Treatment outcome of children with acute lymphoblastic leukemia: the Tokyo Children’s Cancer Study Group (TCCSG) Study L04-16

  • Hiroyuki Takahashi
  • Ryosuke Kajiwara
  • Motohiro Kato
  • Daisuke Hasegawa
  • Daisuke Tomizawa
  • Yasushi Noguchi
  • Kazutoshi Koike
  • Daisuke Toyama
  • Hiromasa Yabe
  • Michiko Kajiwara
  • Junya Fujimura
  • Manabu Sotomatsu
  • Setsuo Ota
  • Miho Maeda
  • Hiroaki Goto
  • Yoko Kato
  • Tetsuya Mori
  • Takeshi Inukai
  • Hiroyuki Shimada
  • Keitaro Fukushima
  • Chitose Ogawa
  • Atsushi Makimoto
  • Takashi Fukushima
  • Kentaro Ohki
  • Katsuyoshi Koh
  • Nobutaka Kiyokawa
  • Atsushi Manabe
  • Akira Ohara
Original Article

Abstract

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.

Keywords

Acute lymphoblastic leukemia Childhood leukemia Clinical trial Novel fusion genes 

Notes

Acknowledgements

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.

Supplementary material

12185_2018_2440_MOESM1_ESM.pdf (1.5 mb)
Supplementary material 1 (PDF 1536 kb)

References

  1. 1.
    Pui CH, Carroll WL, Meshinchi S, Arceci RJ. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol. 2011;29:551–65.CrossRefPubMedGoogle Scholar
  2. 2.
    Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. 2012;120:1165–74.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med. 2015;373:1541–52.CrossRefPubMedGoogle Scholar
  4. 4.
    Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet. 2013;381:1943–55.CrossRefPubMedGoogle Scholar
  5. 5.
    Locatelli F, Schrappe M, Bernardo ME, Rutella S. How I treat relapsed childhood acute lymphoblastic leukemia. Blood. 2012;120:2807–16.CrossRefPubMedGoogle Scholar
  6. 6.
    Bhojwani D, Pui CH. Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol. 2013;14:e205–17.CrossRefPubMedGoogle Scholar
  7. 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. 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. 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
  10. 10.
    Koh K, Tomizawa D, Saito AM, Watanabe T, Miyamura T, Hirayama M, et al. Early use of allogeneic hematopoietic stem cell transplantation for infants with MLL gene-rearrangement-positive acute lymphoblastic leukemia. Leukemia. 2015;29:290–6.CrossRefPubMedGoogle Scholar
  11. 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. 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
  13. 13.
    Gocho Y, Kiyokawa N, Ichikawa H, Nakabayashi K, Osumi T, Ishibashi T, et al. A novel recurrent EP300-ZNF384 gene fusion in B-cell precursor acute lymphoblastic leukemia. Leukemia. 2015;29:2445–8.CrossRefPubMedGoogle Scholar
  14. 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
  15. 15.
    Imamura T, Kiyokawa N, Kato M, Imai C, Okamoto Y, Yano M, et al. Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan. Blood Cancer J. 2016;6:e419.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 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
  17. 17.
    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;14:18–24.CrossRefPubMedGoogle Scholar
  18. 18.
    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Kato M, Ishimaru S, Seki M, Yoshida K, Shiraishi Y, Chiba K, et al. Long-term outcome of 6-month maintenance chemotherapy for acute lymphoblastic leukemia in children. Leukemia. 2017;31:580–4.CrossRefPubMedGoogle Scholar
  20. 20.
    Vora A, Andreano A, Pui CH, Hunger SP, Schrappe M, Möricke A, et al. J Clin Oncol. 2016;34:919–26.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Campana D, Pui CH. Minimal residual disease-guided therapy in childhood acute lymphoblastic leukemia. Blood. 2017;129:1913–8.CrossRefPubMedGoogle Scholar
  22. 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. 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. 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. 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. 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. 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
  28. 28.
    Kobayashi K, Mitsui K, Ichikawa H, Nakabayashi K, Matsuoka M, Kojima Y, et al. ATF7IP as a novel PDGFRB fusion partner in acute lymphoblastic leukaemia in children. Br J Haematol. 2014;165:836–41.CrossRefPubMedGoogle Scholar
  29. 29.
    Tanaka Y, Kato M, Hasegawa D, Urayama KY, Nakadate H, Kondoh K, et al. Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. Br J Haematol. 2015;171:109–15.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2018

