Diagnostic and prognostic significance of chromosome abnormalities in childhood acute lymphoblastic leukemia.
Current intensive chemotherapies cure about 70% of the children with ALL. On the other hand a significant number of the children are not cured despite intensive treatment. At the same time some highly curable patients are treated too intensively and suffer from unnecessary side effects of the chemo- and radiotherapy applied. In order to further improve the therapeutic results in this disease, we have to distinguish between the cases with a better and a worse prognosis. The initial karyotype (both numerical and structural chromosome abnormalities) proved to be one of the most reliable prognostic parameters, leading to the suggestion of developing genotype-specific therapies. Although the prognosis in patients with pseudodiploid karyotype is usually unfavorable, a significantly better prognosis can be observed in those with more than 50 chromosomes. Because the latter patients can achieve remission on a metabolite-based therapy, the toxic effects of more aggressive chemotherapy with anthracyclines and genotoxic agents can be avoided; thus, the reliable and accurate identification of patients with > 50 chromosomes is of particular importance. For this purpose three methods: chromosome analysis, DNA flow cytometry, and fluorescence in situ hybridization can be used. In 1993 it was decided to develop a comprehensive nationwide project in order to perform the initial genetic analysis of all ALL children diagnosed in the hematological/oncological centers of Hungary. Here the data obtained on 187 ALL patients diagnosed in the period from 1993 to 1995 are presented. In about 75% of patients (in 140 of 187) chromosome analysis was performed, in 78 cases (55.7%) successfully. The proportion of patients with abnormal karyotype was 36 of 78 (46.1%), and hyperdiploidy with more than 50 chromosomes was detected in 13 of 78 (16.6%) children. The lower ratio of hyperdiploid cases in our patients as compared to the data in the literature may be due to technical difficulties and the small number of patients studied, but it may reflect real geographic characteristics. Using flow cytometry, seven of 31 patients investigated (22.5%) proved to be hyperdiploid with a DNA index above 1.16. A higher ratio of hyperdiploid patients in this study calls attention to the significance of simultaneous application of the two methods. Taken together, 16 of 80 (20.0%) successfully studied patients proved to be hyperdiploid (> 50 chromosomes and/or DNA index above 1.16). The pattern of chromosome involvement in our study determined by chromosome analysis and/or FISH technique proved also to be different from the data of large international series. In addition to trisomies of chromosomes 4, 6, 10, 14, 17, 18, 21, and X, which are known to be the most frequently involved chromosomes, trisomies of chromosomes 3, 8, 11, and 13 were also observed with a high frequency. Comparison of survival curves of various cytogenetic subgroups showed a significant difference between diploid-pseudodiploid and diploid-hyperdiploid A (with 47-50 chromosomes) subgroups. No favorable prognosis of hyperdiploid patients (> 50 chromosomes) could be proved. Because of the small number of patients studied, prognostic differences of cytogenetic subgroups need further confirmation. The clinical and genetic differences observed, however, call attention to the necessity for further genetic studies of ALL patients in Hungary, because these differences may reflect real geographic characteristics and may be related to different environmental mutagen/carcinogen effects of the given geographic area. It is essential to determine whether or not these differences really exist and if they do to reveal the causes leading to these differences. In our view this is one of the routes by which the therapeutic results in childhood ALL can be further improved simultaneously with the avoidance of early and late toxicity of chemotherapy.
Oláh
E
E
Department of Pediatrics, University Medical School of Debrecen, Hungary. olah_e@gyermek.dote.hu
Balogh
E
E
Kajtár
P
P
Pajor
L
L
Jakab
Z
Z
Kiss
C
C
D002648:Child; D002869:Chromosome Aberrations; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011379:Prognosis