Skip to main content
SpringerLink
Log in

Outcomes following induction failure in Japanese children with acute lymphoblastic leukemia

International Journal of Hematology volume 118, pages 99–106 (2023)Cite this article

Abstract

The characteristics and prognosis of Japanese children with acute lymphoblastic leukemia (ALL) who fail to achieve complete remission after remission induction chemotherapy (i.e., experience induction failure) are poorly understood. Therefore, we retrospectively analyzed data of patients enrolled in Japanese clinical trials for newly diagnosed ALL between 1996 and 2009. Among 4956 participants, 89 (1.8%) experienced induction failure. With a 6.0-year median follow-up, the 5-year overall survival rate of the entire cohort was 43.0% ± 5.5%. Survival rates did not differ between patients with B-cell precursor ALL (BCP-ALL) and T-cell ALL (T-ALL). In multivariate analysis, day 15 M3 marrow (bone marrow blast count ≥ 25%) was significantly correlated with poorer survival in the whole or BCP-ALL cohorts. In T-ALL, age < 6 years was significantly associated with poor survival. However, due to the small sample size, this correlation must be further investigated. Most T-ALL and BCR-ABL-positive BCP-ALL patients underwent allogeneic stem cell transplantation (allo-SCT). Survival rates did not differ between BCR-ABL-negative BCP-ALL patients who did and did not undergo allo-SCT, possibly due to the inclusion of lower-risk patients in the latter group. In conclusion, the induction failure rate and survival after diagnosis of induction failure in our study were comparable to previously reported figures.

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

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

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

Fig. 1

Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request. The request must be reviewed and approved by the four participating groups (CCLSG, KYCCSG, JACLS, TCCSG).

References

  1. Inaba H, Mullighan CG. Pediatric acute lymphoblastic leukemia. Haematologica. 2020;105(11):2524–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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 

  3. Vora A, Goulden N, Wade R, Mitchell C, Hancock J, Hough R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2013;14(3):199–209.

    Article  CAS  PubMed  Google Scholar 

  4. Schrappe M, Hunger SP, Pui CH, Saha V, Gaynon PS, Baruchel A, et al. Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med. 2012;366(15):1371–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yamaji K, Okamoto T, Yokota S, Watanabe A, Horikoshi Y, Asami K, et al. Minimal residual disease-based augmented therapy in childhood acute lymphoblastic leukemia: a report from the Japanese Childhood Cancer and Leukemia Study Group. Pediatr Blood Cancer. 2010;55(7):1287–95.

    Article  PubMed  Google Scholar 

  6. Hyakuna N, Shimomura Y, Watanabe A, Taga T, Kikuta A, Matsushita T, et al. Assessment of corticosteroid-induced osteonecrosis in children undergoing chemotherapy for acute lymphoblastic leukemia: a report from the Japanese Childhood Cancer and Leukemia Study Group. J Pediatr Hematol Oncol. 2014;36(1):22–9.

    Article  CAS  PubMed  Google Scholar 

  7. Nagatoshi Y, Matsuzaki A, Suminoe A, Inada H, Ueda K, Kawakami K, et al. Randomized trial to compare LSA2L2-type maintenance therapy to daily 6-mercaptopurine and weekly methotrexate with vincristine and dexamethasone pulse for children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2010;55(2):239–47.

    Article  PubMed  Google Scholar 

  8. Okamoto Y, Koga Y, Inagaki J, Ozono S, Ueda K, Shimoura M, et al. Effective VCR/DEX pulse maintenance therapy in the KYCCSG ALL-02 protocol for pediatric acute lymphoblastic leukemia. Int J Hematol. 2016;103(2):202–9.

    Article  CAS  PubMed  Google Scholar 

  9. Kobayashi R, Takimoto T, Nakazawa A, Fujita N, Akazai A, Yamato K, et al. Inferior outcomes of stage III T lymphoblastic lymphoma relative to stage IV lymphoma and T-acute lymphoblastic leukemia: long-term comparison of outcomes in the JACLS NHL T-98 and ALL T-97 protocols. Int J Hematol. 2014;99(6):743–9.

    Article  CAS  PubMed  Google Scholar 

  10. Hasegawa D, Imamura T, Yumura-Yagi K, Takahashi Y, Usami I, Suenobu SI, et al. Risk-adjusted therapy for pediatric non-T cell ALL improves outcomes for standard risk patients: results of JACLS ALL-02. Blood Cancer J. 2020;10(2):23.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 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(8):1155–60.

    Article  CAS  PubMed  Google Scholar 

  12. Takahashi H, Kajiwara R, Kato M, Hasegawa D, Tomizawa D, Noguchi Y, et al. Treatment outcome of children with acute lymphoblastic leukemia: the Tokyo Children’s Cancer Study Group (TCCSG) Study L04–16. Int J Hematol. 2018;108(1):98–108.

    Article  PubMed  Google Scholar 

  13. Suzuki N, Yumura-Yagi K, Yoshida M, Hara J, Nishimura S, Kudoh T, et al. Outcome of childhood acute lymphoblastic leukemia with induction failure treated by the Japan Association of Childhood Leukemia study (JACLS) ALL F-protocol. Pediatr Blood Cancer. 2010;54(1):71–8.

    Article  PubMed  Google Scholar 

  14. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3):452–8.

    Article  CAS  PubMed  Google Scholar 

  15. Smith M, Arthur D, Camitta B, Carroll AJ, Crist W, Gaynon P, et al. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol. 1996;14(1):18–24.

    Article  CAS  PubMed  Google Scholar 

  16. Silverman LB, Gelber RD, Young ML, Dalton VK, Barr RD, Sallan SE. Induction failure in acute lymphoblastic leukemia of childhood. Cancer. 1998;85(6):1395–404.

