Prevalence and Prognostic Significance of FLT3 Gene Mutations in Patients with Acute Leukaemia: Analysis of Patients from the Shanghai Leukaemia Co-operative Group

Abstract

This study was designed to evaluate the prevalence of fms-like tyrosine kinase-3 (FLT3) gene mutations in the World Health Organization classified subtypes of acute leukaemia (AL), and their prognostic significance in terms of complete remission (CR), leukaemia-free survival (LFS) and overall survival (OS). Of 468 patients, 374 (79.9%) had acute myeloid leukaemia (AML) and 83 (17.7%) had acute lymphoblastic leukaemia (ALL). Among the AML patients, a FLT3 internal tandem duplication (FLT3/ITD) mutation was present in 59 cases (15.8%), whereas a FLT3/D835 mutation was detected in 15 cases (4.0%). Conversely, in the ALL patients, no FLT3/ITD mutations were detected and a FLT3/D835 mutation was found in only two cases (2.4%). The FLT3/ITD mutation was associated with a lower CR rate compared with those with no mutations (52.3% versus 71.1%) and with a shorter median OS (9 versus 18 months) in AML patients. In conclusion, the FLT3/ITD mutation occurred frequently in AML and was associated with a lower CR and shorter median OS. In contrast, FLT3/D835 mutations were not of prognostic value.

Keywords

Acute leukaemia WHO classification system FAB classification system Mutation Prognostic factors

References

Naoe

Kiyoi

: Normal and oncogenic FLT3. Cell Mol Life Sci 2004; 61: 2932–2938.

Stirewalt

Radich

: The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer 2003; 3: 650–665.

Hayakawa

Towatari

Kiyoi

: Tandem duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene 2000; 19: 624–631.

Yamamoto

Kiyoi

Nakano

: Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001; 97: 2434–2439.

Meshinchi

Woods

Stirewalt

: Prevalence and prognostic significance of FLT3 internal tandem duplication in pediatric acute myeloid leukemia. Blood 2001; 97: 89–94.

Whitman

Archer

Feng

: 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: 7233–7239.

Schlenk

Döhner

Krauter

: Mutations and treatment outcomes in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1909–1918.

Wang

Zhou

Zhang

: Prevalence and clinical significance of FLT3 internal tandem duplication mutation in acute leukemia. Zhonghua Xue Ye Xue Za Zhi 2004; 25: 393–396 [in Chinese].

Bennett

Catovsky

Daniel

: Proposals for the classification of the acute leukemias. French-American-British (FAB) cooperative group. Br J Haematol 1976; 33: 451–458.

10.

Brunning

Matutes

Harris

: Acute myeloid leukemias. In: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues ( Jaffe

Harris

Stein

, eds). Lyon: IARC Press, 2001; pp 75–107.

11.

Kottaridis

Gale

Frew

: 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: 1752–1759.

12.

Wanf

Liu

Liang

: Correlation of FLT3 gene expression level and internal tandem duplication mutation in acute myeloid leukemia and its clinical significance. Zhonghua Xue Ye Xue Za Zhi 2008; 29: 741–745.

13.

Colovic

Tosic

Aveic

: Importance of early detection and follow-up of FLT3 mutations in patients with acute myeloid leukemia. Ann Hematol 2007; 86: 741–747.

14.

Schnittger

Schoch

Drgas

: Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia (AML): Correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study, and usefulness as a marker for detection of minimal residual disease. Blood 2002; 100: 59–66.

15.

Thiede

Steudel

Mohr

: Analysis of FL13-activating mutations in 979 patients with acute myelogenous leukemia: Association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99: 4326–4335.

16.

Rombouts

Blokland

Löwenberg

: Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene. Leukemia 2000; 14: 675–683.

17.

Kiyoi

Naoe

Nakano

: Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 1999; 93: 3074–3080.

18.

Schnittger

Schoch

Kern

: Flt3 length mutations in AML: Correlation to cytogenetics, FAB-subtype, and prognosis in 652 patients. Blood 2000; 96: 826a [abstract].

19.

Moreno

Martín

Bolufer

: Incidence and prognostic value of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia. Haematologica 2003; 88: 19–24.

20.

Preisler

Rustum

Henderson

: Treatment of acute nonlymphocytic leukemia: Use of anthracycline-cytosine arabinoside induction therapy and comparison of two maintenance regimens. Blood 1979; 53: 455–464.