Clinical features of childhood acute myeloid leukaemia with specific gene rearrangements


Specific gene rearrangements seem to distinguish distinct subsets of acute myeloid leukaemia (AML) with different features and prognosis, and some reports suggest that the epidemiological distribution of AML could vary among countries. To date, cytogenetic examination has been used to study the frequency of these genetic alterations in a large series of children with AML; nevertheless, in a proportion of cases, these gene rearrangements may be cryptic and undetectable by conventional cytogenetic techniques. To evaluate the frequency of specific gene rearrangements, the corresponding clinical morphological features at diagnosis and the potential prognostic impact on patients’ long-term survival, we screened by RT-PCR five different chimaeric transcripts (AML1-ETO, CBFb-MYH11, PML-RARa, MLL-AF9 and BCR-ABL) in a series of 270 Italian children with AML, treated with AIEOP-LAM 87– 92, BFM 83-93 and AIDA protocols between 1988 and 1998, and whose RNA were available and morphology had been centrally reviewed. Of the cases, 45% were positive for one fusion gene. The frequency of AML1-ETO, CBFb-MYH11, PML-RARa and MLLAF9 were 14, 6.3, 20 and 4%, respectively, while BCR-ABL was observed in only two cases. The frequency of AML1-ETO, MLLAF9 and CBFb-MYH11 found was comparable with those of t(8;21), t(9;11) and inv(16) reported previously, suggesting that these gene rearrangements do not have geographic heterogeneity. On the contrary, PML-RARa-positive AML represented 20% of our cohort. This is a higher frequency than that reported in other studies of children from Northern Europe or the United States, but the increased frequency of promyelocytic leukaemia in Italian AML children has already been described. Cytogenetic analysis was successfully carried out in 153 patients, while it failed or was not performed in 117 patients. Abnormalities were identified in 90/153 (59%), the frequency of t(8;21), inv(16), t(15;17) and t(9;11) was 9.8, 2, 17 and 2%, respectively; the 63 remaining cases (41%) had a normal karyotype. In the t(8;21)-positive AML cases, the most common associated alterations involved chromosome 9. Among patients with normal karyotype, RT-PCR identified 17/63 (27%) chimaeric transcripts, and six further cases with translocations undetected by cytogenetics were found among the 43 children reported to have an abnormal karyotype. Considering t(8;21), inv(16), t(15;17) and t(9;11) together, 130/153 (85%) patients, who had a successful analysis were correctly classified cytogenetically. Then, in our experience, cytogenetics showed comparable specificity (100%), but lower sensitivity (67%) than RT-PCR. A general agreement exists in considering RT-PCR more sensitive than conventional cytogenetics in identifying specific gene rearrangements and the fusion genes studied have been described in the absence of identifiable translocations. Nevertheless, the molecular technique is not capable of identifying associated abnormalities. Therefore, since the genetic studies in childhood AML allow for the identification of patient subgroups who probably can benefit from a more tailored therapy and the fusion gene identified can represent a useful target for the minimal residual disease study, ideally all cases should be studied by RT-PCR and cytogenetics: two complementary methods in the genetic characterisation of leukaemia. Clinical data collected included FAB subtypes, gender, age, WBC count at diagnosis and extramedullary involvement, whenever available (Table 1). The low number of M7-AML was due to the scarce number of cells collected in megakaryoblastic leukaemia. The median age at diagnosis for all patients was 7.8 (range 0– 19.5). Cases with AML1-ETO and PML-RARa fusion genes were older patients (median age 8.2 and 9.5 years, respectively), while the median age of patients with CBFb-MYH11 and MLLAF9 was 6.7 and 3.2 years, respectively. A strong, although not exclusive, association between M3, M4 and M5 FAB subgroups and the presence of PML-RARa, CBFb-MYH11 and MLL-AF9 gene rearrangements, respectively, was found. The AML1-ETO-positive cases represented 43% of M2 AML; however, this gene rearrangement was frequently found in M1 patients as well. As a whole, 92% (34/37) of AML1ETO-positive AML were classified as FAB-M1 or FAB-M2. The median WBC count at diagnosis was significantly higher in CBFb-MYH11-positive cases, while PML-RARaand AML1ETO-positive cases had the lowest values. Also, among M2 and M1 plus M2 FAB subgroups this value was significantly lower in AML1-ETO-positive AML than in negatives (16 000/ml vs 30 800/ ml, P1⁄4 0.027; 16 000/ml vs 34 200/ml, P1⁄4 0.0005). Extramedullary disease involved the liver (41%), spleen (37%), node (15%), CNS (8%) and other sites (9%). The FABM3 subtype and the presence of PML-RARa or AML1-ETO fusion genes were significantly associated with low frequency of extramedullary involvement (P1⁄4 0.0002, P1⁄4 0.002 and P1⁄4 0.0047, respectively), while a correlation with the presence of extramedullary disease was found with the presence of MLLAF9, M4 and M5 FAB subgroups and a WBC count at diagnosis higher than 20 000/ml (P1⁄4 0.024, P1⁄4 0.017, P1⁄4 0.018 and P1⁄4 0.046, respectively). CNS involvement was found in 19 patients and, in five of them, was the sole extramedullary site involved. A significant correlation was found only between CNS disease and a WBC count of X50 000/ml at diagnosis (P1⁄4 0.002). In our series, the genetic subgroups showed a characteristic clinical and morphological profile with regard to FAB subtype, age distribution, WBC count at diagnosis, extramedullary Received 6 February 2004; accepted 4 May 2004; Published online 17 June 2004 Correspondence: E Frascella, Pediatric Hematology-Oncology, Department of Pediatrics, University of Padova, via Giustiniani 3, Padova 35128, Italy; Fax: þ39 0498211462; E-mail: Leukemia (2004) 18, 1427–1450 & 2004 Nature Publishing Group All rights reserved 0887-6924/04 $30.00

DOI: 10.1038/sj.leu.2403410


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@article{Frascella2004ClinicalFO, title={Clinical features of childhood acute myeloid leukaemia with specific gene rearrangements}, author={Emanuela Frascella and Roberto Rondelli and Martina Pigazzi and Claudia Zampieron and Franca Fagioli and Claudio Favre and A A Lippi and Francesco Locatelli and Matteo Luciani and Giuseppe Menna and Concetta Micalizzi and Carmelo Rizzari and A M Testi and Andrea Pession and Giuseppe Basso}, journal={Leukemia}, year={2004}, volume={18}, pages={1427-1429} }