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.
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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).
Inaba H, Mullighan CG. Pediatric acute lymphoblastic leukemia. Haematologica. 2020;105(11):2524–39.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3):452–8.
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.
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.
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.
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.
Inaba H, Pui CH. Glucocorticoid use in acute lymphoblastic leukaemia. Lancet Oncol. 2010;11(11):1096–106.
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.
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.
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.
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.
Inaba H, Pui CH. Immunotherapy in pediatric acute lymphoblastic leukemia. Cancer Metastasis Rev. 2019;38(4):595–610.
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.
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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.
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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)
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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