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.

  • Original Article
  • Published:

Acute Leukemias

ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy

Leukemia volume 26, pages 265–270 (2012)Cite this article

Abstract

ETV6-RUNX1 fusion is the most common genetic aberration in childhood acute lymphoblastic leukemia (ALL). To evaluate whether outcomes for this drug-sensitive leukemia are improved by contemporary risk-directed therapy, we studied clinical features, response and adverse events of 168 children with newly diagnosed ETV6-RUNX1-positive ALL on St Jude Total Therapy studies XIIIA (N=36), XIIIB (N=38) and XV (N=94). Results were compared with 494 ETV6-RUNX1-negative B-precursor ALL patients. ETV6-RUNX1 was associated with age 1–9 years, pre-treatment classification as low risk and lower levels of minimal residual disease (MRD) on day 19 of therapy (P<0.001). Event-free survival (EFS) or overall survival (OS) did not differ between patients with or without ETV6-RUNX1 in Total XIIIA or XIIIB. By contrast, in Total XV, patients with ETV6-RUNX1 had significantly better EFS (P=0.04; 5-year estimate, 96.8±2.4% versus 88.3±2.5%) and OS (P=0.04; 98.9±1.4% versus 93.7±1.8%) than those without ETV6-RUNX1. Within the ETV6-RUNX1 group, the only significant prognostic factor associated with higher OS was the treatment protocol Total XV (versus XIIIA or XIIIB) (P=0.01). Thus, the MRD-guided treatment schema including intensive asparaginase and high-dose methotrexate in the Total XV study produced significantly better outcomes than previous regimens and demonstrated that nearly all children with ETV6-RUNX1 ALL can be cured.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Pui CH, Relling MV, Downing JR . Acute lymphoblastic leukemia. N Engl J Med 2004; 350: 1535–1548.

    Article  CAS  Google Scholar 

  2. Wiemels JL, Cazzaniga G, Daniotti M, Eden OB, Addison GM, Masera G et al. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet 1999; 354: 1499–1503.

    Article  CAS  Google Scholar 

  3. Morrow M, Horton S, Kioussis D, Brady HJ, Williams O . TEL-AML1 promotes development of specific hematopoietic lineages consistent with preleukemic activity. Blood 2004; 103: 3890–3896.

    Article  CAS  Google Scholar 

  4. Ford AM, Palmi C, Bueno C, Hong D, Cardus P, Knight D et al. The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells. J Clin Invest 2009; 119: 826–836.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Raynaud S, Cave H, Baens M, Bastard C, Cacheux V, Grosgeorge J et al. The 12;21 translocation involving TEL and deletion of the other TEL allele: two frequently associated alterations found in childhood acute lymphoblastic leukemia. Blood 1996; 87: 2891–2899.

    CAS  PubMed  Google Scholar 

  6. Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 2007; 446: 758–764.

    Article  CAS  Google Scholar 

  7. Frost BM, Forestier E, Gustafsson G, Nygren P, Hellebostad M, Jonsson OG et al. Translocation t(12;21) is related to in vitro cellular drug sensitivity to doxorubicin and etoposide in childhood acute lymphoblastic leukemia. Blood 2004; 104: 2452–2457.

    Article  CAS  Google Scholar 

  8. Ramakers-van Woerden NL, Pieters R, Loonen AH, Hubeek I, van Drunen E, Beverloo HB et al. TEL/AML1 gene fusion is related to in vitro drug sensitivity for L-asparaginase in childhood acute lymphoblastic leukemia. Blood 2000; 96: 1094–1099.

    CAS  PubMed  Google Scholar 

  9. 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 

  10. Rubnitz JE, Wichlan D, Devidas M, Shuster J, Linda SB, Kurtzberg J et al. Prospective analysis of TEL gene rearrangements in childhood acute lymphoblastic leukemia: a Children's Oncology Group study. J Clin Oncol 2008; 26: 2186–2191.

    Article  Google Scholar 

  11. Rubnitz JE, Downing JR, Pui CH, Shurtleff SA, Raimondi SC, Evans WE et al. TEL gene rearrangement in acute lymphoblastic leukemia: a new genetic marker with prognostic significance. J Clin Oncol 1997; 15: 1150–1157.

    Article  CAS  Google Scholar 

  12. Borkhardt A, Cazzaniga G, Viehmann S, Valsecchi MG, Ludwig WD, Burci L et al. Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian multicenter therapy trials. Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Munster Study Group. Blood 1997; 90: 571–577.

    CAS  PubMed  Google Scholar 

  13. Forestier E, Heyman M, Andersen MK, Autio K, Blennow E, Borgstrom G et al. Outcome of ETV6/RUNX1-positive childhood acute lymphoblastic leukaemia in the NOPHO-ALL-1992 protocol: frequent late relapses but good overall survival. Br J Haematol 2008; 140: 665–672.

    Article  Google Scholar 

  14. Loh ML, Goldwasser MA, Silverman LB, Poon WM, Vattikuti S, Cardoso A et al. Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01. Blood 2006; 107: 4508–4513.

