Prevalence of FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD+) in de novo acute myeloid leukemia patients categorized according to cytogenetic risk
Keywords:
Receptor protein – tyrosine kinase, Leukemia, myeloid, acute, Cytogenetic analysis, Prognosis, Polymerase chain reactionAbstract
CONTEXT AND OBJECTIVE: The mechanism involved in leukemogenesis remains unclear and more information about the disruption of the cell proliferation, cell differentiation and apoptosis of neoplastic cells is required. DESIGN AND SETTING: Cross-sectional prevalence study at the Discipline of Hematology, Hospital São Paulo, Universidade Federal de São Paulo. METHODS: We investigated FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD+) in 40 adult patients with de novo acute myeloid leukemia (AML), categorized according to cytogenetic results, from September 2001 to May 2005. RESULTS: Thirteen patients (32.5%) were classified as presenting the favorable karyotype, 11 patients (27.5%) as an intermediate group, 7 patients (17%) as an undefined group and 9 patients (22.5%) as the unfavorable group. FLT3/ITD+ was found in 10 patients (25%): 3 with FLT3/ITD+ and favorable karyotype; 4 with FLT3/ITD+ and intermediate karyotype; 2 with FLT3/ITD+ and undefined karyotype; and only 1 with FLT3/ITD+ and unfavorable karyotype. Among the patients without FLT3/ITD+ , 10 presented favorable karyotype, 8 intermediate, 4 undefined and 8 unfavorable karyotype. The cytogenetic results showed no correlations between FLT3/ITD presence and the prognostic groups (P = 0.13). We found that 2 patients were still alive more than 24 months later, FLT3/ITD+ did not influence the patients’ survival rate. CONCLUSION: We found the same frequency of AML with FLT3/ITD+ in both the favorable and intermediate prognosis groups. Only one patient presented AML, FLT3/ITD+ and unfavorable karyotype (the hypothetical worst clinical situation). Therefore, the prognostic advantage of favorable cytogenetics among patients with FLT3/ITD+ remains to be elucidated, for it to be better understood.
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References
Licht JD, Sternberg DW. The molecular pathology of acute myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2005;137-42.
Gilliland DG. Hematologic malignancies. Curr Opin Hematol. 2001;8(4):189-91.
Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100(5):1532-42.
Small D, Levenstein M, Kim E, et al. STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc Natl Acad Sci U S A. 1994;91(2):459-63.
Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10(12):1911-8.
Reilly JT. FLT3 and its role in the pathogenesis of acute myeloid leukaemia. Leuk Lymphoma. 2003;44(1):1-7.
Kiyoi H, Naoe T, Nakano Y, et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood. 1999;93(9):3074-80.
Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97(8):2434-9.
Kottaridis PD, Gale RE, Frew ME, 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.
Ozeki K, Kiyoi H, Hirose Y, et al. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood. 2004;103(5):1901-8.
Levis M, Small D. FLT3: ITDoes matter in leukemia. Leukemia. 2003;17(9):1738-52.
Jaffe ES, Harris NL, Stein H, Vardiman JW. World Health Organization. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2001.
Chauffaille ML, Figueiredo MS, Beltrani R, Antunes SV, Yamamoto M, Kerbauy J. Acute promyelocytic leukemia: the study of t(15;17) translocation by fluorescent in situ hybridi- zation, reverse transcriptase-polymerase chain reaction and cytogenetic techniques. Braz J Med Biol Res. 2001;34(6):735-43.
Mitelman F. An International System for Human Cytogenetic Nomenclature (ISCN 1995). Basel: Karger; 1995.
Grimwade D, Walker H, Harrison G, et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 pa- tients entered into the United Kingdom Medical Research Council AML11 trial. Blood. 2001;98(5):1312-20.
Kiyoi H, Naoe T, Yokota S, et al. Internal tandem duplication of FLT3 associated with leu- kocytosis in acute promyelocytic leukemia. Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho). Leukemia. 1997;11(9):1447-52.
Pabst T, Mueller BU, Harakawa N, et al. AML1-ETO downregulates the granulocytic differen- tiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nat Med. 2001;7(4):444-51.
Moore MA. Converging pathways in leukemogenesis and stem cell self-renewal. Exp Hema- tol. 2005;33(7):719-37.
Kuchenbauer F, Kern W, Schoch C, et al. Detailed analysis of FLT3 expression levels in acute myeloid leukemia. Haematologica. 2005;90(12):1617-25.
Pinheiro RF, Moreira Ede S, Silva MR, Greggio B, Alberto FL, Chauffaille Mde L. FLT3 mutation and AML/ETO in a case of Myelodysplastic syndrome in transformation corroborates the two hit model of leukemogenesis. Leuk Res. 2007;31(7):1015-8.
Reilly JT. Class III receptor tyrosine kinases: role in leukaemogenesis. Br J Haematol. 2002;116(4):744-57.
Tallman MS. Current management and new approaches in the treatment of APL. Clin Adv Hematol Oncol. 2003;1(10):580-1.
Mrózek K, Heinonen K, Bloomfield CD. Clinical importance of cytogenetics in acute myeloid leukaemia. Best Pract Res Clin Haematol. 2001;14(1):19-47.
Klaus M, Haferlach T, Schnittger S, Kern W, Hiddemann W, Schoch C. Cytogenetic profile in de novo acute myeloid leukemia with FAB subtypes MO, M1, and M2: a study based on 652 cases analyzed with morphology, cytogenetics, and fluorescence in situ hybridization. Cancer Genet Cytogenet. 2004;155(1):47-56.
Whitman SP, Archer KJ, Feng L, 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 du- plication of FLT3: a cancer and leukemia group B study. Cancer Res. 2001;61(19):7233-9.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in OncologyTM. Acute Myeloid Leukemia v.1.2009. Available from: http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed in 2008 (Dec 22).
