TEL/AML1-positive childhood acute lymphoblastic leukemias (ALLs) generally have low-risk features, but still about 20% of patients relapse. Our initial molecular genetic analyses in 2 off-treatment relapses suggested that the initial and relapse clones represent different subclones that evolved from a common TEL/ AML1-positive, treatment-resistant precursor. In order to further elaborate on this hypothesis, we studied 2 patients with late systemic relapses of their TEL/ AML1-positive ALL (41 months and 49 months after initial diagnosis, respectively) who had distinct clonal antigen receptor gene rearrangements at diagnosis and relapse. These clone-specific markers enabled us to determine the responsiveness of the individual clones to treatment. The matching genomic TEL/ AML1 breakpoints of the initial and the relapse clones in these patients confirmed their origin from a common progenitor cell. This proof was especially important in one of these 2 leukemias without a common antigen receptor gene rearrangement. Our retrospective analysis revealed that in both cases the relapse clone was already present at diagnosis. Despite their small sizes (5 ؋ 10 ؊3 and 1 ؋ 10 ؊4 , respectively), we were able to detect their much slower responses to therapy compared with the dominant leukemic clone. Moreover, in all instances, these initially slow-responding clones, after they had developed into the relapse leukemia, were rapidly eradicated by the relapse treatment, underlining their different biology at the 2 time points of leukemia manifestation. We thus hypothesize that the minor clone was not fully malignant at initial diagnosis but acquired further mutations that may be necessary for the manifestation of relapse. (Blood. 2003; 101:3635-3640)

Purpose: TEL (ETV6)-AML1 (RUNX1) chimeric gene fusions are frequent genetic abnormalities in childhood acute lymphoblastic leukemia (ALL). They often arise prenatally as early events or initiating events and are complemented by secondary postnatal genetic events of which deletion of the non-rearranged, second TEL allele is the most common. This consistent sequence of molecular pathogenesis facilitates an analysis of the clonal origins of relapse in this leukemia, which has some unusual clinical features.Experimental Design: We compared the boundaries, by microsatellite mapping, of TEL deletions at relapse versus diagnosis in 15 informative patients. Moreover, we compared the relatedness of diagnostic and relapse clones using immunoglobulin and T-cell receptor genes rearrangements and clonotypic TEL-AML1 genomic fusion.Results: Five patients retained the apparent same size TEL deletion, seven had larger deletions, and three had smaller deletions at relapse. In all of the cases evaluated, the clonal relatedness of diagnostic and relapse cells was confirmed by the retention of clonotypic TEL-AML1 genomic sequence and/or at least one identical immunoreceptor gene rearrangement.Conclusions: These data provide further evidence that TEL deletions are secondary to TEL-AML1 fusions in ALL. They are compatible with the novel idea that in at least some cases of childhood ALL, remission occurs with persistence of a preleukemic "fetal" clone, and subsequent relapse reflects the emergence of a new subclone from this reservoir after an independent "second hit," i.e., independent TEL deletion. To our knowledge, the study is the most extensive and comprehensive analysis of the relationship between diagnostic and relapse clones in childhood ALL presented thus far.

Risk-adapted individualisation of treatment led to a reduction of chemotherapy in the low and standard risk group without compromising survival. The outcome of RME and RMA was similar in this cohort of patients. These preliminary results after a median observation time of 2.5 years confirm the CWS 96 strategy.