FMS-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD): a villain among others

Acute myeloid leukemia (AML) is the most frequent acute leukemia of adult patients with an estimated 10,070 new cases in Brazil in 2016. Most of the cases are de novo, without a defined etiology, and around two thirds of the patients will die of the disease, according to the Instituto Nacional de Câncer (INCA).¹ Genetic aberrations may help to differentiate patients who have a good from those with a dismal prognosis.

In fact, chromosomal abnormalities detected by G-banding karyotype and gene rearrangements revealed by molecular tests are important tools to stratify patients into favorable, intermediate or unfavorable prognoses. The World Health Organization (WHO) classification of hematopoietic tumors lists recurrent genetic abnormalities.²

FMS-related tyrosine kinase 3 (FLT3), a tyrosine kinase receptor usually expressed in hematopoietic progenitors, is the most common genetic lesion in AML with mutations detected in from 25% to 40% of the cases.³ These mutations may occur in any subtype of AML (including acute promyelocytic leukemia - APL), and are frequent with the normal karyotype or t(6;9).

There are two main types of mutations: internal tandem duplication (ITD), which is the most common (∼25% of cases), and a point mutation (D835) (∼5%).⁴

Except for APL, AML patients with FLT3-ITD present increased chance of relapse, short disease-free survival and reduced overall survival, despite an unchanged complete remission rate.⁵ The detection of FLT3-ITD is important for prognosis particularly in those with a normal karyotype.

However, there remains some controversy about the impact of the size of FLT3-ITD fragment on the prognosis. One study showed that 48-60 base-pair duplications are associated with a worse outcome⁶ and other authors reported that it is not possible to confirm this relationship by the length of FLT3-ITD alone. There is a large variation in the clinical characteristics of patients, making it difficult to correlate data and set standards.^7,8

Aiming to evaluate the length of duplication in Brazilian patients, we evaluated AML cases diagnosed from January 2013 until July 2015 at the Fleury Medicina Diagnóstica laboratory according to the WHO classification using bone marrow morphology and flow cytometry immunophenotyping. We identified 26 (29%) out of 89 AML cases with FLT3-ITD. The mean age of the patients was 54 years old (range: 13-79 years) and the male to female ratio was 1:0.7. The size of the duplication varied from 21 to 87 base pairs (mean: 57 base pairs) and only two cases had two peaks, showing a very heterogeneous pattern. From these cases, ten (38%) had follow-ups with no differences being found (unpaired t-test: p-value = 0.44) in respect to the size of the duplication and survival, probably due to the low number of cases studied. Indeed, many factors contribute to the lack of success and deaths during induction remains a significant problem in AML independently of the mutation. In fact, age, white blood cell count and primary or secondary leukemia add to the prognostic difficulties.⁷

Moreover, the impact of FLT3-ITD on prognosis may depend on the presence of biallelic mutations. Studies have shown a significantly worse prognosis in patients with higher mutant to wild-type allelic ratios (>0.4).⁸

As FLT3-ITD is a common mutation, tyrosine kinase inhibitors have been recognized as potential therapeutic agents, and many drugs are in clinical development including sorafenib, sunitinib, midostaurin, quizartinib, lestaurtinib, crenolanib and gilteritinib, in the hope of reducing this therapeutic failure.⁹ Nevertheless, taking into account the multiple hits that are thought necessary in leukemogenesis, FLT3 plays a small role. It activates proliferation pathways (class I mutations, such as of the K/N RAS, TP53 and c-KIT genes), while other mutations impair differentiation (class II: NPM1 and CEBPa genes), epigenetic regulation (class III: DNMT3A, TET2 and IDH1/2 genes), the p53 pathway, with even more also playing a role.¹⁰ In this scenario, the FLT3 mutation is not the only villain.

In conclusion, further studies are needed to confirm whether the size of the FLT3-ITD mutation is correlated to a worse prognosis.^7,8,11

References

• ¹
  Instituto Nacional de Câncer (INCA), Tipos de Cancer. Leucemia. Available from: http://www2.inca.gov.br/wps/wcm/connect/tiposdecancer/site/home/leucemia/definicao [cited 30.4.16].
  » http://www2.inca.gov.br/wps/wcm/connect/tiposdecancer/site/home/leucemia/definicao
• ²
  Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391-405.
• ³
  Lucena-Araujo AR, Souza DL, Morato de Oliveira F, Benicio MT, Figueiredo-Pontes LL, Santana-Lemos BA, et al. Results of FLT3 mutation screening and correlations with immunophenotyping in 169 Brazilian patients with acute myeloid leukemia. Ann Hematol. 2010;89(2):225-8.
• ⁴
  Yaghmaie M, Alimoghaddam K, Mozdarani H, Ghavamzadeh A, Hajhashemi M, Aznab M, et al. Cytogenetic and FMS-like tyrosine kinase 3 mutation analyses in acute promyelocytic leukemia patients. Iran Biomed J. 2012;16(1):10-7.
• ⁵
  Estey EH. Acute myeloid leukemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol. 2012;87(1):89-99.
• ⁶
  Koszarska M, Meggyesi N, Bors A, Batai A, Csacsovszki O, Lehoczky E, et al. Medium-sized FLT3 internal tandem duplications confer worse prognosis than short and long duplications in a non-elderly acute myeloid leukemia cohort. Leuk Lymphoma. 2014;55(7):1510-7.
• ⁷
  Kusec R, Jaksic O, Ostojic S, Kardum-Slelin I, Vrhovac R, Jakisic B. More on prognostic significance of FLT3/ITD size in acute myeloid leukemia (AML). Blood. 2006;108(1):405-6.
• ⁸
  Gale RE, Green C, Allen C, Mead AJ, Burnett AK, Hills RK, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood. 2008;111(5):2776-84.
• ⁹
  Stein EM, Tallman MS. Emerging therapeutic drugs for AML. Blood. 2016;127(1):71-8.
• ¹⁰
  Dombret H. Gene mutation and AML pathogenesis. Blood. 2011;118(20):5366-7.
• ¹¹
  Ponziani V, Gianfaldoni G, Mannelli F, Leoni F, Ciolli S, Guglielmelli P, et al. The size of duplication does not add to the prognostic significance of FLT3 internal tandem duplication in acute myeloid leucemia patients. Leukemia. 2006;20(11):2074-6.

Publication Dates

• Publication in this collection
  Jul-Sep 2017

History

• Received
  23 Nov 2016
• Accepted
  7 Mar 2017