We prospectively assigned 289 consecutive children with acute lymphoblastic leukemia to receive one of two treatment programs on the basis of the presence or absence of certain risk factors at the time of diagnosis. Patients at high risk (62 percent of the total) had one or more of the following risk factors: age below two or above nine years, a white-cell count of 20,000 per cubic millimeter or more, the presence of T-cell immunologic markers, radiologic evidence of a mediastinal mass, and involvement of the central nervous system. Patients in both the standard-risk and high-risk groups were treated for two years, receiving intensive remission-induction therapy, central nervous system prophylaxis, weekly administration of high-dose asparaginase, and multiple-drug continuation therapy (which in the high-risk group included doxorubicin and a larger dose of prednisone). At a median follow-up of 35 months, the mean (+/- SE) event-free survival rates at four years among the patients in the standard-risk and high-risk groups were 86 +/- 4 percent and 71 +/- 4 percent, respectively (P = 0.003), for a total event-free survival of 77 +/- 3 percent. Within the high-risk group, the white-cell count at diagnosis and the sex of the patient were not significant prognostic indicators, but age below 12 months at diagnosis was associated with a very poor outcome. As compared with previous methods, this treatment program using four-drug induction and intensive asparaginase therapy has resulted in improved event-free survival in children with acute lymphoblastic leukemia.

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Between 1972 and 1979, 214 children with acute lymphoblastic leukemia and no evidence of central nervous system (CNS) disease prior to CNS prophylaxis were treated with 2400 rad cranial irradiation and concurrent intrathecal methotrexate. Only nine children developed CNS leukemia; five of them in the CNS only and four concurrently in the CNS and another site. Major acute effects of CNS prophylaxis were seizures in seven patients (3%). Sixty-nine children who had a minimum follow-up of 4 yr were evaluable for late effects of therapy. Small cataracts, incomplete regrowth of hair, and learning disabilities were noted. The latter occurred in 18% of patients, an incidence similar to that encountered in a normal community of school-age children. However, the incidence of learning disabilities in patients who were under 5 yr of age at the time of diagnosis was much higher, 35%. We conclude that the combination of cranial irradiation and intrathecal methotrexate was highly efficacious. The incidence and severity of neuropsychologic abnormalities, the principal late morbidity of this treatment program, varies among reporting institutions. Prospective longitudinal studies of neuropsychologic function are necessary to better define the incidence of abnormalities. Future programs should attempt to decrease late morbidity, but must also assure equal efficacy and improve overall disease-free survival.

Between 1972 and 1979, 214 children with acute lymphoblastic leukemia and no evidence of central nervous system (CNS) disease prior to CNS prophylaxis were treated with 2400 rad cranial irradiation and concurrent intrathecal methotrexate. Only nine children developed CNS leukemia; five of them in the CNS only and four concurrently in the CNS and another site. Major acute effects of CNS prophylaxis were seizures in seven patients (3%). Sixty-nine children who had a minimum follow-up of 4 yr were evaluable for late effects of therapy. Small cataracts, incomplete regrowth of hair, and learning disabilities were noted. The latter occurred in 18% of patients, an incidence similar to that encountered in a normal community of school-age children. However, the incidence of learning disabilities in patients who were under 5 yr of age at the time of diagnosis was much higher, 35%. We conclude that the combination of cranial irradiation and intrathecal methotrexate was highly efficacious. The incidence and severity of neuropsychologic abnormalities, the principal late morbidity of this treatment program, varies among reporting institutions. Prospective longitudinal studies of neuropsychologic function are necessary to better define the incidence of abnormalities. Future programs should attempt to decrease late morbidity, but must also assure equal efficacy and improve overall disease-free survival.

We evaluated event-free survival (EFS) and leukemia-free interval (LFI) of children treated for acute lymphoblastic leukemia (ALL). Patients were randomized to receive either a low dose or high dose of methotrexate (MTX) as a single agent at the time of diagnosis. Five days later, multidrug therapy was begun. We assessed the early antileukemic efficacy of the two doses of MTX, as well as toxicity and long-term efficacy. An increase in cell kill, as indicated by a larger decrease in the percentage of viable cells in the bone marrow between days 0 and 5, was observed for the high-dose MTX group when compared with the low-dose MTX group (P = .04). At 7.1 years of median follow- up, the 38 children randomized to receive high-dose MTX had a better EFS and LFI compared with the 39 patients randomized to receive low- dose MTX. The 7-year percentages (+/- SE) for EFS were 82% +/- 6% for high-dose MTX and 69% +/- 7% for low-dose MTX (P = .13). The 7-year percentages for LFI were 91% +/- 5% and 69% +/- 7%, respectively (P = .01). We recommend that high-dose MTX be considered as an effective addition to induction therapy in childhood ALL.