CONCEPT AND INTERIM ANALYSIS OF TRIAL ALL -BFM 90 FOR THE TREATMENT OF CHILDREN AND ADOLESCENTS WITH ACUTE LYMPHOBLASTIC-LEUKEMIA - SIGNIFICANCE OF THERAPY RESPONSE IN PERIPHERAL-BLOOD AND BONE-MARROW

In the ongoing trial ALL-BFM 90 for the treatment of childhood non-B c ell acute lymphoblastic leukemia (ALL) 1468 unselected patients (pts) were enrolled from 84 centers in Germany and Switzerland from 4/90 to 12/93. Based on the results of the previous trial ALL/NHL-BFM 86 this treatment program focused especially on therapy modifications for aver age (MRG) and high risk (HRG) pts, on the evaluation of therapy respon se for prognosis, and on the identification of high risk pts by molecu lar genetics. For average risk pts consolidation therapy was intensifi ed by the addition of L-asparaginase (L-ASP) on a randomized basis. In HRG induction and consolidation therapy was modified by introduction of early intensification elements that had proved to be effective in r elapsed pts. This patient group was randomized for the evaluation of t he effects of G-CSF administered in the intervals between the intensif ication elements. Distribution of the 1376 eligible pts into the three treatment arms SRG (standard risk), MRG, and HRG was as expected (17 pts not yet assigned): 385 pts (28.0%), 834 pts (60.6%), and 140 pts ( 10.2%), respectively. Treatment consisted of the 8-drug induction (Pro tocol I), consolidation (Protocol M), reinduction (Protocol II), and m aintenance therapy (total therapy duration 24 months). The drug doses and combinations were only slightly modified compared to the previous study ALL-BFM 86 with the exception of the randomized L-ASP containing arm MRG-2 (Protocol M-A) and group HRG. Preventive cranial irradiatio n was reduced to 12 Gy and applied to MRG and HRG pts only. As in stud y ALL-BFM 86, the initial response to a 7-day exposure to prednisone a nd to the first intrathecal injection of MTX at diagnosis was evaluate d at day 8 of treatment with regard to blast count in peripheral blood (PB). In addition, pts were now investigated for the presence of blas ts in the bone marrow (BM) at day 15 of treatment to compare the progn ostic power of both response parameters. Identification of translocati on t(9; 22) and/or BCR-ABL rearrangement characterized a small subgrou p of pts that were not detected by poor initial therapy response. Thes e pts were enrolled in HRG for more intensive treatment including allo geneic bone marrow transplantation (BMT). After a median observation t ime of 22 months, the overall probability for event-free survival (p-E FS) is 82 +/- 2%. 11 pts (0.8%) died before complete remission (CR) wa s achieved, 15 pts (1.1%) died while in CR for reasons other than rela pse. At this time p-EFS for each strategic group is: 86 +/- 3% for SRG . 86 +/- 2% for MRG. and 43 +/- 6% for HRG. Results in the randomized subgroups will not be disclosed before the study is closed sin 1994. T hese preliminary results indicate that for 90% of ALL pts risk-adapted intensive therapy can provide a very high chance for cure with a very low complication rate. However, those pts that are mainly identified by an inadequate initial response to prednisone remain to be the criti cal poor prognosis group. Interestingly, pts with more than 20% blasts in the BM at day 15 suffer from twice as many relapses as those with 5-20%, and four times more than those with less than 5% blasts. Only h alf of the pts within the subgroup with > 20% blasts in the BM at day 15 were prednisone poor responders, i.e. they revealed > 1000 blasts i n the PB at day 8 of therapy. Thus, the new response evaluation might identify additional pts at high risk for failure.