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.

  • Article
  • Published:

Hematopoietic stem-cell transplantation in children with refractory acute myeloid leukemia

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) can be used to treat children with refractory acute myeloid leukemia (AML). This retrospective analysis aimed to describe the outcomes and risk factors in such children. Data were collected through the nation-wide registry program in Japan. A total of 417 AML (median age: 13 years) patients 20 years or younger at HSCT, between January 2001 and December 2015, were included. A total of 314 patients died, and the median follow-up duration of the survivors was 1052 days. The most frequent cause of death was leukemia progression (58%). The 3-year overall survival (OS) rate was 23% (95% confidence interval [CI]: 19–28%). Chronic GVHD was associated with improved 3-year OS (47%, 95% CI, 36–57%, hazard ratio: 0.603, p = 0.001). Low performance status, presence of more than 25% of marrow blasts, presence of blasts in the blood at transplantation, FAB (other than M1 or M2), male donors, and number of transplantations ≥ 2 were adverse pre-HSCT variables. Patients with 0, 1–2, 3–4, 5, and 6–7 pre-HSCT variables had 3-year OS rates of 52%, 32%, 19%, 8, and 0%, respectively. Our findings may help experts decide if HSCT should be performed in such cases.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Duval M, Klein JP, He W, Cahn JY, Cairo M, Camitta BM, et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol. 2010;28:3730–8.

    Article  Google Scholar 

  2. Bunin NJ, Davies SM, Aplenc R, Camitta BM, DeSantes KB, Goyal RK, et al. Unrelated donor bone marrow transplantation for children with acute myeloid leukemia beyond first remission or refractory to chemotherapy. J Clin Oncol. 2008;26:4326–32.

    Article  Google Scholar 

  3. Godder KT, Hazlett LJ, Abhyankar SH, Chiang KY, Christiansen NP, Bridges KD, et al. Partially mismatched related-donor bone marrow transplantation for pediatric patients with acute leukemia: Younger donors and absence of peripheral blasts improve outcome. J Clin Oncol. 2000;18:1856–66.

    Article  CAS  Google Scholar 

  4. Goldman FD, Rumelhart SL, DeAlacron P, Holida MD, Lee NF, Miller J, et al. Poor outcome in children with refractory/relapsed leukemia undergoing bone marrow transplantation with mismatched family member donors. Bone Marrow Transplant. 2000;25:943–8.

    Article  CAS  Google Scholar 

  5. Michallet M, Thomas X, Vernant JP, Kuentz M, Socié G, Espérou-Bourdeau H, et al. Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: A retrospective study of 379 patients reported to the Sociètè Francaise de Greffe de Moelle (SFGM). Bone Marrow Transplant. 2000;26:1157–63.

    Article  CAS  Google Scholar 

  6. Nemecek ER, Gooley TA, Woolfrey AE, Carpenter PA, Matthews DC, Sanders JE. Outcome of allogeneic bone marrow transplantation for children with advanced acute myeloid leukemia. Bone Marrow Transplant. 2004;34:799–806.

    Article  CAS  Google Scholar 

  7. Quarello P, Fagioli F, Basso G, Maude SL, Fitzgerald JC, Fisher BT, et al. Outcome of children with acute myeloid leukaemia (AML) experiencing primary induction failure in the AIEOP AML 2002/01 clinical trial. Br J Haematol. 2015;171:566–73.

    Article  Google Scholar 

  8. Jaiswal SR, Chakrabarti A, Chatterjee S, Bhargava S, Ray K, O’Donnell P, et al. Haploidentical peripheral blood stem cell transplantation with post-transplantation cyclophosphamide in children with advanced acute leukemia with fludarabine-, busulfan-, and melphalan-based conditioning. Biol Blood Marrow Transplant. 2016;22:499–504.

    Article  CAS  Google Scholar 

  9. Jaiswal SR, Zaman S, Chakrabarti A, Sen S, Mukherjee S, Bhargava S, et al. Improved outcome of refractory/relapsed acute myeloid leukemia after post-transplantation cyclophosphamide-based haploidentical transplantation with myeloablative conditioning and early prophylactic granulocyte colony-stimulating factor-mobilized donor lymphocyte infusions. Biol Blood Marrow Transplant. 2016;22:1867–73.

