, Martin PJ, Sandmaier BM et al. Outcome of allogeneic hematopoietic cell transplantation from HLA-identical siblings for severe aplastic anemia in patients over 40 years of age. Biol Blood Marrow Transplant 2010; 16: 1411–1418.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Socie G . Allogeneic BM transplantation for the treatment of aplastic anemia: current results and expanding donor possibilities. Hematology Am Soc Hematol Educ Program 2013; 2013: 82–86.

    Article  PubMed  Google Scholar 

  11. Storb R, Etzioni R, Anasetti C, Appelbaum FR, Buckner CD, Bensinger W et al. Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia. Blood 1994; 84: 941–949.

    CAS  PubMed  Google Scholar 

  12. Locatelli F, Bruno B, Zecca M, Van-Lint MT, McCann S, Arcese W et al. Cyclosporin A and short-term methotrexate versus cyclosporin A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling: results of a GITMO/EBMT randomized trial. Blood 2000; 96: 1690–1697.

    CAS  PubMed  Google Scholar 

  13. Ades L, Mary JY, Robin M, Ferry C, Porcher R, Esperou H et al. Long-term outcome after bone marrow transplantation for severe aplastic anemia. Blood 2004; 103: 2490–2497.

    Article  CAS  PubMed  Google Scholar 

  14. Kahl C, Leisenring W, Deeg HJ, Chauncey TR, Flowers ME, Martin PJ et al. Cyclophosphamide and antithymocyte globulin as a conditioning regimen for allogeneic marrow transplantation in patients with aplastic anaemia: a long-term follow-up. Br J Haematol 2005; 130: 747–751.

    Article  CAS  PubMed  Google Scholar 

  15. Champlin RE, Perez WS, Passweg JR, Klein JP, Camitta BM, Gluckman E et al. Bone marrow transplantation for severe aplastic anemia: a randomized controlled study of conditioning regimens. Blood 2007; 109: 4582–4585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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: 649–654.

    Article  CAS  PubMed  Google Scholar 

  17. 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 Transplant 2007; 40: 13–18.

    Article  CAS  PubMed  Google Scholar 

  18. Kim H, Lee JH, Joo YD, Bae SH, Hyun MS, Lee JH 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 2012; 91: 1459–1469.

    Article  CAS  PubMed  Google Scholar 

  19. 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: 305–314.

    Article  CAS  PubMed  Google Scholar 

  20. Gomez-Almaguer D, Vela-Ojeda J, Jaime-Perez JC, Gutierrez-Aguirre CH, Cantu-Rodriguez OG, Sobrevilla-Calvo P et al. Allografting in patients with severe, refractory aplastic anemia using peripheral blood stem cells and a fludarabine-based conditioning regimen: the Mexican experience. Am J Hematol 2006; 81: 157–161.

    Article  CAS  PubMed  Google Scholar 

  21. Cho BS, Eom KS, Kim YJ, Kim HJ, Lee S, Min CK et al. HLA-matched sibling transplantation with BM and CD34(+)-purified PBSCs in adult patients with high-risk severe aplastic anemia to overcome graft rejection without an increase in GVHD. Bone Marrow Transplant 2010; 45: 1497–1501.

    Article  CAS  PubMed  Google Scholar 

  22. Choi SM, Lee DG, Lim J, Park SH, Choi JH, Yoo JH et al. Comparison of quantitative cytomegalovirus real-time PCR in whole blood and pp65 antigenemia assay: clinical utility of CMV real-time PCR in hematopoietic stem cell transplant recipients. J Korean Med Sci 2009; 24: 571–578.

    Article  PubMed  PubMed Central  Google Scholar 

  23. 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: 1312–1315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Oelschlaegel U, Besson I, Arnoulet C, Sainty D, Nowak R, Naumann R et al. A standardized flow cytometric method for screening paroxysmal nocturnal haemoglobinuria (PNH) measuring CD55 and CD59 expression on erythrocytes and granulocytes. Clin Lab Haematol 2001; 23: 81–90.

    Article  CAS  PubMed  Google Scholar 

  25. Battiwalla M, Hepgur M, Pan D, McCarthy PL, Ahluwalia MS, Camacho SH et al. Multiparameter flow cytometry for the diagnosis and monitoring of small GPI-deficient cellular populations. Cytometry B Clin Cytom B 2010; 78: 348–356.

