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Six Months of Maintenance Chemotherapy After Intensified Treatment for Acute Lymphoblastic Leukemia of Childhood

From the Department of Oncology, Kanagawa Children’s Medical Center, and Department of Pediatrics, Yokohama City University School of Medicine, Yokohama; Department of Pediatric Hematology/Oncology, The University of Tokyo, The Institute of Medical Science; The First Department of Pediatrics, Toho University School of Medicine; Departments of Pediatrics at Tokyo Medical and Dental University School of Medicine, Keio University School of Medicine, Juntendo University School of Medicine, Nippon Medical School, St Lukes International Hospital, and Teikyo University School of Medicine; Department of Hematology/Oncology, Tokyo Metropolitan Kiyose Children’s Hospital; Department of Hematology, National Children’s Hospital; and Environmental Epidemiology, National Children’s Med-ical Research Center, Tokyo; Department of Pediatrics, Ibaraki Children’s Hospital, Mito; Department of Hematology/Oncology, Saitama Children’s Medical Center, Iwatsuki; Department of Hematology/Oncology, Chiba Children’s Hospital, and Department of Pediatrics, Chiba University School of Medicine, Chiba; Department of Pediatrics, University of Shinshu School of Medicine, Matsumoto; Department of Hematology/Oncology, Gunma Children’s Medical Center, Maebashi; and Department of Pediatrics, Yamanashi Medical University, Kohfu, Japan.

Address reprint requests to Yasunori Toyoda, MD, Kanagawa Children’s Medical Center, 2-138-4, Mutsukawa, Minami-ku, Yokohama, 232-8555, Japan.

PURPOSE: We postulated that intensification of chemotherapy immediately after remission induction might reduce the leukemic cell burden sufficiently to allow an abbreviated period of antimetabolite therapy.

PATIENTS AND METHODS: Three hundred forty-seven children (ages 1 to 15 years) with previously untreated acute lymphoblastic leukemia (ALL) were enrolled onto the Tokyo L92–13 study, which excluded patients with mature B-cell ALL and patients less than 1 year old. One hundred twenty-four patients were classified as standard risk, 122 as high risk, and 101 as extremely high risk, according to age, peripheral-blood leukocyte count, selected genetic abnormalities, and immunophenotype. All subjects received four drugs for remission induction, followed by a risk-directed multidrug intensification phase and therapy for presymptomatic leukemia in the CNS. Maintenance chemotherapy with oral mercaptopurine and methotrexate was administered for 6 months, with all treatment stopped by 1 year after diagnosis.

RESULTS: The mean (± SD) event-free survival (EFS) and overall survival rates for all patients were 59.5% ± 3.4% and 81.5% ± 2.2%, respectively, at 5.5 years after diagnosis. EFS rates by risk category were similar (60.2% ± 6.0% for standard risk, 57.7% ± 5.6% for high risk, and 62.5% ± 5.7% for extremely high risk), whereas overall survival rates differed significantly (91.2% ± 2.7%, 80.0% ± 4.1%, and 72.1% ± 4.5%, respectively, P < .0001 by the log-rank test). There were 107 relapses. Eighty-five (79.4%) of these 107 patients achieved second complete remissions, with subsequent EFS rates of 61.5% ± 7.9% (standard risk), 42.6% ± 8.1% (high risk), and 9.6% ± 6.4% (extremely high risk). Of the five risk factors analyzed, only the response to prednisolone monotherapy among extremely high-risk patients proved important.

CONCLUSION: Early treatment intensification did not compensate for a truncated phase of maintenance chemotherapy in children with standard- or high-risk ALL. However, 6 months of antimetabolite treatment seemed adequate for extremely high-risk patients who were good responders to prednisolone and received intensified chemotherapy that included high-dose cytarabine early in the clinical course.

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