Four thousand, four hundred and forty eligible children of up to 18 years of age were treated in four consecutive trials between 1981 and 1995 with the treatment protocols of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). The probability for event-free 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 involvement 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% in study ALL-BFM 81 to 1.1% in study ALL-BFM 90). Four major findings were derived from this series of trials performed by 37 to 96 centers in Germany, Austria, and Switzerland: (1) Reintensification is a crucial part of treatment, even in low risk patients; (2) presymptomatic cranial radiotherapy can be safely reduced to 12 Gy, or even be eliminated if it is replaced by early intensive systemic and intrathecal methotrexate applied; (3) maintenance therapy given a total of 24 months from diagnosis provides a lower rate of systemic relapses than treatment for 18 months; (4) inadequate response to an initial 7-day prednisone window (combined with one intrathecal injection 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 effectively 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 failure.

The pleiotropic transcription factor NF-B controls cellular apoptotic and growth processes and increasing evidence suggests a role in tumorigenesis. We describe here that constitutively activated NF-B complexes are found in the vast majority (39 out of 42 samples) of childhood acute lymphoblastic leukemia (ALL) without any subtype restriction. Electrophoretic shift analysis further demonstrates that these complexes are composed of p50-p50 and p65-p50 dimers. Proteasome inhibition in primary ALL cultures results in a hyperphosphorylated form of I B␣, indicating that activation of upstream kinases, which trigger I B␣ degradation, has led to nuclear translocation of NF-B. Careful inhibition of cellular proteolytic activities is of importance when analyzing extracts from primary ALL cells. Degradation of p65 and other proteins in ALL samples could be specifically suppressed by ␣-1 antitrypsin. Constitutive NF-B activation is thus a common characteristic of childhood ALL and strongly suggests a critical role of this factor for leukemia cell survival. Leukemia (2000) 14, 399-402.

In trial ALL-BFM 86, the largest multicenter trial of the Berlin- Frankfurt-Munster (BFM) study group for childhood acute lymphoblastic leukemia (ALL), treatment response was used as an overriding stratification factor for the first time. In the previous trial ALL-BFM 83, the in vivo response to initial prednisone treatment was evaluated prospectively. A blast cell count of > or = 1,000/microL peripheral blood after a 7-day exposure to prednisone and one intrathecal dose of methotrexate (MTX) identified 10% of the patients as having a significantly worse prognosis. In trial ALL-BFM 86 patients with > or = 1,000/microL blood blasts on day 8 were included in an experimental branch EG. Patients with < 1,000/microL blood blasts on day 8 were stratified by their leukemic cell burden into two branches, Standard Risk Group (SRG) and Risk Group (RG). SRG patients received an eight- drug induction followed by consolidation protocol M (6-mercaptopurine, high-dose [HD] MTX 4 x 5 g/m2) and maintenance. RG patients were treated with an additional eight-drug reinduction element. For EG patients protocol M was replaced by protocol E (prednisone, HD-MTX, HD- cytarabine, ifosfamide, mitoxantrone). All patients received intrathecal MTX therapy; only those of branches RG and EG received cranial irradiation. In branch RG, patients were randomized to receive or not to receive late intensification (prednisone, vindesine, teniposide, ifosfamide, HD-cytarabine) in the 13th month. During the trial reinduction therapy was introduced in branch SRG, because in the follow-up of trial ALL-BFM 83 the randomized low-risk patients receiving reinduction did significantly better. Nine hundred ninety- eight evaluable patients were enrolled, 28.6% in SRG, 61.1% in RG, 10.3% in EG. At a median follow-up of 5.0 (range 3.4 to 6.9) years, the estimated 6-year event-free survival was 72% +/- 2% for the study population, 58% +/- 5% in branch SRG for the first 110 patients without reinduction therapy, 87% +/- 3% for the next 175 patients with reinduction therapy, 75% +/- 2% in branch RG, and 48% +/- 5% in branch EG. Late intensification did not significantly affect treatment outcome of RG patients; however, only 23% of the eligible patients were randomized. Prednisone poor response remained a negative prognostic parameter despite intensified therapy. The results confirmed the benefit of intensive reinduction therapy even for low-risk patients. The strategy of induction, consolidation, and intensive reinduction may offer roughly 75% of unselected childhood ALL patients the chance for an event-free survival.