Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Acute Leukemias

Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984–1999

Abstract

We report the long-term results of Tokyo Children's Cancer Study Group's studies L84-11, L89-12, L92-13, and L95-14 for 1846 children with acute lymphoblastic leukemia, which were conducted between 1984 and 1999. The value of event-free survival (EFS)±s.e. was 67.2±2.2% at 10 years in L84-11, which was not improved in the following two studies, and eventually improved to 75.0±1.8% at 10 years in L95-14 study. The lower EFS of the L89-12 reflected a high rate of induction failure because of infection and delayed remission in very high-risk patients. The L92-13 study was characterized by short maintenance therapy; it resulted in poor EFS, particularly in the standard-risk (SR) group and boys. Females did significantly better than males in EFS in the early three studies. The gender difference was not significant in overall survival, partly because >60% of the males survived after the testicular relapse. Randomized studies in the former three protocols revealed that intermediate- or high-dose methotrexate therapy significantly reduced the testicular relapse rate. In the L95-14 study, gender difference disappeared in EFS. Contrary to the results of larger-scale studies, the randomized control study in the L95-14 reconfirmed with updated data that dexamethasone 8 mg/m2 had no advantage over prednisolone 60 mg/m2 in the SR and intermediate-risk groups. Prophylactic cranial irradiation was assigned to 100, 80, 44, and 44% of the patients in the studies, respectively. Isolated central nervous system relapse rates decreased to <2% in the last two trials. Secondary brain tumors developed in 12 patients at 8–22 years after cranial irradiation. Improvement of the remission induction rates and the complete omission of irradiation are currently main objectives in our studies.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Tsuchida M, Ikuta K, Hanada R, Saito T, Isoyama K, Sugita K et al. Long-term follow-up of childhood acute lymphoblastic leukemia in Tokyo Children's Cancer Study Group 1981–1995. Leukemia 2000; 14: 2295–2306.

    Article  CAS  Google Scholar 

  2. Tsuchida M, Akatsuka J, Bessho F, Chihara H, Hayashi Y, Hoshi Y et al. Treatment of acute lymphoblastic leukemia in the Tokyo Children′s Cancer Study Group—preliminary results of L84-11 protocol. Acta Pediatr Jpn 1991; 33: 522–532.

    Article  CAS  Google Scholar 

  3. Aur RJA, Simone JV, Verzosa MS, Hutsu HO, Barker LF, Pinkel DP et al. Childhood acute lymphocytic leukemia. Cancer 1978; 42: 2133–2134.

    Article  Google Scholar 

  4. Schrappe M, Beck J, Brandeis WE, Feickert HJ, Gadner H, Graf N et al. Treatment of acute lymphoblastic leukemia in childhood and adolescence: results of the multicenter therapy study ALL-BFM81. Klin Padiatr 1987; 199: 133–150.

    Article  CAS  Google Scholar 

  5. Manabe A, Tsuchida M, Hanada R, Ikuta K, Toyoda Y, Okimoto Y et al. Delay of the diagnostic lumbar puncture and intrathecal chemotherapy in children with acute lymphoblastic leukemia who undergo routine corticosteroid testing: Tokyo Children′s Cancer Study Group study L89-12. J Clin Oncol 2001; 19: 3182–3187.

    Article  CAS  Google Scholar 

  6. Toyoda Y, Manabe A, Tsuchida M, Hanada R, Ikuta K, Okimoto Y, et al. for the Acute Lymphoblastic Leukemia Committee of the Tokyo Children's Cancer Study Group. Six months of maintenance chemotherapy after intensified treatment for acute lymphoblastic leukemia of childhood. J Clin Oncol 2000; 18: 1508–1515.

    Article  CAS  Google Scholar 

  7. Igarashi S, Manabe A, Ohara A, Kumagai M, Saito T, Okimoto Y et al. No advantage of dexamethasone over prednisolone for the outcome of standard- and intermediate-risk childhood acute lymphoblastic leukemia in the Tokyo Children′s Cancer Study Group L95-14 protocol. J Clin Oncol 2005; 23: 6489–6498.

