Skip to main content
SpringerLink
Log in

Favorable outcome in non-infant children with MLL-AF4-positive acute lymphoblastic leukemia: a report from the Tokyo Children’s Cancer Study Group

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

Abstract

Unlike acute lymphoblastic leukemia (ALL) in infants, MLL gene rearrangement (MLL-r) is rare in ALL children (≥1 year old). The outcome and optimal treatment options for MLL-r ALL remain controversial. Among the 1827 children enrolled in the Tokyo Children’s Cancer Study Group ALL studies L95–14, L99–15, L99–1502, L04–16, and L07–1602 (1995–2009), 25 MLL-r ALL patients (1.3 %) were identified. Their median age and leukocyte count at diagnosis was 2 years old (range 1–15 years) and 27,690/μL (range 1800–1,113,000/μL), respectively. All but one patient achieved complete remission (CR) after induction therapy, and 19 underwent allogeneic hematopoietic stem cell transplantation (HSCT) in first CR according to the protocol. The 5-year event-free survival (EFS) and overall survival (OS) rate were 60.0 % [standard error (SE), 9.7 %] and 64.0 % (SE 9.6 %), respectively. Notably, 9/12 cases with MLL-AF4-positive ALL are alive in continuous CR with a 75.0 % (SE 12.5 %) EFS rate. The causes of treatment failure were as follows: one induction failure, five relapses, and five transplant-related deaths. With intensive chemotherapy and allogeneic HSCT, favorable outcome of children (≥1 year old) with MLL-AF4-positive ALL was observed. However, considering the risk of acute and late toxicities associated with HSCT, its indication should be restricted.

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
Fig. 2

Similar content being viewed by others

References

  1. Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer. 2007;7:823–33.

    Article  CAS  PubMed  Google Scholar 

  2. Pieters R, Schrappe M, de Lorenzo P, Hann I, De Rossi G, Felice M, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet. 2007;370:240–50.

    Article  CAS  PubMed  Google Scholar 

  3. Koh K, Tomizawa D, Moriya Saito A, Watanabe T, Miyamura T, Hirayama M, et al. Early use of allogeneic hematopoietic stem cell transplantation for infants with MLL gene-rearrangement-positive acute lymphoblastic leukemia. Leukemia. 2015;29:290–6.

    Article  CAS  PubMed  Google Scholar 

  4. Dreyer ZE, Hilden JM, Jones TL, Devidas M, Winick NJ, Willman CL, et al. Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3). Pediatr Blood Cancer. 2015;62:419–26.

    Article  PubMed  Google Scholar 

  5. Pui C-H, Gaynon PS, Boyett JM, Chessells JM, Baruchel A, Kamps W, et al. Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet. 2002;359:1909–15.

    Article  PubMed  Google Scholar 

  6. Pui CH, Chessells JM, Camitta B, Baruchel A, Biondi A, Boyett JM, et al. Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements. Leukemia. 2003;17:700–6.

    Article  CAS  PubMed  Google Scholar 

  7. Tsuchida M, Manabe A, Kumagai M, Shimada H, Kikuchi A, Mori T, et al. Long-term results of Tokyo Children’s Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984–1999. Leukemia. 2010;24:383–96.

    Article  CAS  PubMed  Google Scholar 

  8. Igarashi S, Manabe A, Ohara A, Kumagai M, Saito T, Okimoto Y, et al. No advantage of dexamethasone over prednisolone for the outcome of standard- and intermediate-risk childhood acute lymphoblastic leukemia in the Tokyo Children’s Cancer Study Group L95–14 protocol. J Clin Oncol. 2005;23:6489–98.

    Article  CAS  PubMed  Google Scholar 

  9. Manabe A, Ohara A, Hasegawa D, Koh K, Saito T, Kiyokawa N, et al. Significance of the complete clearance of peripheral blasts after 7 days of prednisolone treatment in children with acute lymphoblastic leukemia: the Tokyo Children’s Cancer Study Group Study L99–15. Haematologica. 2008;93:1155–60.

    Article  CAS  PubMed  Google Scholar 

  10. Hasegawa D, Manabe A, Ohara A, Kikuchi A, Koh K, Kiyokawa N, et al. The utility of performing the initial lumbar puncture on day 8 in remission induction therapy for childhood acute lymphoblastic leukemia: TCCSG L99–15 study. Pediatr Blood Cancer. 2012;58:23–30.

    Article  PubMed  Google Scholar 

  11. Kato M, Koh K, Manabe A, Saito T, Hasegawa D, Isoyama K, et al. No impact of high-dose cytarabine and asparaginase as early intensification with intermediate-risk paediatric acute lymphoblastic leukaemia: results of randomized trial TCCSG study L99–15. Br J Haematol. 2014;164:376–83.

