Analysis of the FLT3-ITD ratio as a prognostic factor in acute myeloid leukemias
First cases studied in Uruguay
Keywords:
ACUTE MYELOID LEUKEMIA, FLT3-ITD, CYTOGENETIC ANALYSISAbstract
Introduction: In recent years, significant progress has been made in the biological knowledge of acute myeloid leukemia (AML), which has been reflected on treatment of affected patients being guided by cytogenetics and molecular profiling. FLT3 internal tandem duplications (FLT3/ITDs) represent the most frequent mutations in AML and confer a bad prognosis in patients with intermediate cytogenetic risk. It has been reported that the presence of a high FLT3-ITD ratio (relationship between number of ITD carrier allele and wild type allele).
Objective: To standardize a technique, still not available in Uruguay, to determine the FLT3-ITD ratio in patients carriers of AML of intermediate cytogenetic risk. To discuss the first cases of AML FLT3+ who underwent ratio analysis.
Methods: In order to identify FLT3-ITD, the fragment corresponding to exons 14 and 15 of the gene was amplified in bone marrow samples upon debut of the disease. In the cases it was positive, the FLT3-ITD ratio was determined by the analysis of fragments with capillary electrophoresis.
Results: This study presented the standardization of a method to determine the FLT3-ITD ratio and the first cases analysed in our country. Twelve patients were studied and the presence of FLT3-ITD was detected in three of them. In two cases, the FLT3-ITD ratio found was below 0.8 and in one case it was greater than or equal to 0.8.
Conclusions: We have a technique to determine the FLT3-ITD ratio with an important prognostic value for patients carriers of AML.
References
(2) Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, et al; German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358(18):1909-18.
(3) Levis M, Small D. FLT3: ITDoes matter in leukemia. Leukemia 2003; 17(9):1738-52.
(4) Fröhling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, et al; AML Study Group Ulm. Acute myeloid leukemia. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002; 100(13):4372-80.
(5) Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001; 98(6):1752-9.
(6) Thiede C, Steudel C, Mohr B, Schaich M, Schäkel U, Platzbecker U, et al. FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99(12):4326-35.
(7) Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 1999; 93(9):3074-80.
(8) Whitman SP, Archer KJ, Feng L, Baldus C, Becknell B, Carlson BD, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res 2001; 61(19):7233-9.
(9) Schlenk RF, Kayser S, Bullinger L, Kobbe G, Casper J, Ringhoffer M, et al; German-Austrian AML Study Group. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood 2014; 124(23):3441-9.
