Long-term results of four consecutive trials in childhood ALL performed bythe ALL-BFM study group from 1981 to 1995

Four thousand, four hundred and forty eligible children of up to 18 years o f age were treated in four consecutive trials between 1981 and 1995 with th e treatment protocols of the Berlin-Frankfurt-Munster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). The probability for event-fr ee survival (pEFS) at 8 years improved from 65.8% in study ALL-BFM 81 to 75 .9% in study ALL-BFM 90. The cumulative incidence of recurrences with CNS i nvolvement was 10.1% and 9.3% in studies ALL-BFM 81 and 83, but was reduced to less than 5% in study ALL-BFM 90 (for isolated CNS relapses from 5.3% i n study ALL-BFM 81 to 1.1% in study ALL-BFM 90). Four major findings were d erived from this series of trials performed by 37 to 96 centers in Germany, Austria, and Switzerland: (1) Reintensification is a crucial part of treat ment, even in low risk patients; (2) presymptomatic cranial radiotherapy ca n be safely reduced to 12 Gy, or even be eliminated if it is replaced by ea rly intensive systemic and intrathecal methotrexate applied; (3) maintenanc e therapy given a total of 24 months from diagnosis provides a lower rate o f systemic relapses than treatment for 18 months; (4) inadequate response t o an initial 7-day prednisone window (combined with one intrathecal injecti on of methotrexate on day 1) defines about 10% of the patients with a very high risk of relapse. For patients with adequate early response (90% of all ) an 8-year pEFS of 80% has been achieved in the most recent trial ALL-BFM 90. While it has proven so far to be impossible to improve the outcome for the small group of high risk patients, the number of recurrences could be e ffectively reduced for the large group of patients responding adequately to the prednisone in vivo sensitivity test. Apart from inadequate prednisone response, patients with hyperleukocytosis, age <1 year, or the presence of the Philadelphia-chromosome (Ph+ ALL) are at a particularly high risk of fa ilure.