Discontinuation of l-asparaginase and poor response to prednisolone are associated with poor outcome of ETV6-RUNX1-positive pediatric B-cell precursor acute lymphoblastic leukemia

Abstract

ETV6-RUNX1-positive B precursor acute lymphoblastic leukemia (B-ALL) is a common subtype of pediatric B-ALL that has shown excellent outcomes in contemporary clinical trials for pediatric B-ALL. Examinations of the possibility of reducing therapeutic intensity may thus be explored. This prospective study examined outcomes in 205 pediatric patients with ETV6-RUNX1-positive B-ALL uniformly treated following the Japan Association of Childhood Leukemia Study Group (JACLS) ALL-02 protocol. The JACLS ALL-02 protocol does not employ minimal residual disease detected by polymerase chain reaction (PCR-MRD)-based risk stratification; however, 4-year event-free survival (EFS) and overall survival (OS) were 94.4 ± 1.6 and 97.5 ± 1.1%, respectively. In particular, 92 of 205 (44.9%) patients were successfully treated with a less intensive regimen involving only two cycles of high dose methotrexate and one course of re-induction therapy comprising vincristine, l-asparaginase (L-asp), pirarubicin, and prednisolone. Multivariate analysis revealed that discontinuation of L-asp and poor response to prednisolone was, respectively, associated with poor EFS (HR 6.3; 95% CI 1.3–27.0) and OS (HR 17.5; 95% CI 2.3–130), suggesting that the majority of ETV6-RUNX1-positive B-ALL cases may be cured by a less-intensive chemotherapy regimen if the risk stratification system including PCR-MRD monitoring and insufficient use of L-asp is avoided.

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

Fig. 1
Fig. 2

References

  1. 1.

    Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukemia. Lancet. 2013;381:1943–55.

    Article  PubMed  Google Scholar 

  2. 2.

    Bhojwani D, Pei D, Sandlund JT, Jeha S, Ribeiro RC, Rubnitz JE, et al. ETV6 RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy. Leukemia. 2012;26:265–70.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grümayer R, Möricke 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;115:3206–14.

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    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;107:4508–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Piette C, Suciu S, Clappier E, Bertrand Y, Drunat S, Girard S, et al. Differential impact of drugs on the outcome of ETV6-RUNX1 positive childhood B-cell precursor acute lymphoblastic leukemia: results of the EORTC CLG 58881 and 58951 trials. Leukemia. 2018;32:244–8.

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Asai D, Imamura T, Suenobu S, Saito A, Hasegawa D, Deguchi T, et al. IKZF1 deletion is associated with a poor outcome in pediatric B-cell precursor acute lymphoblastic leukemia in Japan. Cancer Med. 2013;2:412–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Sakamoto K, Imamura T, Kihira K, Suzuki K, Ishida H, Morita H, et al. Low incidence of osteonecrosis in childhood acute lymphoblastic leukemia treated with ALL-97 and ALL-02 Study of Japan Association of Childhood Leukemia Study Group. J Clin Oncol. 2018;36:900–7.

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Horibe K, Yumura-Yagi K, Kudoh T, Nishimura S, Oda M, Yoshida M, et al. Long-term results of the risk-adapted treatment for childhood B-cell acute lymphoblastic leukemia: report from the Japan Association of Childhood Leukemia Study ALL-97 Trial. J Pediatr Hematol Oncol. 2017;39:81–89.

    Article  PubMed  Google Scholar 

  9. 9.

    Borgmann A, von Stackelberg A, Hartmann R, Ebell W, Klingebiel T, Peters C, et al. Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis. Blood. 2003;101:3835–9.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Toft N, Birgens H, Abrahamsson J, Griškevičius L, Hallböök H, Heyman M, et al. Results of NOPHO ALL2008 treatment for patients aged 1–45 years with acute lymphoblastic leukemia. Leukemia. 2017;32:606–15.

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    O’Connor D, Enshaei A, Bartram J, Hancock J, Harrison CJ, Hough R, et al. Genotype-specific minimal residual disease interpretation improves stratification in pediatric acute lymphoblastic leukemia. J Clin Oncol. 2018;36:34–43.

    Article  PubMed  Google Scholar 

  12. 12.

    Gandemer V, Chevret S, Petit A, Vermylen C, Leblanc T, Michel G, et al. Excellent prognosis of late relapses of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia: lessons from the FRALLE 93 protocol. Haematologica. 2012;97:1743–50.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Kuster L, Grausenburger R, Fuka G, Kaindl U, Krapf G, Inthal A, et al. ETV6/RUNX1-positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling. Blood. 2011;117:2658–67.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank all patients (and their guardians) who participated in this study. The authors also thank the staff at the OSCR data center for data management and all physicians who registered the patients in the JACLS ALL-02 clinical trial.

Author information

Affiliations

Authors

Consortia

Corresponding author

Correspondence to Toshihiko Imamura.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to declare.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Usami, I., Imamura, T., Takahashi, Y. et al. Discontinuation of l-asparaginase and poor response to prednisolone are associated with poor outcome of ETV6-RUNX1-positive pediatric B-cell precursor acute lymphoblastic leukemia. Int J Hematol 109, 477–482 (2019). https://doi.org/10.1007/s12185-019-02599-w

Download citation

Keywords

  • Poor prednisolone response
  • l-asparaginase
  • ETV6-RUNX1
  • Pediatric acute lymphoblastic leukemia