Authors and Affiliations

  • Hiroyuki Takahashi
    • 1
  • Ryosuke Kajiwara
    • 2
  • Motohiro Kato
    • 3
  • Daisuke Hasegawa
    • 4
  • Daisuke Tomizawa
    • 3
  • Yasushi Noguchi
    • 5
  • Kazutoshi Koike
    • 6
  • Daisuke Toyama
    • 7
  • Hiromasa Yabe
    • 8
  • Michiko Kajiwara
    • 9
  • Junya Fujimura
    • 10
  • Manabu Sotomatsu
    • 11
  • Setsuo Ota
    • 12
  • Miho Maeda
    • 13
  • Hiroaki Goto
    • 14
  • Yoko Kato
    • 15
  • Tetsuya Mori
    • 16
  • Takeshi Inukai
    • 17
  • Hiroyuki Shimada
    • 18
  • Keitaro Fukushima
    • 19
  • Chitose Ogawa
    • 20
  • Atsushi Makimoto
    • 21
  • Takashi Fukushima
    • 22
  • Kentaro Ohki
    • 23
  • Katsuyoshi Koh
    • 24
  • Nobutaka Kiyokawa
    • 23
  • Atsushi Manabe
    • 4
  • Akira Ohara
    • 1
  1. 1.Department of PediatricsToho UniversityTokyoJapan
  2. 2.Department of PediatricsYokohama City UniversityYokohamaJapan
  3. 3.Children’s Cancer Center, National Center for Child Health and DevelopmentTokyoJapan
  4. 4.Department of PediatricsSt Luke’s International HospitalTokyoJapan
  5. 5.Department of PediatricsJapanese Red Cross Narita HospitalNaritaJapan
  6. 6.Division of Pediatric Hematology and OncologyIbaraki Children’s HospitalMitoJapan
  7. 7.Department of PediatricsShowa University Fujigaoka HospitalYokohamaJapan
  8. 8.Department of Cell Transplantation and Regenerative MedicineTokai University School of MedicineIseharaJapan
  9. 9.Department of PediatricsTokyo Medical and Dental UniversityTokyoJapan
  10. 10.Department of PediatricsJuntendo UniversityTokyoJapan
  11. 11.Department of PediatricsGunma Children’s Medical CenterShibukawaJapan
  12. 12.Department of PediatricsTeikyo University Chiba Medical CenterIchiharaJapan
  13. 13.Department of PediatricsNippon Medical SchoolTokyoJapan
  14. 14.Division of Hemato-Oncology/Regenerative MedicineKanagawa Children’s Medical CenterYokohamaJapan
  15. 15.Department of PediatricsJikei University School of MedicineTokyoJapan
  16. 16.Department of PediatricsSt. Marianna UniversityKawasakiJapan
  17. 17.Department of PediatricsUniversity of YamanashiChuoJapan
  18. 18.Department of PediatricsKeio University School of MedicineTokyoJapan
  19. 19.Department of PediatricsDokkyo Medical UniversityShimotsugaJapan
  20. 20.Department of Pediatric OncologyNational Cancer Center HospitalTokyoJapan
  21. 21.Department of Hematology-OncologyTokyo Metropolitan Children’s Medical CenterTokyoJapan
  22. 22.Department of PediatricsUniversity of TsukubaTsukubaJapan
  23. 23.Department of Pediatric Hematology and Oncology ResearchNational Research Institute for Child Health and DevelopmentTokyoJapan
  24. 24.Department of Hematology/OncologySaitama Children’s Medical CenterSaitamaJapan

Personalised recommendations