    Article  Google Scholar 

  17. Oudot C, Auclerc MF, Levy V, Porcher R, Piguet C, Perel Y, et al. Prognostic factors for leukemic induction failure in children with acute lymphoblastic leukemia and outcome after salvage therapy: the FRALLE 93 study. J Clin Oncol. 2008;26(9):1496–503.

    Article  CAS  PubMed  Google Scholar 

  18. O’Connor D, Moorman AV, Wade R, Hancock J, Tan RM, Bartram J, et al. Use of minimal residual disease assessment to redefine induction failure in pediatric acute lymphoblastic leukemia. J Clin Oncol. 2017;35(6):660–7.

    Article  PubMed  Google Scholar 

  19. Inaba H, Pui CH. Glucocorticoid use in acute lymphoblastic leukaemia. Lancet Oncol. 2010;11(11):1096–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Domenech C, Suciu S, De Moerloose B, Mazingue F, Plat G, Ferster A, et al. Dexamethasone (6 mg/m2/day) and prednisolone (60 mg/m2/day) were equally effective as induction therapy for childhood acute lymphoblastic leukemia in the EORTC CLG 58951 randomized trial. Haematologica. 2014;99(7):1220–7.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Buchmann S, Schrappe M, Baruchel A, Biondi A, Borowitz M, Campbell M, et al. Remission, treatment failure, and relapse in pediatric ALL: an international consensus of the Ponte-di-Legno Consortium. Blood. 2022;139(12):1785–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, Pei D, et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol. 2009;10(2):147–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jeha S, Choi J, Roberts KG, Pei D, Coustan-Smith E, Inaba H, et al. Clinical significance of novel subtypes of acute lymphoblastic leukemia in the context of minimal residual disease-directed therapy. Blood Cancer Discov. 2021;2(4):326–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Inaba H, Pui CH. Immunotherapy in pediatric acute lymphoblastic leukemia. Cancer Metastasis Rev. 2019;38(4):595–610.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank all patients and their families. We acknowledge the work of the past and present members of the Childhood Cancer and Leukemia Study Group, Kyushu–Yamaguchi Childhood Cancer Study Group, Japan Association of Childhood Leukemia Study, Tokyo Children’s Cancer Study Group, Japan Pediatric Leukemia/Lymphoma Study Group, and Japan Children’s Cancer Group. We would like to thank Editage (www.editage.com) for English language editing.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuou-Ku, Niigata City, Niigata, 951-8510, Japan

    Chihaya Imai

  2. Department of Hematology and Oncology, Miyagi Children’s Hospital, Miyagi, Japan

    Atsushi Sato

  3. Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Mitsuteru Hiwatari

  4. Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan

    Mitsuteru Hiwatari

  5. Department of Pediatrics, Aichi Medical University, Aichi, Japan

    Yasuto Shimomura & Toshinori Hori

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

    Souichi Suenobu

  7. Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Toshihiko Imamura

  8. Department of Pediatric Hematology and Oncology, Osaka City General Hospital, Osaka, Japan

    Junichi Hara

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

    Daisuke Hasegawa

  10. Department of Pediatrics, Toho University Omori Medical Center, Tokyo, Japan

    Hiroyuki Takahashi

  11. Department of Pediatrics, Tohoku University Graduate School of Medicine, Miyagi, Japan

    Kunihiko Moriya & Saori Katayama

  12. Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan

    Daisuke Tomizawa

  13. Department of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

    Hiroshi Moritake

  14. Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan

    Takashi Taga

  15. Clinical Research Center, Nagoya Medical Center, Nagoya, Japan

    Keizo Horibe

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

    Katsuyoshi Koh

  17. Department of Pediatrics, Hokkaido University Graduate School of Medicine, Hokkaido, Japan

    Atsushi Manabe

  18. Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    Yasuhiro Okamoto

Authors
  1. Chihaya Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Atsushi Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mitsuteru Hiwatari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasuto Shimomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Toshinori Hori
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Souichi Suenobu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Toshihiko Imamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Junichi Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daisuke Hasegawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hiroyuki Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kunihiko Moriya
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Saori Katayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Daisuke Tomizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hiroshi Moritake
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Takashi Taga
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Keizo Horibe
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Katsuyoshi Koh
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Atsushi Manabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Yasuhiro Okamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CI, AS, MH, YO, and AM designed the study; TH, YS, SS, TI, JH, DH, HT, KM, SK, DT, HM, TT, KH, and KK provided clinical data from each steering committee of the trials; CI, AS, MH, and YO contributed to the collection and management of individual patient data; CI performed statistical analyses; CI, AS, MH, and YO drafted the manuscript; and all authors have read and approved the final manuscript.

Corresponding author

Correspondence to Chihaya Imai.

Ethics declarations

Conflict of interest

CI reports patent royalties from Juno Therapeutics, patent royalties, research funds, and advisory fees from CURED Inc. The other 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.

Supplementary Information

Below is the link to the electronic supplementary material.

12185_2023_3600_MOESM1_ESM.pdf

Supplementary file1 Figure S1. The impact of the use of allogeneic stem cell transplantation on overall survival in non-BCR-ABL BCP-ALL. Kaplan–Meier analysis of OS in non-BCR-ABL BCP-ALL is shown. Black and red lines indicate patients treated with or without SCT, respectively. (PDF 52 KB)

Supplementary file2 (DOCX 24 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Imai, C., Sato, A., Hiwatari, M. et al. Outcomes following induction failure in Japanese children with acute lymphoblastic leukemia. Int J Hematol 118, 99–106 (2023). https://doi.org/10.1007/s12185-023-03600-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-023-03600-3

Keywords

search

Navigation