    Article  CAS  Google Scholar 

  8. Conter V, Aricò M, Valsecchi MG, Rizzari C, Testi AM, Messina C et al. Extended intrathecal methotrexate may replace cranial irradiation for prevention of CNS relapse in children with intermediate-risk acute lymphoblastic leukemia treated with Berlin-Frankfurt-Münster-based intensive chemotherapy. The Associazione Italiana di Ematologia ed Oncologia Pediatrica. J Clin Oncol 1995; 13: 2497–2502.

    Article  CAS  Google Scholar 

  9. Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W et al. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 2000; 95: 3310–3322.

    CAS  Google Scholar 

  10. Pui CH, Boyett JM, Relling MV, Harrison PL, Rivera GK, Behm FG et al. Sex differences in prognosis for children with acute lymphoblastic leukemia. J Clin Oncol 1999; 17: 818–824.

    Article  CAS  Google Scholar 

  11. Shuster JJ, Wacker P, Pullen J, Humbert J, Land VJ, Mahoney Jr DH et al. Significance of sex in childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group Study. J Clin Oncol 1998; 16: 2854–2863.

    Article  CAS  Google Scholar 

  12. Chessells JM, Richards SM, Bailey CC, Lilleyman JS, Eden OB . Gender and treatment outcome in childhood lymphoblastic leukaemia: report from the MRC UKALL trials. Br J Haematol 1995; 89: 364–372.

    Article  CAS  Google Scholar 

  13. 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.

    Article  CAS  Google Scholar 

  14. Ishii E, Okamura J, Tsuchida M, Kobayashi M, Akiyama Y, Nakahata T et al. Infant leukemia in Japan: clinical and biological analysis of 48 cases. Med Pediatr Oncol 1991; 19: 28–32.

    Article  CAS  Google Scholar 

  15. Isoyama K, Okawa H, Hayashi Y, Hanada R, Okimoto Y, Maeda M et al. Clinical and biological aspects of acute lymphoblastic leukemia in 62 infants: retrospective analysis of the Tokyo Children′s Cancer Study Group. Pediatr Int 1999; 41: 477–483.

    Article  CAS  Google Scholar 

  16. Kosaka Y, Koh K, Kinukawa N, Wakazono Y, Isoyama K, Oda T et al. Infant acute lymphoblastic leukemia with MLL gene rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell transplantation. Blood 2004; 104: 3527–3534.

    Article  CAS  Google Scholar 

  17. Riehm H, Schrappe M . Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood 1999; 94: 1209–1217.

    Google Scholar 

  18. Kikuchi A, Maeda M, Hanada R, Okimoto Y, Ishimoto K, Kaneko T et al. Tokyo Children's Cancer Study Group (TCCSG). Moyamoya syndrome following childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 2007; 48: 268–272.

    Article  Google Scholar 

  19. Dördelmann M, Reiter A, Zimmermann M, Fengler R, Henze G, Riehm H et al. Intermediate dose methotrexate is as effective as high dose methotrexate in preventing isolated testicular relapse in childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 1998; 20: 444–450.

    Article  Google Scholar 

  20. Aricò M, Valsecchi MG, Rizzari C, Barisone E, Biondi A, Casale F et al. Long-term results of the AIEOP-ALL-95 Trial for Childhood Acute Lymphoblastic Leukemia: insight on the prognostic value of DNA index in the framework of Berlin-Frankfurt-Muenster based chemotherapy. J Clin Oncol 2008; 26: 283–289.

    Article  Google Scholar 

  21. Mori T, Manabe A, Tsuchida M, Hanada R, Yabe H, Ohara A et al. Allogeneic bone marrow transplantation in first remission rescues children with Philadelphia chromosome-positive acute lymphoblastic leukemia: Tokyo Children's Cancer Study Group (TCCSG) studies L89-12 and L92-13. Med Pediatr Oncol 2001; 37: 426–431.

