Skip to main content

Advertisement

SpringerLink
Log in

Transplantation for juvenile myelomonocytic leukemia: a retrospective study of 30 children treated with a regimen of busulfan, fludarabine, and melphalan

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

We report the outcomes of 30 patients with juvenile myelomonocytic leukemia (JMML) who received unmanipulated hematopoietic stem cell transplantation (HSCT) with oral or intravenous busulfan, fludarabine, and melphalan between 2001 and 2011. Mutations in PTPN11 were detected in 15 patients. Six patients received human leukocyte antigen (HLA)-matched HSCT from related donors, and 24 patients received HSCT from alternative donors, including 13 HLA-mismatched donors. Primary engraftment failed in five patients, all of whom had received allografts from HLA-mismatched donors. HLA-mismatched HSCT resulted in poorer event-free survival than HLA-matched HSCT (28.8 vs. 70.6 %). Three patients died of transplantation-related causes, and eight patients experienced hematological relapse (including five patients who died due to disease progression). Eight patients received a second HSCT, and four of these patients have survived. The 5-year estimated overall survival for all patients was 72.4: 88.9 % for the patients without a mutation in PTPN11 (n = 10) and 58.3 % for the patients with a mutation in PTPN11 (n = 15) (P = 0.092). The conditioning regimen reported in the present study achieved hematological and clinical remission in >50 % of patients with JMML who received HSCT from alternative donors, and may also be effective for JMML patients with PTPN11 mutation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Horibe K, Saito AM, Takimoto T, Tsuchida M, Manabe A, Shima M, et al. Incidence and survival rates of hematological malignancies in Japanese children and adolescents (2006–2010): based on registry data from the Japanese Society of Pediatric Hematology. Int J Hematol. 2013;98:74–88.

    Article  PubMed  Google Scholar 

  2. Niemeyer CM, Arico M, Basso G, Biondi A, Cantu R, Creutzug U, et al. Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Blood. 1997;89:3534–43.

    CAS  PubMed  Google Scholar 

  3. Yoshida N, Yagasaki H, Xu Y, Matsuda K, Yoshimi A, Takahashi Y, et al. Correlation of clinical features with the mutational status of GM–CSF signaling pathway-related genes in juvenile myelomonocytic leukemia. Pediatr Res. 2009;65:334–40.

    Article  CAS  PubMed  Google Scholar 

  4. Sakaguchi H, Okuno Y, Muramatsu H, Yoshida K, Shiraishi Y, Takahashi M, et al. Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet. 2013;45:937–41.

    Article  CAS  PubMed  Google Scholar 

  5. Matsuda K, Yoshida N, Miura S, Nakazawa Y, Sakashita K, Tyakunan N, et al. Long-term haematological improvement after non-intensive or no chemotherapy in juvenile myelomonocytic leukemia and poor correlation with adult myelodysplasia spliceosome-related mutations. Br J Haematol. 2012;157:647–50.

    Article  PubMed  Google Scholar 

  6. Niemeyer CM, Kratz CP. Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukemia: molecular classification and treatment points. Br J Haematol. 2008;140:610–24.

    Article  CAS  PubMed  Google Scholar 

  7. Yabe M, Sako M, Yabe H, Kurosawa H, Nara T, Tokuyama M, et al. A conditioning regimen of busulfan, fludarabine, and melphalan for allogeneic stem cell transplantation in children with juvenile myelomonocytic leukemia. Pediatr Transplant. 2008;12:862–7.

    Article  CAS  PubMed  Google Scholar 

  8. Hasle H, Niemeyer CM, Chessells JM, Baumann I, Bennett JM, Kemdrup G, et al. A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative disease. Leukemia. 2003;17:277–82.

    Article  CAS  PubMed  Google Scholar 

  9. Locatelli F, Nöllke P, Zecca M, Korthof E, Lanino E, Peters C, et al. Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood. 2005;105:410–9.

    Article  CAS  PubMed  Google Scholar 

  10. Wall DA, Chan KW, Nieder ML, Hayashi RJ, Yeager AM, Kadota R, et al. Safety, efficacy, and pharmacokinetics of intravenous Busulfan in children undergoing allogeneic hematopoietic stem cell transplantation. Pediatr Blood Cancer. 2010;54:291–8.

