Treatment outcome of children with acute lymphoblastic leukemia: the Tokyo Children’s Cancer Study Group (TCCSG) Study L04-16
The survival rate of children with acute lymphoblastic leukemia (ALL) has increased to approximately 90% after substantial progress in risk-oriented treatment strategies. Between 2005 and 2013, the Tokyo Children’s Cancer Study Group (TCCSG) conducted a risk-oriented, non-randomized study, L04-16. The principal aim of this study was to assemble background characteristics and treatment outcomes, and gather genetic information on leukemic cells under central diagnosis. This report outlines the background characteristics and treatment outcomes of 1033 children with ALL treated according to a TCCSG platform. The 5-year event-free and overall survival (OS) rates for all children were 78.1 ± 1.3 and 89.6 ± 1.0%, respectively. The OS rate was significantly higher in children with B-cell precursor (BCP)-ALL (91.9 ± 1.0%, n = 916) than in those with T-ALL (71.9 ± 4.3%, n = 117, p < 0.001). In univariate analysis for BCP-ALL, children aged 1–6 years (5y-OS: 94.2 ± 1.0%), with an initial white blood cell count of < 20,000/μL (94.0 ± 1.0%), high hyperdiploidy (95.4 ± 1.6%), ETV6-RUNX1 (97.4 ± 1.2%) or TCF3-PBX1 (96.9 ± 2.1%), and “Day8NoBlasts” (96.4 ± 1.1%) had the best outcomes. Genetic investigation revealed two novel fusion genes within this cohort: ETV6-ZNF385A and ZNF362-TCF4. Our study highlighted the clinical aspects of genomic features of ALL in Japanese children. We provide fundamental information for the further molecular investigation of this disease.
KeywordsAcute lymphoblastic leukemia Childhood leukemia Clinical trial Novel fusion genes
The authors would like to thank the participating institutes and physicians in the TCCSG. They would also like to thank Ms. Kaori Itagaki for preparing and refining the protocol data. This work was supported, in part, by grants from the Children’s Cancer Association of Japan and the Grant of the National Center for Child Health and Development (26-20).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
- 7.Manabe A, Ohara A, Hasegawa D, Koh K, Saito T, Kiyokawa N, et al. Tokyo Children’s Cancer Study Group. 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;93:1155–60.CrossRefPubMedGoogle Scholar
- 8.Hasegawa D, Manabe A, Ohara A, Kikuchi A, Koh K, Kiyokawa N, et al. Tokyo Children’s Cancer Study Group. The utility of performing the initial lumbar puncture on day 8 in remission induction therapy for childhood acute lymphoblastic leukemia: TCCSG L99-15 study. Pediatr Blood Cancer. 2012;58:23–30.CrossRefPubMedGoogle Scholar
- 9.Kato M, Koh K, Manabe A, Saito T, Hasegawa D, Isoyama K, et al. No impact of high-dose cytarabine and asparaginase as early intensification with intermediate-risk paediatric acute lymphoblastic leukaemia: results of randomized trial TCCSG study L99-15. Br J Haematol. 2014;164:376–83.CrossRefPubMedGoogle Scholar
- 11.Manabe A, Kawasaki H, Shimada H, Kato I, Kodama Y, Sato A, et al. Imatinib use immediately before stem cell transplantation in children with Philadelphia chromosome-positive acute lymphoblastic leukemia: results from Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Study Ph(+) ALL04. Cancer Med. 2015;4:682–9.CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Tsurusawa M, Mori T, Kikuchi A, Mitsui T, Sunami S, Kobayashi R, et al. Lymphoma committee of Japanese Pediatric Leukemia/Lymphoma Study Group. Improved treatment results of children with B-cell non-Hodgkin lymphoma: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group B-NHL03 study. Pediatr Blood Cancer. 2014;61:1215–21.CrossRefPubMedGoogle Scholar
- 14.Hirabayashi S, Ohki K, Nakabayashi K, Ichikawa H, Momozawa Y, Okamura K, et al. Tokyo Children’s Cancer Study Group (TCCSG). ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype. Haematologica. 2017;102:118–29.CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Möricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dördelmann M, et al. German-Austrian-Swiss ALL-BFM Study Group. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood. 2008;111:4477–89.CrossRefPubMedGoogle Scholar
- 22.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.CrossRefPubMedGoogle Scholar
- 23.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;15:809–18.CrossRefPubMedGoogle Scholar
- 24.Pui CH, Pei D, Coustan-Smith E, Jeha S, Cheng C, Bowman WP, et al. Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study. Lancet Oncol. 2015;16:465–74.CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, et al. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children’s Oncology Group Study AALL0232. J Clin Oncol. 2016;34:2380–8.CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Pieters R, de Groot-Kruseman H, Van der Velden V, Fiocco M, van den Berg H, de Bont E, et al. Successful therapy reduction and intensification for childhood acute lymphoblastic leukemia based on minimal residual disease monitoring: study ALL10 from the Dutch Childhood Oncology Group. J Clin Oncol. 2016;34:2591–601.CrossRefPubMedGoogle Scholar
- 27.Wood BL, Winter SS, Dunsmore KP, Devidas M, Chen S, Asselin B, et al. T-lymphoblastic leukemia (T-ALL) shows excellent outcome, lack of significance of the early thymic precursor (ETP) immunophenotype, and validation of the prognostic value of end-induction minimal residual disease (MRD) in Children’s Oncology Group (COG) Study AALL0434. Blood. 2014;124:1 (abstract).CrossRefGoogle Scholar