Modern treatment strategies, consisting of intensive chemotherapy and cranial irradiation, have remarkably improved the prognosis for children with acute lymphoblastic leukemia. However, patients with a potential for cure are at risk of severe acute and late adverse effects of treatment. Furthermore, in 25-30% of patients treatment still fails. The objectives of the DCLSG study ALL 8 were to decrease the toxicity and to increase the effectivity of BFM-oriented treatment. Decrease of toxicity was aimed at by confirmation of the results of the previous DCLSG study ALL-7, showing that the majority (94%) of children with ALL can succesfully be treated with BFM-oriented therapy without cranial irradiation, and by reduction of treatment for standard risk (SRG) patients. To increase the cure rate in medium risk (MRG) patients the efficacy of high doses of intravenous 6-mercaptopurine (HD-6MP) during protocol M and in SRG patients the efficacy of high doses of L-asparaginase (HD-L-ASP) during maintenance treatment was studied in randomized studies. Patient stratification and treatment were identical to protocol ALL-BFM90, with the following differences: no prophylactic cranial irradiation, SRG patients received only phase 1 of protocol I. Four hundred and sixtyseven patients entered the protocol: 170 SRG, 241 MRG and 56 HRG patients. The 5 years event-free survival rate for all patients was 73% (s.e. 2%); for SRG, MRG and HRG patients 85% (s.e. 3%), 73% (s.e. 3%) and 39% (s.e. 7%), respectively. In patients Ͼ1 year of age at diagnosis unfavorable prognostic factors were male sex, Ͼ25% blasts in the bone marrow at day 15 and initial white blood cell count (WBC) Ͼ50 × 10 9 /l. The cumulative risk of CNS relapse rate was 5% (s.e. 1%) at 5 years. These results confirm that the omission of cranial irradiation in BFM-oriented treatment does not jeopardize the overall good treatment results, nor does early reduction of chemotherapy in SRG patients. No benefit was observed from treatment intensification with HD-L-ASP in SRG patients, nor from HD-6MP in MRG patients.

This paper reports clinical and cytogenetic data from 125 cases with t(9;11)(p21-22;q32) which were accepted for a European Union Concerted Action Workshop on 11q23. This chromosome abnormality is known to occur predominantly in acute myeloid leukemia (AML) FAB type M5a and less often in AML M4; in this series it was also found to occur, uncommonly, in other AML FAB types, in childhood acute lymphoblastic leukemia (ALL) (nine cases), in relatively young patients with myelodysplastic syndrome (MDS) (five cases), acute biphenotypic leukemia (two cases), and acute undifferentiated leukemia (one case). All age groups were represented but 50% of the patients were aged less than 15 years. The t(9;11) was the sole abnormality in 57 cases with AML; trisomy 8 was the most common additional abnormality (23 cases, including seven with further abnormalities), and 28 cases had other additional abnormalities. Among the t(9;11)+ve patients with AML, the white cell count (WBC) and age group were significant predictors of event-free survival; central nervous system (CNS) involvement or karyotype class (sole, with trisomy 8, or with other), also contributed to prognosis although our data could not show these to be independent factors. The best outcome was for patients aged 1-9 years, with low WBC, and with absence of CNS disease or presence of trisomy 8. For patients aged less than 15 years, the event-free survival for ALL patients was not significantly worse than that of AML patients.

The prevalent with the t(4;11)(q21;q23), but cases of ANLL have also been described with this translocation. Further the t(11;19)(q23;pll) is seen in early B-ALL, common-ALL (c-ALL), ANLL, and occasionally in T-ALL. Other translocations, such as t(10;11)(p11-15;q23) and t(11;17)(q23;q21), are found in ANLL tumors that are otherwise indistinguishable from those discussed above.Recently, a gene on chromosome 11q23 designated MLL (also ALL-1 and HRX) (18-23) has been described that is rearranged in t(4;11) and t(11;19) (18-22, 24-27). These translocations have been studied at the molecular level (18,19,21), and the breakpoints create a fusion of the MLL gene with a gene called AF4 in the case of the t(4;11) (19) or ENL in t(11;19) (21). The MLL breakpoints seem restricted in both t(4;11) and t(11;19) around exon 7 and 8. No information on the comparable breaks in AF4 or ENL genes is yet available. In this paper we determine the breakpoint within MLL of several additional translocations [namely, t(1;11), t(6;11), t(9;11), t(10;11), t(11;17), t(11;22)], two different t(X;11), and two interstitial deletions of llq, as well as a panel of t(4;11) and t(11;19) patient samples. All major hematopoietic lineages are represented. Restricted breakpoints occur in MLL andAF4 and ENL, irrespective oftumor phenotype. Our data suggest that gene fusion of MLL occurs in multipotent hematopoietic precursor cells.MATERIALS AND METHODS DNA Analysis of Acute Leukemia Sampls: Fiter Hybridization. Ten microgrms of genomic DNA was digested with restriction enzyme, and the digestion products were separated on 0.8% agarose gels. The gels were blotted (28) onto nylon membranes and hybridized as described (28) with either the myeloid-lymphoid leukemia (MLL) genomic probe P4 (27) [containing exon 8, a 5' MLL probe (EX5/GEB13) which was prepared by reverse transcriptase (RT)-PCR from RS411 cDNA extending from residues 3869 to 4443 of the published MLL sequence (19,21], or a 3' MLL probe (VAR8F/EX11B), which was also prepared by RT-PCR from RS411 cDNA, extending from residues 4318 to the BamHI site, in exon 11, at residue 4609 of the published MLL sequence.