    Article  CAS  Google Scholar 

  10. O’Hare P, Lucchini G, Cummins M, Veys P, Potter M, Lawson S, et al. Allogeneic stem cell transplantation for refractory acute myeloid leukemia in pediatric patients: the UK experience. Bone Marrow Transplant. 2017;52:825–31.

    Article  Google Scholar 

  11. Atsuta Y. Introduction of Transplant Registry Unified Management Program 2 (TRUMP2): scripts for TRUMP data analyses, part I (variables other than HLA-related data). Int J Hematol. 2016;103:3–10.

    Article  Google Scholar 

  12. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96:4075–83.

    CAS  PubMed  Google Scholar 

  13. Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant. 2009;15:367–9.

    Article  Google Scholar 

  14. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009;15:1628–33.

    Article  Google Scholar 

  15. 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;15:825–8.

    CAS  Google Scholar 

  16. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, et al. Chronic graft-versus-host syndrome in man: a long term clinicopathologic study of 20 Seattle patients. Am J Med. 1980;69:204–17.

    Article  CAS  Google Scholar 

  17. Weisdorf D, Spellman S, Haagenson M, Horowitz M, Lee S, Anasetti C, et al. Classification of HLA-matching for retrospective analysis of unrelated donor transplantation: revised definitions to predict survival. Biol Blood Marrow Transplant. 2008;14:748–58.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Wong R, Shahjahan M, Wang X, Thall PF, De Lima M, Khouri I, et al. Prognostic factors for outcomes of patients with refractory or relapsed acute myelogenous leukemia or myelodysplastic syndromes undergoing allogeneic progenitor cell transplantation. Biol Blood Marrow Transplant. 2005;11:108–14.

    Article  Google Scholar 

  20. Hosing C, Saliba RM, Shahjahan M, Estey EH, Couriel D, Giralt S, et al. Disease burden may identify patients more likely to benefit from second allogeneic hematopoietic stem cell transplantation to treat relapsed acute myelogenous leukemia. Bone Marrow Transplant. 2005;36:157–62.

    Article  CAS  Google Scholar 

  21. Oyekunle AA, Kröger N, Zabelina T, Ayuk F, Schieder H, Renges H, et al. Allogeneic stem-cell transplantation in patients with refractory acute leukemia: a long-term follow-up. Bone Marrow Transplant. 2006;37:45–50.

    Article  CAS  Google Scholar 

  22. Hemmati PG, Terwey TH, Na IK, Jehn CF, le Coutre P, Vuong LG, et al. Allogeneic stem cell transplantation for refractory acute myeloid leukemia: a single center analysis of long-term outcome. Eur J Haematol. 2015;95:498–506.

    Article  Google Scholar 

  23. Kollman C, Spellman SR, Zhang MJ, Hassebroek A, Anasetti C, Antin JH, et al. The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy. Blood. 2016;127:260–7.

    Article  CAS  Google Scholar 

  24. Stern M, Brand R, de Witte T, Sureda A, Rocha V, Passweg J, et al. Female-versus-male alloreactivity as a model for minor histocompatibility antigens in hematopoietic stem cell transplantation. Am J Transplant. 2008;8:2149–57.

    Article  CAS  Google Scholar 

  25. Gratwohl A, Stern M, Brand R, Apperley J, Baldomero H, de Witte T, et al. European Group for Blood and Marrow Transplantation and the European Leukemia Net. Risk score for outcome after allogeneic hematopoietic stem cell transplantation: a retrospective analysis. Cancer. 2009;115:4715–26.

    Article  Google Scholar 

  26. Gratwohl A. The EBMT risk score. Bone Marrow Transplant. 2012;47:749–56.

    Article  CAS  Google Scholar 

  27. Craddock C, Labopin M, Pillai S, Finke J, Bunjes D, Greinix H, et al. Factors predicting outcome after unrelated donor stem cell transplantation in primary refractory acute myeloid leukaemia. Leukemia. 2011;25:808–13.