    Article  CAS  Google Scholar 

  15. Pui CH, Mahmoud HH, Rivera GK, Hancock ML, Sandlund JT, Behm FG et al. Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 1998; 92: 411–415.

    CAS  PubMed  Google Scholar 

  16. Pui CH, Sandlund JT, Pei D, Campana D, Rivera GK, Ribeiro RC et al. Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 2004; 104: 2690–2696.

    Article  CAS  Google Scholar 

  17. 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 

  18. Mathew S, Shurtleff SA, Raimondi SC . Novel cryptic, complex rearrangements involving ETV6-CBFA2 (TEL-AML1) genes identified by fluorescence in situ hybridization in pediatric patients with acute lymphoblastic leukemia. Genes Chromosomes Cancer 2001; 32: 188–193.

    Article  CAS  Google Scholar 

  19. Coustan-Smith E, Sancho J, Behm FG, Hancock ML, Razzouk BI, Ribeiro RC et al. Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood 2002; 100: 52–58.

    Article  CAS  Google Scholar 

  20. Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K et al. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 2003; 101: 3809–3817.

    Article  CAS  Google Scholar 

  21. Pui CH, Relling MV, Behm FG, Hancock ML, Boyett JM, Raimondi SC et al. L-asparaginase may potentiate the leukemogenic effect of the epipodophyllotoxins. Leukemia 1995; 9: 1680–1684.

    CAS  PubMed  Google Scholar 

  22. Mantel N . Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163–170.

    CAS  PubMed  Google Scholar 

  23. 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 

  24. Moorman AV, Ensor HM, Richards SM, Chilton L, Schwab C, Kinsey SE et al. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial. Lancet Oncol 2010; 11: 429–438.

    Article  CAS  Google Scholar 

  25. Matloub Y, Bostrom BC, Hunger SP, Stork LC, Angiolillo A, Sather H et al. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 2011; 118: 243–251.

    Article  CAS  Google Scholar 

  26. Krishna Narla R, Navara C, Sarquis M, Uckun FM . Chemosensitivity of TEL-AML1 fusion transcript positive acute lymphoblastic leukemia cells. Leuk Lymphoma 2001; 41: 615–623.

    Article  CAS  Google Scholar 

  27. Fung KL, Liang RH, Chan GC . Vincristine but not imatinib could suppress mesenchymal niche's support to lymphoid leukemic cells. Leuk Lymphoma 2010; 51: 515–522.

    Article  CAS  Google Scholar 

  28. Iwamoto S, Mihara K, Downing JR, Pui CH, Campana D . Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase. J Clin Invest 2007; 117: 1049–1057.

    Article  CAS  Google Scholar 

  29. Yang L, Panetta JC, Cai X, Yang W, Pei D, Cheng C et al. Asparaginase may influence dexamethasone pharmacokinetics in acute lymphoblastic leukemia. J Clin Oncol 2008; 26: 1932–1939.

    Article  CAS  Google Scholar 

  30. Whitehead VM, Payment C, Cooley L, Lauer SJ, Mahoney DH, Shuster JJ et al. The association of the TEL-AML1 chromosomal translocation with the accumulation of methotrexate polyglutamates in lymphoblasts and with ploidy in childhood B-progenitor cell acute lymphoblastic leukemia: a Pediatric Oncology Group study. Leukemia 2001; 15: 1081–1088.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by grants (CA21765, CA60419, CA36401 and GM92666) from the National Institutes of Health and by American Lebanese Syrian Associated Charities (ALSAC).

Author information

Authors and Affiliations

  1. Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA

    D Bhojwani, J T Sandlund, S Jeha, R C Ribeiro, J E Rubnitz, E Coustan-Smith, S C Howard, M L Metzger, H Inaba, W Leung, D Campana & C-H Pui

  2. Department of Pediatrics, University of Tennessee Health Sciences Center, College of Medicine, Memphis, TN, USA

    D Bhojwani, J T Sandlund, S Jeha, R C Ribeiro, J E Rubnitz, S C Howard, M L Metzger, H Inaba, W Leung, W E Evans, D Campana, M V Relling & C-H Pui

  3. Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA

    D Pei & C Cheng

  4. Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA

    S C Raimondi, S Shurtleff, M Onciu, D Campana & C-H Pui

  5. Department of Pediatrics, Cook Children's Medical Center, Fort Worth, TX, USA

    W P Bowman

  6. Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA

    W E Evans & M V Relling

Authors
  1. D Bhojwani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Pei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J T Sandlund
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Jeha
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R C Ribeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J E Rubnitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S C Raimondi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Shurtleff
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Onciu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. E Coustan-Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. W P Bowman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. S C Howard
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M L Metzger
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. H Inaba
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. W Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. W E Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. D Campana
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. M V Relling
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. C-H Pui
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Bhojwani.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bhojwani, D., Pei, D., Sandlund, J. et al. ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy. Leukemia 26, 265–270 (2012). https://doi.org/10.1038/leu.2011.227

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.227

Keywords

This article is cited by

Search

Advanced search

Quick links