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 trial ALL-BFM 95 for treatment of childhood acute lymphoblastic leukemia was designed to reduce acute and longterm toxicity in selected patient groups with favorable prognosis and to improve outcome in poor-risk groups by treatment intensification. These aims were pursued through a stratification strategy using white blood cell count, age, immunophenotype, treatment response, and unfavorable genetic aberrations providing an excellent discrimination of risk groups.
More than one third of patients in this large, population-based trial were cured. Neither R3 nor adaptation of chemotherapy intensity was capable of improving pEFS or of overcoming prognostic factors. In high-risk patients, remission induction regimens must be improved, and allogeneic SCT should be recommended in patients achieving second complete remission.
MRD is an important predictor for post-transplantation outcome. As a result, new strategies with modified stem-cell transplantation procedures will be evaluated in ALL-BFM trials.
An unselected patient population of 2169 children with acute lymphoblastic leukemia (ALL) was enrolled in the multicenter trial ALL-BFM 95 of the Berlin-Frankfurt-Münster (BFM) study group. The study was designed to minimize acute and long-term toxicity through well-directed treatment reduction in a large patient subset with expectedly good prognosis. On the other hand extensive therapy intensification was implemented in a subgroup with very poor prognosis. The precondition was the clear definition of distinct risk groups enabled by a new risk stratification: patients (pts) with translocation t(9;22) and t(4;11), poor response to the cytoreductive prednisone prephase and/or to induction treatment were allocated to the high-risk (HR) group. Non-HR pts were stratified by age, white blood cell count (WBC) and immunophenotype to standard risk (SR, age 1–5 years, WBC <20 Gp/L, and no T-immunology) or medium risk (MR, all other pts). Compared to the previous trial ALL-BFM 90, the following treatment modifications were made in ALL-BFM 95: 1. reduction of the daunorubicin dose by 50% in induction in SR pts; 2. extension of maintenance by 12 months in SR boys; 3. in the MR group, randomized evaluation of intermediate-dose (ID) cytarabine in addition to high-dose methotrexate in the extracompartment/consolidation phase; 4. omission of preventive cranial radiotherapy (pCRT) in all MR pts with Non-T-ALL; 5. intensification of consolidation/reinduction in HR pts by dose increase in the block elements and reintroduction of protocol II as element providing a continuous drug exposure. Except for the randomized question, event-free survival was analyzed in comparison to the matching subsets of the historical control group treated in ALL-BFM 90. Estimated 6-year event-free survival (6y-pEFS) for the total group was 80±1% (median follow-up 7.3 years). The large SR group (35% of pts) achieved excellent 6y-pEFS of 89±1% despite significant reduction of the daunorubicin dose. The elongation of maintenance in boys yielded no significant relapse reduction. In MR (53% of pts), 6y-pEFS was 80±1%; no improvement was accomplished by the use of additional ID-cytarabine. Omission of pCRT in non-T-ALL MR pts was possible without reduction of EFS though the 6-year cumulative incidence of CNS relapses increased from 2.0±0.5% to 4.5±0.8%%. In the small HR group (12% of pts), treatment intensification led to considerable improvement over the previous ALL-BFM trials yielding a 6y-pEFS of 49±3%. Compared with the previous trial ALL-BFM 90, favorable results in SR and MR were firmly established despite significant treatment reduction in the majority of these patients.
The improved design of the study incorporating risk-adapted radiotherapy allowed treatment to be reduced for selected groups of patients without compromising survival.
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