    Article  CAS  Google Scholar 

  22. Hijiya N, Hudson M, Lensing S, Zacher M, Onciu M, Behm FG et al. Cumulative incidence of secondary neoplasms as the first event after treatment of childhood acute lymphoblastic leukemia increases over 30 years. JAMA 2007; 297: 1207–1215.

    Article  CAS  Google Scholar 

  23. Pui CH, Ribeiro RC, Hancock ML, Rivera GK, Evans WE, Raimondi SC et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med 1991; 325: 1682–1687.

    Article  CAS  Google Scholar 

  24. Pui C-H, Relling MV, Rivera GK, Hancock ML, Raimondi SC, Heslop HE et al. Epipodophyllotoxin-related acute myeloid leukemia—a study of 35 cases. Leukemia 1995; 9: 1990–1996.

    CAS  Google Scholar 

  25. Silber JH, Jakachi RI, Larsen RL, Goldwein JW, Barber G . Forecasting cardiac function after anthracyclines in childhood: the role of dose, age, gender. In: Bricker JT, Green DM and D’Angio GJ (eds). Cardiac Toxicity After Treatment for Childhood Cancer. Wiley-Liss: New York, 1994, pp 95–102.

    Google Scholar 

  26. Waber DP, Urion DK, Tarbell NJ, Niemeyer C, Gelber R, Sallan SE . Late effects of central nervous system treatment of acute lymphoblastic leukemia in childhood are sex-dependent. Dev Med Child Neurol 1990; 32: 238–248.

    Article  CAS  Google Scholar 

  27. Schmiegelow K, Forestier E, Kristinsson J, Soderhall S, Vettenranta K, Weinshilboun R, et al., on behalf of the Nordic Society of Pediatric Haematology and Oncology (NOPHO). Thiopurine methyltransferase activity is related to the risk of relapse of children of acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Leukemia 2009; 23: 557–564.

    Article  CAS  Google Scholar 

  28. Schmiegelow K, Al-Modhwahi I, Andersen MK, Behrendtz M, Forestier E, Hasle H, et al., Nordic Society for Paediatric Haematology and Oncology. Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Blood 2009; 113: 6077–6084.

    Article  CAS  Google Scholar 

  29. Krappmann P, Paulides M, Stöhr W, Ittner E, Plattig B, Nickel P et al. Almost normal cognitive function in patients during therapy for childhood acute lymphoblastic leukemia without cranial irradiation according to ALL-BFM 95 and COALL 06-97 protocols: results of an Austrian-German multicenter longitudinal study and implications for follow-up. Pediatr Hematol Oncol 2007; 24: 101–109.

    Article  CAS  Google Scholar 

  30. Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009; 360: 2730–2741.

    Article  CAS  Google Scholar 

  31. Vilmer E, Suciu S, Ferster A, Bertrand Y, Cavé H, Thyss A et al. Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report. Children Leukemia Cooperative Group. Leukemia 2000; 14: 2257–2266.

    Article  CAS  Google Scholar 

  32. Gustafsson G, Schmiegelow K, Forestier E, Clausen N, Glomstein A, Jonmundsson G et al. Improving outcome through two decades in childhood ALL in the Nordic countries: the impact of high-dose methotrexate in the reduction of CNS irradiation. Nordic Society of Pediatric Haematology and Oncology (NOPHO). Leukemia 2000; 14: 2267–2275.

    Article  CAS  Google Scholar 

  33. Kamps WA, Bökkerink JP, Hählen K, Hermans J, Riehm H, Gadner H et al. Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy: results of Dutch Childhood Leukemia Study Group Protocol ALL-7 (1988–1991). Blood 1999; 94: 1226–1236.

