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.

Acute lymphoblastic leukemia

Long-term outcome of 6-month maintenance chemotherapy for acute lymphoblastic leukemia in children

Subjects

Abstract

In the treatment of childhood acute lymphoblastic leukemia (ALL), excess shortening of maintenance therapy resulted in high relapse rate, as shown by our previous trial, TCCSG L92-13, in which maintenance therapy was terminated at 1 year from initiation of treatment. In this study, we aimed to confirm the long-term outcome of L92-13, and to identify who can or cannot be cured by shorter duration of maintenance therapy. To obtain sentinel cytogenetics information that had been missed before, we performed genetic analysis with genomic microarray and target intron-capture sequencing from diagnostic bone marrow smear. Disease-free survival (DFS) at 10 years from the end of therapy was 66.0±2.8%. Females (n=138) had better DFS (74.6±3.7%) than males (n=142, 57.5±4.2%, P=0.002). Patients with TCF3-PBX1 (n=11) and ETV6-RUNX1 (n=16) had excellent DFS (90.9±8.7% and 93.8±6.1%, respectively), whereas high hyperdiploidy (n=23) was the most unfavorable subgroup, with 56.6±10.3% of DFS. Short duration of therapy can cure more than half of pediatric ALL, especially females, TCF3-PBX1 and ETV6-RUNX1. Our retrospective observations suggest a gender/karyotype inhomogeneity on the impact of brief therapy.

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

Figure 1
Figure 2
Figure 3

References

  1. Inaba H, Greaves M, Mullighan CG . Acute lymphoblastic leukaemia. Lancet 2013; 381: 1943–1955.

    Article  Google Scholar 

  2. Lonsdale D, Gehan EA, Fernbach DJ, Sullivan MP, Lane DM, Ragab AH . Interrupted vs. continued maintenance therapy in childhood acute leukemia. Cancer 1975; 36: 341–352.

    Article  CAS  Google Scholar 

  3. Moricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 2010; 24: 265–284.

    Article  CAS  Google Scholar 

  4. Toyoda Y, Manabe A, Tsuchida M, Hanada R, Ikuta K, Okimoto Y et al. Six months of maintenance chemotherapy after intensified treatment for acute lymphoblastic leukemia of childhood. J Clin Oncol 2000; 18: 1508–1516.

    Article  CAS  Google Scholar 

  5. Childhood ALL Collaborative Group. Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview of 42 trials involving 12 000 randomised children. Lancet 1996; 347: 1783–1788.

    Article  Google Scholar 

  6. Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009; 360: 2730–2741.

    Article  CAS  Google Scholar 

  7. Vora A, Goulden N, Mitchell C, Hancock J, Hough R, Rowntree C et al. Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial. Lancet Oncol 2014; 15: 809–818.

    Article  Google Scholar 

  8. Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grumayer R, Moricke A et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 2010; 115: 3206–3214.

    Article  CAS  Google Scholar 

  9. Toft N, Birgens H, Abrahamsson J, Bernell P, Griskevicius L, Hallbook H et al. Risk group assignment differs for children and adults 1-45 yr with acute lymphoblastic leukemia treated by the NOPHO ALL-2008 protocol. Eur J Haematol 2013; 90: 404–412.

    Article  Google Scholar 

  10. Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL et al. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer 2015; 62: 1176–1183.

    Article  CAS  Google Scholar 

  11. Yeoh AE, Ariffin H, Chai EL, Kwok CS, Chan YH, Ponnudurai K et al. Minimal residual disease-guided treatment deintensification for children with acute lymphoblastic leukemia: results from the Malaysia-Singapore acute lymphoblastic leukemia 2003 study. J Clin Oncol 2012; 30: 2384–2392.

    Article  CAS  Google Scholar 

  12. O'Connor D, Bate J, Wade R, Clack R, Dhir S, Hough R et al. Infection-related mortality in children with acute lymphoblastic leukemia: a retrospective analysis of infectious deaths on UKALL 2003. Blood 2014; 124: 1056–1061.

    Article  CAS  Google Scholar 

  13. Schmiegelow K, Al-Modhwahi I, Andersen MK, Behrendtz M, Forestier E, Hasle H et al. Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Blood 2009; 113: 6077–6084.