    Article  Google Scholar 

  26. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106: 2912–2919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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 

  28. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945–956.

    Article  PubMed  Google Scholar 

  29. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 1993; 118: 255–267.

    Article  CAS  PubMed  Google Scholar 

  30. Silva Lde P, Patah PA, Saliba RM, Szewczyk NA, Gilman L, Neumann J et al. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplants is the complex result of BK virus infection, preparative regimen intensity and donor type. Haematologica 2010; 95: 1183–1190.

    Article  PubMed  Google Scholar 

  31. The National Cancer Institute Common Terminology Criteria for adverse events version 3.0. Available at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf (accessed 14 December 2015).

  32. Copelan E, Casper JT, Carter SL, van Burik JA, Hurd D, Mendizabal AM et al. A scheme for defining cause of death and its application in the T cell depletion trial. Biol Blood Marrow Transplant 2007; 13: 1469–1476.

    Article  PubMed  Google Scholar 

  33. Deeg HJ, Maris MB, Scott BL, Warren EH . Optimization of allogeneic transplant conditioning: not the time for dogma. Leukemia 2006; 20: 1701–1705.

    Article  CAS  PubMed  Google Scholar 

  34. Slattery JT, Kalhorn TF, McDonald GB, Lambert K, Buckner CD, Bensinger WI et al. Conditioning regimen-dependent disposition of cyclophosphamide and hydroxycyclophosphamide in human marrow transplantation patients. J Clin Oncol 1996; 14: 1484–1494.

    Article  CAS  PubMed  Google Scholar 

  35. Morandi P, Ruffini PA, Benvenuto GM, Raimondi R, Fosser V . Cardiac toxicity of high-dose chemotherapy. Bone Marrow Transplant 2005; 35: 323–334.

    Article  CAS  PubMed  Google Scholar 

  36. Seber A, Shu XO, Defor T, Sencer S, Ramsay N . Risk factors for severe hemorrhagic cystitis following BMT. Bone Marrow Transplant 1999; 23: 35–40.

    Article  CAS  PubMed  Google Scholar 

  37. Or R, Weiss L, Amir G, Tejman S, Polliack A . The prophylactic potential of fludarabine monophosphate in graft-versus-host disease after bone marrow transplantation in murine models. Bone Marrow Transplant 2000; 25: 263–266.

    Article  CAS  PubMed  Google Scholar 

  38. Weiss L, Abdul-Hai A, Or R, Amir G, Polliack A . Fludarabine in combination with cyclophosphamide decreases incidence of GVHD and maintains effective graft-versus-leukemia effect after allogeneic stem cell transplantation in murine lymphocytic leukemia. Bone Marrow Transplant 2003; 31: 11–15.

    Article  CAS  PubMed  Google Scholar 

  39. Morishima Y, Kawase T, Malkki M, Morishima S, Spellman S, Kashiwase K et al. Significance of ethnicity in the risk of acute graft-versus-host disease and leukemia relapse after unrelated donor hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19: 1197–1203.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Remberger M, Aschan J, Lonnqvist B, Carlens S, Gustafsson B, Hentschke P et al. An ethnic role for chronic, but not acute, graft-versus-host disease after HLA-identical sibling stem cell transplantation. Eur J Haematol 2001; 66: 50–56.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology, Yeouido St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

    S H Shin

  2. Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

    Y W Jeon, J H Yoon, S E Lee, B S Cho, K S Eom, Y J Kim, S Lee, C K Min, H J Kim, S G Cho, D W Kim, W S Min & J W Lee

  3. Department of Hematology, Incheon St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

    S A Yahng

Authors
  1. S H Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y W Jeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J H Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S A Yahng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S E Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B S Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K S Eom
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y J Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C K Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H J Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S G Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D W Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. W S Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J W Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J W Lee.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shin, S., Jeon, Y., Yoon, J. et al. Comparable outcomes between younger (⩽40 years) and older (>40 years) adult patients with severe aplastic anemia after HLA-matched sibling stem cell transplantation using fludarabine-based conditioning. Bone Marrow Transplant 51, 1456–1463 (2016). https://doi.org/10.1038/bmt.2016.171

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2016.171

This article is cited by

Search

Advanced search

Quick links