    PubMed  Google Scholar 

  11. Locatelli F, Crotta A, Ruggeri A, Eapen M, Wagner JE, Macmillan ML, et al. Analysis of risk factors influencing outcomes after cord blood transplantation in children with juvenile myelomonocytic leukemia: a EUROCORD, EBMT, EWOG-MDS, CIBMTR study. Blood. 2013;122:2135–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Manabe A, Okamura J, Yumura-Yagi K, Akiyama Y, Sako M, Uchiyama H, et al. Allogeneic hematopoietic stem cell transplantation for 27 children with juvenile myelomonocytic leukemia diagnosed based on the criteria of the international JMML Working Group. Leukemia. 2002;16:645–9.

    Article  CAS  PubMed  Google Scholar 

  13. Yoshimi A, Bader P, Matthes-Martin S, Stary J, Sedlacek P, Duffner U, et al. Donor leukocyte infusion after hematopoietic stem cell transplantation in patients with juvenile myelomonocytic leukemia. Leukemia. 2005;19:971–7.

    Article  CAS  PubMed  Google Scholar 

  14. Yoshimi A, Mohamed M, Bierings M, Urban C, Korthof E, Zecca M, et al. Second allogeneic hematopoietic stem cell transplantation (HSCT) for patients with juvenile myelomonocytic leukemia. Leukemia. 2007;21:556–60.

    Article  CAS  PubMed  Google Scholar 

  15. Inagaki J, Fukano R, Nishikawa T, Nakashima K, Sawa D, Ito N, et al. Outcomes of immunological investigations for mixed chimerism following allogeneic stem cell transplantation in children with juvenile myelomonocytic leukemia. Pediatr Blood Cancer. 2012;60:116–20.

    Article  PubMed  Google Scholar 

  16. Yoshimi A, Niemeyer CM, Bohmer V, Duffner U, Strahm B, Kreyenberg H, et al. Chimaerism analyses and subsequent immunological intervention after stem cell transplantation in patients with juvenile myelomonocytic leukemia. Br J Haematol. 2005;129:542–9.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to express their gratitude to Dr. Yuko Osugi (Osaka City General Hospital), Dr. Chie Kobayashi (Ibaraki Children’s Hospital), Dr. Akira Ohara (Toho University School of Medicine), Dr. Masakatsu Yanagimachi (Yokohama City University School of Medicine), Dr. Naomi Sakata (Kinki University School of Medicine), Dr. Atsushi Ogawa (Niigata Cancer Center), Dr. Asahito Hama (Nagoya University School of Medicine), Dr. Hiroyuki Shimada (Keio University School of Medicine), Dr. Takashi Kaneko (Tokyo Metropolitan Children’s Medical Centre), Dr. Hiroyuki Ishida (Matsushita Memorial Hospital), and Dr. Keiichiro Kawasaki (Hyogo Children’s Hospital) for their invaluable contribution to the data.

Conflict of interest

The authors declare no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Cell Transplantation and Regenerative Medicine, Tokai University Hospital, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan

    Miharu Yabe & Hiromasa Yabe

  2. Department of Pediatrics, Hyogo Medical College, Nishinomiya, Japan

    Yoshitoshi Ohtsuka

  3. Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Kenichiro Watanabe

  4. Department of Pediatrics, National Kyushu Cancer Centre, Fukuoka, Japan

    Jiro Inagaki

  5. Department of Hematology and Oncology, Children’s Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Nao Yoshida

  6. Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan

    Kazuo Sakashita

  7. Department of Hematology and Oncology, Chiba Children’s Hospital, Chiba, Japan

    Harumi Kakuda

  8. Department of Pediatrics, Dokkyo Medical University School of Medicine, Mibu, Japan

    Hidemitsu Kurosawa

  9. Division of Hematology and Oncology, Shizuoka Children’s Hospital, Shizuoka, Japan

    Kazuko Kudo

  10. Department of Pediatrics, St. Luke’s International Hospital, Tokyo, Japan

    Atsushi Manabe

Authors
  1. Miharu Yabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshitoshi Ohtsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenichiro Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiro Inagaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nao Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazuo Sakashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Harumi Kakuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiromasa Yabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hidemitsu Kurosawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kazuko Kudo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Atsushi Manabe
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Japanese Pediatric Myelodysplastic Syndrome Study Group

Corresponding author

Correspondence to Miharu Yabe.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yabe, M., Ohtsuka, Y., Watanabe, K. et al. Transplantation for juvenile myelomonocytic leukemia: a retrospective study of 30 children treated with a regimen of busulfan, fludarabine, and melphalan. Int J Hematol 101, 184–190 (2015). https://doi.org/10.1007/s12185-014-1715-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-014-1715-7

Keywords

Search

Navigation