    Article  CAS  Google Scholar 

  14. Schmiegelow K, Levinsen MF, Attarbaschi A, Baruchel A, Devidas M, Escherich G et al. Second malignant neoplasms after treatment of childhood acute lymphoblastic leukemia. J Clin Oncol 2013; 31: 2469–2476.

    Article  CAS  Google Scholar 

  15. Pui CH, Evans WE . Treatment of acute lymphoblastic leukemia. N Engl J Med 2006; 354: 166–178.

    Article  CAS  Google Scholar 

  16. Golub TR, Barker GF, Bohlander SK, Hiebert SW, Ward DC, Bray-Ward P et al. Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Proc Natl Acad Sci USA 1995; 92: 4917–4921.

    Article  CAS  Google Scholar 

  17. Nannya Y, Sanada M, Nakazaki K, Hosoya N, Wang L, Hangaishi A et al. A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays. Cancer Res 2005; 65: 6071–6079.

    Article  CAS  Google Scholar 

  18. Yamamoto G, Nannya Y, Kato M, Sanada M, Levine RL, Kawamata N et al. Highly sensitive method for genomewide detection of allelic composition in nonpaired, primary tumor specimens by use of affymetrix single-nucleotide-polymorphism genotyping microarrays. Am J Hum Genet 2007; 81: 114–126.

    Article  CAS  Google Scholar 

  19. Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat Genet 2015; 47: 1304–1315.

    Article  CAS  Google Scholar 

  20. Kanda Y . Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 2013; 48: 452–458.

    Article  CAS  Google Scholar 

  21. Goto H . Childhood relapsed acute lymphoblastic leukemia: biology and recent treatment progress. Pediatr Int 2015; 57: 1059–1066.

    Article  Google Scholar 

  22. Hunger SP, Mullighan CG . Acute lymphoblastic leukemia in children. N Engl J Med 2015; 373: 1541–1552.

    Article  CAS  Google Scholar 

  23. Rivera GK, Raimondi SC, Hancock ML, Behm FG, Pui CH, Abromowitch M et al. Improved outcome in childhood acute lymphoblastic leukaemia with reinforced early treatment and rotational combination chemotherapy. Lancet 1991; 337: 61–66.

    Article  CAS  Google Scholar 

  24. Uckun FM, Sensel MG, Sather HN, Gaynon PS, Arthur DC, Lange BJ et al. Clinical significance of translocation t(1;19) in childhood acute lymphoblastic leukemia in the context of contemporary therapies: a report from the Children's Cancer Group. J Clin Oncol 1998; 16: 527–535.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Kaori Itagaki for preparing and refining the protocol data for ALL in the TCCSG. We also thank Ms Masayo Matsumura and Ms Yin Yi (the University of Tokyo) and Ms Maki Nakamura and Ms Hitomi Higashi (Kyoto University) for special technical assistance. We thank Dr Julian Tang of the Department of Education for Clinical Research, National Center for Child Health and Development, for proofreading and editing this manuscript. This study was supported in part by the Japan Society for the Promotion of Science (JSPS) through Grants-in-Aid for Scientific Research (KAKENHI) Grant Numbers 26713037 and 26670492, and by the Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and development, AMED, Grant Number 15ck0106066h0002. This study was also supported by grants from the Takeda Science Foundation, the Japan Leukemia Research Fund and the Children’s Cancer Association of Japan.

Author contributions

MK, TI, AO and AM contributed to the writing of the manuscript. MK, AM, K Koh, MT and AO designed the study. MK, AM, SI, DT, DH, TO, TI, YA, TA, MO, K Kaizu, K Kato, YT, HG, TT and MT contributed to the data gathering. MS, KY, NK, HU, Y Sato, Y Shiraishi, KC, HT, JT, MS and SO contributed to the data analysis. MK, MS, YK and AM interpreted the data. All authors critically reviewed the manuscript and agreed to submit the paper for publication.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M Kato.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kato, M., Ishimaru, S., Seki, M. et al. Long-term outcome of 6-month maintenance chemotherapy for acute lymphoblastic leukemia in children. Leukemia 31, 580–584 (2017). https://doi.org/10.1038/leu.2016.274

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2016.274

This article is cited by

Search

Quick links