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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

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

References

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 18.

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

  19. 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.

  20. 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.

  21. 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.

  22. 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.

  23. 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.

  24. 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.

  25. 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.

  26. 26.

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

  27. 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.

  28. 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.

  29. 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.

  30. 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.

  31. 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.

  32. 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.

  33. 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.

  34. 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.

  35. 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.

  36. 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.

  37. 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.

  38. 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.

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

Affiliations

  1. Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan

    • Yasuhiro Okamoto
  2. Department of Pediatrics, Fujita Health University Hospital, 1-98 Dengakugakubo Kutsukake-cho, Toyoake-city, Aichi, 470-1192, Japan

    • Kazuko Kudo
  3. Department of Pediatrics, Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan

    • Ken Tabuchi
  4. Children’s Cancer Center, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan

    • Daisuke Tomizawa
  5. Department of Pediatrics, Shiga University of Medical Science Hospital, Seta Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan

    • Takashi Taga
  6. Division of Hematology/Oncology, Kanagawa Children’s Medical Center, 2-138-4 Mutsukawa, Minami-ku, Yokohama, Kanagawa, 232-8555, Japan

    • Hiroaki Goto
  7. Department of Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, 4-1-1 Kitakaname, Hiratsuka, Kanagawa, 259-1292, Japan

    • Hiromasa Yabe
  8. Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan

    • Yozo Nakazawa
  9. Department of Hematology/Oncology, Saitama Children’s Medical Center, 1-2 Shintoshin, Chuo-ku, Saitama, 330-8777, Japan

    • Katsuyoshi Koh
  10. Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan

    • Kazuhiro Ikegame
  11. Department of Hematology and Oncology, Children’s Medical Center, Japanese Red Cross Nagoya First Hospital, 3-35 Michishita-cho, Namamura-ku, Nagoya, Aichi, 453-0046, Japan

    • Nao Yoshida
    •  & Koji Kato
  12. Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan

    • Naoyuki Uchida
  13. Department of Hematology and Oncology, Shizuoka Children’s Hospital, 860 Urushiyama, Aoi-ku, Shizuoka, 420-8660, Japan

    • Kenichiro Watanabe
  14. Department of Pediatrics, Kyushu University Hospital, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    • Yuuki Koga
  15. Department of Hematology/Oncology, Osaka Women’s and Children’s Hospital, 840 Murodo-cho, Izumi, Osaka, 594-1101, Japan

    • Masami Inoue
  16. Department of Healthcare Administration, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    • Yoshiko Atsuta
  17. Japanese Data Center for Hematopoietic Cell Transplantation, 1-1-20 Daikominami, Higashi-ku, Nagoya, Aichi, 461-0047, Japan

    • Yoshiko Atsuta
  18. Department of Pediatrics, Kyoto City Hospital, 1-2 Mibuhigashitakadacho, Nakagyo Ward, Kyoto, 604-8845, Japan

    • Hiroyuki Ishida

Authors

  1. Search for Yasuhiro Okamoto in:

  2. Search for Kazuko Kudo in:

  3. Search for Ken Tabuchi in:

  4. Search for Daisuke Tomizawa in:

  5. Search for Takashi Taga in:

  6. Search for Hiroaki Goto in:

  7. Search for Hiromasa Yabe in:

  8. Search for Yozo Nakazawa in:

  9. Search for Katsuyoshi Koh in:

  10. Search for Kazuhiro Ikegame in:

  11. Search for Nao Yoshida in:

  12. Search for Naoyuki Uchida in:

  13. Search for Kenichiro Watanabe in:

  14. Search for Yuuki Koga in:

  15. Search for Masami Inoue in:

  16. Search for Koji Kato in:

  17. Search for Yoshiko Atsuta in:

  18. Search for Hiroyuki Ishida in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Yasuhiro Okamoto.

About this article

Publication history

Received

Revised

Accepted

Published

DOI

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