    CAS  Google Scholar 

  34. Gajjar A, Harrison PL, Sandlund JT, Rivera GK, Ribeirio RC, Rubnitz JE et al. Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia. Blood 2000; 96: 3381–3384.

    CAS  Google Scholar 

  35. 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: 1155–1160.

    Article  CAS  Google Scholar 

  36. Seibel NL, Steinherz PG, Sather HN, Nachman JB, Delaat C, Ettinger LJ et al. Early post-induction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Blood 2008; 111: 2548–2555.

    Article  CAS  Google Scholar 

  37. Riehm H, Reiter A, Schrappe M, Berthold F, Dopfer R, Gerein V et al. Corticosteroid-dependent reduction of leukocyte count in blood as a prognostic factor in acute lymphoblastic leukemia in childhood (therapy study ALL-BFM 83). Klin Padiatr 1987; 199: 151–160.

    Article  CAS  Google Scholar 

  38. Reiter A, Schrappe M, Ludwig WD, Hiddemann W, Sauter S, Henze G et al. Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86. Blood 1994; 84: 3122–3133.

    CAS  Google Scholar 

  39. Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K et al., Children’s Cancer Group. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children′s Cancer Group. Blood 2003; 101: 3809–3817.

    Article  CAS  Google Scholar 

  40. Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A, Eden TO . Medical Research Council Childhood Leukaemia Working Party. Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol 2005; 129: 734–745.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Tomohiro Saito and Mrs Kaori Itagaki for statistical analysis and preparing and refining the data of the protocols of ALL in TCCSG. We also thank all the pediatricians and nurses participated in the treatment and follow-up of the patients for their works. Grant of Children's Cancer Association, Japan, supported this study.

Author information

Authors and Affiliations

Authors

Consortia

Corresponding author

Correspondence to M Tsuchida.

Appendix: current participating members and institutions of TCCSG (bold letter indicates authors)

Appendix: current participating members and institutions of TCCSG (bold letter indicates authors)