    Article  CAS  PubMed  Google Scholar 

  12. Möricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dördelmann M, et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood. 2008;111:4477–89.

    Article  PubMed  Google Scholar 

  13. van Dongen JJ, Seriu T, Panzer-Grümayer ER, Biondi A, Pongers-Willemse MJ, Corral L, et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet. 1998;352:1731–8.

    Article  PubMed  Google Scholar 

  14. Tomizawa D, Koh K, Sato T, Kinukawa N, Isoyama K, Kosaka Y, et al. Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group. Leukemia. 2007;21:2258–63.

    Article  CAS  PubMed  Google Scholar 

  15. Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W, et al. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood. 2000;95:3310–22.

    CAS  PubMed  Google Scholar 

  16. Conter V, Valsecchi MG, Parasole R, Putti MC, Locatelli F, Barisone E, et al. Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study. Blood. 2014;123:1470–8.

    Article  CAS  PubMed  Google Scholar 

  17. Pieters R, den Boer ML, Durian M, Janka G, Schmiegelow K, Kaspers GJL, et al. Relation between age, immunophenotype and in vitro drug resistance in 395 children with acute lymphoblastic leukemia-implications for treatment of infants. Leukemia. 1998;12:1344–8.

    Article  CAS  PubMed  Google Scholar 

  18. Stam RW, den Boer ML, Meijerink JPP, Ebus MEG, Peters GJ, Noordhuis P, et al. Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia. Blood. 2003;101:1270–6.

    Article  CAS  PubMed  Google Scholar 

  19. Jansen MWJC, Corral L, Van der Velden VHJ, Panzer-Grümayer R, Schrappe M, Schrauder A, et al. Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement. Leukemia. 2007;21:633–41.

    CAS  PubMed  Google Scholar 

  20. Bernt KM, Zhu N, Sinha AU, Vempati S, Faber J, Krivtsov AV, et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell. 2011;20:66–78.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Stumpel DJPM, Schneider P, van Roon EHJ, Boer JM, de Lorenzo P, Valsecchi MG, et al. Specific promoter methylation identifies different subgroups of MLL-rearranged infant acute lymphoblastic leukemia, influences clinical outcome, and provides therapeutic options. Blood. 2009;114:5490–8.

    Article  CAS  PubMed  Google Scholar 

  22. Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L, Boriack-Sjodin PA, et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013;122:1017–25.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Vu LP, Luciani L, Nimer SD. Histone-modifying enzymes: their role in the pathogenesis of acute leukemia and their therapeutic potential. Int J Hematol. 2013;97:198–209.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank all the investigators, coworkers, and members of participating hospitals in the TCCSG, and especially to Ms. Kaori Itagaki of TCCSG central office for her devotion to the group including data management. The authors also thank Dr. Julian Tang of the Department of Education for Clinical Research, National Center for Child Health and Development, for critical comments and editorial assistance. This work was supported in part by a Grant for the National Center for Child Health and Development (27-4).

Author information

Authors and Affiliations

  1. Division of Leukemia and Lymphoma, Children’s Cancer Center, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan

    Daisuke Tomizawa

  2. Division of Transplantation and Cell Therapy, Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan

    Motohiro Kato

  3. Department of Pediatrics, Toho University, Tokyo, Japan

    Hiroyuki Takahashi & Akira Ohara

  4. Department of Pediatrics and Adolescent Medicine, Juntendo University School of Medicine, Tokyo, Japan

    Junya Fujimura

  5. Department of Pediatrics, Yamanashi University, Kofu, Japan

    Takeshi Inukai

  6. Department of Pediatrics, University of Tsukuba, Tsukuba, Japan

    Takashi Fukushima

  7. Department of Pediatric Hematology and Oncology Research, National Center for Child Health and Development, Tokyo, Japan

    Nobutaka Kiyokawa

  8. Department of Hematology/Oncology, Saitama Children’s Medical Center, Saitama, Japan

    Katsuyoshi Koh

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

    Atsushi Manabe

Authors
  1. Daisuke Tomizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Motohiro Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroyuki Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Junya Fujimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takeshi Inukai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takashi Fukushima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nobutaka Kiyokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Katsuyoshi Koh
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Atsushi Manabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Akira Ohara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daisuke Tomizawa.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 329 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tomizawa, D., Kato, M., Takahashi, H. et al. Favorable outcome in non-infant children with MLL-AF4-positive acute lymphoblastic leukemia: a report from the Tokyo Children’s Cancer Study Group. Int J Hematol 102, 602–610 (2015). https://doi.org/10.1007/s12185-015-1869-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-015-1869-y

Keywords

Search

Navigation