Leukemia (2000) 14, 2295–2306  2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu Long-term follow-up of childhood acute lymphoblastic leukemia in Tokyo Children’s Cancer Study Group 1981–1995 M Tsuchida 1 , K Ikuta 2 , R Hanada 3 , T Saito 4 , K Isoyama 5 , K Sugita 6 , Y Toyoda 7 , A Manabe 8 , K Koike 9 , A Kinoshita 10 , M Maeda 11 , K Ishimoto 12 , T Sato 13 , Y Okimoto 14 , T Kaneko 15 , M Kajiwara 16 , M Sotomatsu 17 , Y Hayashi 18 , H Yabe 19 , R Hosoya 20 , Y Hoshi 21 , M Ohira 22 , F Bessho 23 , Y Tsunematsu 24 , I Tsukimoto 25 , S Nakazawa 26 , for the Tokyo Children’s Cancer Study Group 1 Department of Pediatrics, Ibaraki Children’s Hospital, Mito; 2 Departments of Pediatrics and Blood Transfusion, Yokohama City University, School of Medicine, Yokohama; 3 Department of Hematology and Oncology, Saitama Children’s Medical Center, Iwatsuki; 4 Division of Environmental Epidemiology, National Children’s Medical Research Center, Tokyo; 5 Department of Pediatrics, Showa University, School of Medicine, Fujigaoka Hospital, Yokohama; 6 Division of Hematology, Department of Pediatrics, Dokkyo Medical College Tochigi; 7 Departments of Hematology and Oncology, Kanagawa Children’s Medical Center, Yokohama; 8 Department of Pediatric Hematology/Oncology, The University of Tokyo, The Institute of Medical Science, Tokyo; 9 Department of Pediatrics, University of Shinshu, School of Medicine, Matsumoto; 10 Department of Pediatrics, Keio University, School of Medicine, 11 Department of Pediatrics, Nippon Medical School; 12 Department of Pediatrics, and Juntendo University, School of Medicine, Tokyo; 13 Department of Pediatrics, Chiba University, School of Medicine, 14 Department of Hematology and Oncology, Chiba Children’s Hospital, Chiba; 15 Department of Hematology, Tokyo Metropolitan Kiyose Children’s Hospital, 16 Department of Pediatrics, Tokyo Medical and Dental University, School of Medicine, Tokyo; 17 Department of Pediatrics, University of Gunma, School of Medicine, Maebashi; 18 Department of Pediatrics, The University of Tokyo, Faculty of Medicine, Tokyo; 19 Department of Pediatrics, Tokai University, School of Medicine, Isehara; 20 Department of Pediatrics, St. Luke’s International Hospital, 21 Departments of Pediatrics and Blood Transfusion, Jikei University, School of Medicine, 22 Department of Pediatrics, National Cancer Center Central Hospital, 23 Department of Pediatrics, Kyorin University, School of Medicine, 24 Departments of Hematology and Oncology, National Children’s Hospital, 25 The First Department of Pediatrics, Toho University, School of Medicine, Tokyo; and 26 Department of Pediatrics, Yamanashi Medical University, School of Medicine, Kofu, Japan The objectives were as follows: Firstly, to estimate the overall probability of event-free survival (EFS) and isolated CNS relapse in the studies for children with acute lymphoblastic leu- kemia (ALL) during the 1980s and 1990s. Secondly, to report the EFS according to presenting features and lineage. Thirdly, to evaluate the treatment results re-classified by the risks of NCI criteria. Four consecutive protocol studies were performed in the Tokyo Children’s Cancer Study Group: L81–10 protocol (1981–1984, 189 patients), L84–11 (1984–1989, 484 patents), L89–12 (1989–1992, 418 patients) and L92–13 (1992–1995, 347 patients). Overall EFS at 5 years in each protocol was 56.5  3.8(1 s.e.)%, 71.0  2.1%, 67.8  2.3%, and 63.4  2.7%, respect- ively. The cumulative isolated CNS relapse rate at 5 years was 8.1  2.1%, 3.5  0.9%, 3.6  1.0%, 1.0  0.6. The EFS in SR/HR (standard risk/high risk) according to the NCI criteria in B-pre- cursor ALL at 5 years was 61.9  4.3%/41.4  7.4% (lineage was not confirmed.), 72.5  2.6%/63.4  5.0%, 77.4  2.7%/56.3  4.7%, and 67.8  3.4%/56.7  5.4% in each protocol. Also EFSs according to NCI SR/HR at 5 years of T-ALL in protocols L84–11, L89–12 and L92–13 were 55.6  16.6%/60.9  10.1%, 72.7  13.4%/51.6  9.1%, and 77.1  14.4%/53.6/10.1%, respectively. The truncation of maintenance therapy to 6 months resulted in a decreased EFS in L92–13, particularly due to an increase of bone marrow relapse after cessation of ther- apy in SR and HR. The NCI risk criteria work properly even in the patients treated by different intensities, so that it makes the comparison possible among the patients in various groups. The overall EFSs in childhood ALL improved in 1980s, but it seemed stable or decreased in 1990s. The short maintenance therapy resulted in poor outcome in SR on the L92–13 protocol. Many of these late relapsers were effectively rescued and over- all survival remained at a high level. The proportion of patients who received cranial irradiation reduced without any increase of the CNS events. Leukemia (2000) 14, 2295–2306. Keywords: Childhood acute lymphoblastic leukemia; long-term fol- low-up; event-free survival; CNS relapse Correspondence: M Tsuchida, Department of Pediatrics, Ibaraki Chil- dren’s Hospital, 3-3-1, Futabadai, Mito-shi, 311-4145, Japan; Fax: +81-29-252-4031. Received 31 July 2000; accepted 4 August 2000 Introduction In the 1970s there was a breakthrough in the improvement of outcome for childhood acute lymphoblastic leukemia (ALL). The development of prophylactic cranial irradiation greatly contributed to the improvement of outcome of childhood ALL. 1,2 Trials to reduce the utilization of cranial irradiation had already been initiated in the 1970s and the results were reported in 1980. 3,4 From the 1980s to 1990s, fundamental prognostic factors such as age, leukocyte count, cell lineage and chromosomal abnormalities were elucidated and applied to the risk-adopted strategy. 5 The multi-agent intensive induc- tion and intensification regimens were developed in this era. Varieties of randomized comparative studies were executed as large-scale studies. 6–8 The Tokyo Children’s Cancer Study Group (TCCSG) started prophylactic cranial irradiation in the protocol of 1975. A ran- domized trial for ALL was opened in 1981 9 with the partici- pation of 23 institutions. Currently, 42 major institutions (listed in the appendix) in the Tokyo metropolitan area and other districts are participating. The first objective of this article is to estimate the overall probability of EFS and isolated CNS relapse in the studies between 1981 and 1995 in TCCSG. The second objective is to evaluate the EFS according to essential presenting features and lineage for each regimen, and the third is to evaluate the treatment results according to the risk groups of NCI criteria. This may provide insights that will lead to better treatment of children with ALL. Materials and methods From 1981 to 1995, 1450 previously untreated children aged 1 to 15 with acute lymphoblastic leukemia (ALL) were entered and 1438 were eligible for the four consecutive studies of Tokyo Children’s Cancer Study Group (TCCSG): L81–10 (1981–1984, 189 patients), (Table 1), 9 L84–11 (1984–1989, 484 patients) (Table 2), 10–12 L89–12 (1989–1992, 418 patients) (Table 3) 13–16 and L92–13 (1992–1995, 347 patients)