M Tsuchida, Kaz Koike, K Kato, C Kobayashi: Department of Pediatric Hematology and Oncology, Ibaraki Children's Hospital, H Kigasawa: Department of Hematology and Oncology, Kanagawa Children's Medical Center, M Hashiyama: Department of Pediatrics, University of Kumamoto, School of Medicine, M Migita: Department of Pediatrics, Kumamoto Red Cross Hospital, T Kanazawa: Department of Pediatrics, University of Gunma, School of Medicine, A Matsui: Department of Pediatrics, Maebashi Red Cross Hospital, H Shimada, H Yoshihawa: Department of Pediatrics, Keio University, School of Medicine, H Kawaguchi: Department of Pediatrics, Tokyo Medical University, Ichikawa Hospital, A Makimoto, A Hosono: Department of Pediatrics, National Cancer Center Hospital, K Takagi, S Morinaga: Department of Pediatrics, National Hospital Organization Kumamoto Medical Center, M Kumagai, C Kiyotani, T Mori, Y Shiota: Department of Pediatric Hematology/Oncology, National Center for Child Health and Development, International Medical Center, K Moriwaki: Department of Pediatrics, Saitama Medical University, Medical Center, K Ko, Y Hanada, S Mochizuki, D Toyama: Department of Hematology/Oncology, Saitama Children's Medical Center, M Akiyama, Y Kato, Y Hoshi: Department of Pediatrics, Tokyo Jikei University, School of Medicine,Y Gunji, Y Kashii, T Morimoto: Department of Pediatrics, Jichi Medical School, M Saito, J Fujimura, K Ishimoto: Department of Pediatrics, Juntendo University, School of Medicine, Tokyo, K Isoyama, M Yamamoto, T Hirota: Department of Pediatrics, Showa University, School of Medicine, Fujigaoka Hospital, Ken Koike, R Yanagisawa, M Shiobara: Department of Pediatrics, University of Shinshu, School of Medicine, E Ishii: Department of Hematology/Oncology, Nagano Children's Hospital, A Kinoshita, K Kondo, M Morimoto: Department of Pediatrics, St Marianna University School of Medicine, Y Hosoya, C Ogawa, Y Ishida, A Manabe, M Ozawa, D Hasegawa, T Kamiya: Department of Pediatrics, St Luke's International Hospital, Tokyo, H Ochiai, Y Sato, E Sakao, K Ito: Department of Pediatrics, Chiba University, School of Medicine, Chiba, K Sunami, Y Noguchi, T Igarashi: Department of Pediatric Hematology/Oncology, Narita Red Cross Hospital, I Komori: Department of Pediatrics, Matsudo City Hospital, S Oota: Department of Pediatrics, Teikyo University, Chiba Medical Center, Y Okimoto, H Kakuta: Department of Hematology/Oncology, Chiba Children's Hospital, S Kato, K Morimoto, S Yabe, M Yabe: Department of Pediatrics and Blood Transfusion, Tokai University, School of Medicine, S Mizutani, M Kajiwara, M Nagasawa, D Tomizawa: Department of Pediatrics, Tokyo Medical and Dental University, School of Medicine, Tokyo, S Koana, Y Kashiwagi: Department of Pediatrics, Tokyo Medical University Hospital, K Ida, J Takita, K M Kato, K Ooki: Department of Pediatrics, Tokyo University, School of Medicine, E Wada, F Kato: Department of Pediatrics, Tokyo Women's Medical College, East Medical Center, A Ohara, Y Kojima, K Mitsui, Y Uchino: Department of First Pediatrics, Toho University Medical Center, Oomori Hospital, A Watanabe: Department of Second Pediatrics, Toho University Medical Center, Oomori Hospital, K Sugita, K Fukushima, H Kurosawa, S Hagisawa, Y Sato: Department of Pediatrics, Dokkyo Medical College, Tochigi, T Kaneko, K Fukuoka, M Sugita: Department of Hematology/Oncology, Tokyo Metropolitan Kiyose Children's Hospital, H Kaku, M Kawamura: Department of Pediatrics, Tokyo Metropolitan Komagome Hospital, M Maeda, Y Fukunaga, S Migita, T Ueda: Department of Pediatrics, Nippon Medical School, K Asano: Department of Pediatrics, Nippon Medical School Chiba Hokusoh Hospital, K Sugita, T Inukai, K Goi: Department of Pediatrics: University of Yamanashi Hospital, H Goto, H Fugii, K Ikuta, M Yanagimachi, T Yokosuka: Department of Pediatrics, Yokohama City University, School of Medicine, S Kai, H Takahashi, A Goto, F Tanaka: Department of Pediatrics, Yokohama Saiseikai Nanbu Hospital, Yokohama, K Tsuji, Y Ebihara: Department of Pediatric, Blood Transfusion, The University of Tokyo, The Institute of Medical Science, N Nakadate: Department of Pediatrics, Kitazato University, School of Medicine, Y Ishiguro, T Suzuki: Department of Pediatrics, Teikyo University, Mizonokuchi Hospital, K Fukushima, S Nakao: Department of Pediatrics, Tsukuba University Hospital, Y Hayashi, M Sotomatsu, A Paku: Department of Hematology/Oncology, Gunma Chidren's Hospital, F Bessho, H Yoshino, M Ishii, Y Genma: Department of Pediatrics, Kyorin University, School of Medicine, Tokyo, K Kogawa, Y Tsuji, K Imai: Department of Pediatircs, National Defense Medical college, F Sawa: Department of Pediatrics, Saiseikai Yokohama City, Tobu Hospital, Yokohaya.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsuchida, M., Ohara, A., Manabe, A. et al. Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984–1999. Leukemia 24, 383–396 (2010). https://doi.org/10.1038/leu.2009.260

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2009.260

Keywords

This article is cited by

Search

Quick links