    Article  CAS  Google Scholar 

  28. Mancusi A, Ruggeri L, Velardi A. Haploidentical hematopoietic transplantation for the cure of leukemia: from its biology to clinical translation. Blood. 2016;128:2616–23.

    Article  CAS  Google Scholar 

  29. Kato M, Kurata M, Kanda J, Kato K, Tomizawa D, Kudo K, et al. Impact of graft-versus-host disease on relapse and survival after allogeneic stem cell transplantation for pediatric leukemia. Bone Marrow Transplant. https://doi.org/10.1038/s41409-018-0221-6.

    Article  Google Scholar 

  30. Locatelli F, Rocha V, Chastang C, Arcese W, Michel G, Abecasis M, et al. Factors associated with outcome after cord blood transplantation in children with acute leukemia: Eurocord-Cord Blood Transplant Group. Blood. 1999;93:3662–71.

    CAS  PubMed  Google Scholar 

  31. Michel G, Rocha V, Chevret S, Arcese W, Chan KW, Filipovich A, et al. Unrelated cord blood transplantation for childhood acute myeloid leukemia: a Eurocord Group analysis. Blood. 2003;102:4290–7.

    Article  CAS  Google Scholar 

  32. Isoyama K, Oda M, Kato K, Isoyama K, Oda M, Kato K, et al. Long-term outcome of cord blood transplantation from unrelated donors as an initial transplantation procedure for children with AML in Japan. Bone Marrow Transplant. 2010;45:69–77.

    Article  CAS  Google Scholar 

  33. Eapen M, Rubinstein P, Zhang MJ, Stevens C, Kurtzberg J, Scaradavou A, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet. 2007;369:1947–54.

    Article  Google Scholar 

  34. Alyea EP, Kim HT, Ho V, Cutler C, DeAngelo DJ, Stone R, et al. Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant. 2006;12:1047–55.

    Article  Google Scholar 

  35. Bitan M, He W, Zhang MJ, Abdel-Azim H, Ayas MF, Bielorai B, et al. Transplantation for children with acute myeloid leukemia: a comparison of outcomes with reduced intensity and myeloablative regimens. Blood. 2014;123:1615–20.

    Article  CAS  Google Scholar 

  36. Craddock C, Nagra S, Peniket A, Brookes C, Buckley L, Nikolousis E, et al. Factors predicting long-term survival after T-cell depleted reduced intensity allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica. 2010;95:989–95.

    Article  Google Scholar 

  37. Marks R, Potthoff K, Hahn J, Marks R, Potthoff K, Hahn J, et al. Reduced toxicity conditioning with fludarabine, BCNU, and melphalan in allogeneic hematopoietic cell transplantation: Particular activity against advanced hematologic malignancies. Blood. 2008;112:415–25.

    Article  CAS  Google Scholar 

  38. Schmid C, Schleuning M, Schwerdtfeger R, Hertenstein B, Mischak-Weissinger E, Bunjes D, et al. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood. 2006;108:1092–9.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to all the clinicians, hospital, and health-center administrators who provided precise data via the registry of the Japan Society for Hematopoietic Cell Transplantation. This work was supported in part by the Practical Research Project for Allergic Diseases and Immunology (Research Technology of Medical Transplantation) from the Japan Agency for Medical Research and Development, AMED under Grant Number 18ek0510023h0002. We acknowledge the efforts of Dr. Chihaya Koriyama, Professor of Epidemiology and Preventive Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University regarding statistical analysis.

Author contributions

YO designed the study, reviewed and analyzed data, and wrote the paper; HI, KKudo, KT, DT, and TT contributed to the critique of the manuscript; HG, HY, YN, KKoh, KI, NY, NU, KW, and YK identified patients for this study; and MI, KKato, and YA contributed to data collection and the critique of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yasuhiro Okamoto.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Okamoto, Y., Kudo, K., Tabuchi, K. et al. Hematopoietic stem-cell transplantation in children with refractory acute myeloid leukemia. Bone Marrow Transplant 54, 1489–1498 (2019). https://doi.org/10.1038/s41409-019-0461-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-019-0461-0

This article is cited by

Search

Quick links