INCIDENCE AND CLINICAL RELEVANCE OF TEL AML1 FUSION GENES IN CHILDRENWITH ACUTE LYMPHOBLASTIC-LEUKEMIA ENROLLED IN THE GERMAN AND ITALIAN MULTICENTER THERAPY TRIALS/

The molecular approach for the analysis of leukemia associated chromos omal translocations has led to the identification of prognostic releva nt subgroups. In pediatric acute lymphoblastic leukemia (ALL), the mos t common translocations, t(9;22) and t(4;11), have been associated wit h a poorer clinical outcome. Recently the TEL gene at chromosome 12p13 and the AML1 gene at chromosome 21q22 were found to be involved in th e translocation t(12;21)(p13;q22). By conventional cytogenetics, howev er, this chromosomal abnormality is barely detectable and occurs in le ss than 0.05% of childhood ALL. To investigate the frequency of the mo lecular equivalent of the t(12;21), the TEL/AML1 gene fusion, we have undertaken a prospective screening in the running German Berlin-Frankf urt-Munster (BFM) and Italian Associazione Italiana Ematologia Oncolog ia Pediatrica (AIEOP) multicenter ALL therapy trials. We have analysed 334 unselected cases of pediatric ALL patients consecutively referred over a period of 5 and 9 months, respectively. The overall incidence of the t(12;21) in pediatric ALL is 18.9%. The 63 cases positive for t he TEL/AML1 chimeric products ranged in age between 1 and 12 years, an d all but one showed CD10 and pre-B immunophenotype. Interestingly, on e case displayed a pre-pre-B immunophenotype. Among the B-lineage subg roup, the t(12;21) occurs in 22.0% of the cases. Fifteen of 67 (24.6%) cases coexpressed at least two myeloid antigens (CD13, CD33, or CDw65 ) in more than 20% of the gated blast cells. DNA index was available f or 59 of the 63 TEL/AML1 positive cases; a hyperdiploid DNA content (g reater than or equal to 1.16) was detected in only four patients, bein g nonhyperdiploid in the remaining 55. Based on this prospective analy sis, we retrospectively evaluated the impact of TEL/AML1 in prognosis by identifying the subset of B-lineage ALL children enrolled in the cl osed German ALL-BFM-90 and Italian ALL-AIEOP-91 protocols who had suff icient material for analysis. A total of 342 children were investigate d for the presence of TEL/AML1 fusion gene and 99 cases (28.9%) were p ositive. The patients expressing the TEL/AML1 fusion mRNA appeared to have a better event-free survival (EFS) than the patients who lacked t his chimeric product. Whereas three of the TEL/AML1 positive cases (3. 0%) have relapsed to date, 27 patients without TEL/AML1 rearrangement (11.1%) suffered from relapse. To date, the only subset of B-lineage A LL with a favorable prognosis has been the hyperdiploid group (DNA ind ex greater than or equal to 1.16 <1.6). Our findings reinforce the nee d to include the molecular screening of the t(12;21) translocation wit hin ongoing prospective ALL trials to prove definitively its prognosti c impact. (C) 1997 by The American Society of Hematology.