FLT3-ITD Mutation in MDS Patients Is Associated with Early Transformation to AML

Aim: One-third of acute myeloid leukemia (AML) patients show FLT3 (FMS-like tyrosine kinase 3) internal tandem duplication-mutants in juxtamembrane domain (FLT3-ITD) which indicates poor outcome. FLT3-ITD is also associated with poor outcome in favorable karyotype AML including t(8;21) and t(15;17). The incidence of FLT3-ITD in myelodysplastic syndrome (MDS) reportedly occurs at a lower frequency than AML, and FLT3-ITD in MDS is not correlated to poor outcome. Revised International Prognostic Scoring System (IPSS-R) shows that 25% of high risk and very high risk MDS groups transform to AML within 1.3 years and 0.7 years, respectively, and factors of IPSS-R include chromosomal aberrations but not gene mutations. We retrospectively analyzed our MDS patient cases to investigate if the FLT3-ITD mutation at their disease onset is associated with the duration to AML transformation.

Method: Bone marrow samples were obtained from newly diagnosed MDS patients, who admitted to our hospital between January, 2010 and May, 2017. DNA and RNA were extracted from mononuclear cell fractions, and were analyzed with genomic PCR and RT-PCR using FLT3-specific primers. MDS and AML were defined and classified by WHO 2016 revised criteria. AML patients with dysplasia and/or multiple chromosomal mutations at the disease onset were not included.

Result: 69 cases were analyzed, in which 16 showed FLT3-ITD mutation. Ten (1 MDS-MLD, 3 MDS-EB-1, 6 MDS-EB-2) transformed within a median of 6 months (range, 3-18) and 8 patients deceased at the analysis in FLT3-ITD mutated patients. In IPSSR classification low risk was one, intermediate 2, high 4, and very high 3. In 53 cases of wild-type FLT3, 11 patients transformed to AML within a median of 28 months (range, 4-70).

Discussion: It is reported that the median overall survival (OS) in FLT3 -mutated MDS patients (19.0 months) is not significantly different from FLT3 -nonmutated MDS patients (16.4 months) and FLT3 mutation does not predict poor outcome; however, another report indicates that AML transformed from FLT3-ITD + MDS shows very poor outcome with OS of one month. In our experienced cases FLT3-ITD mutation in MDS showed shorter duration to AML transformation and very poor prognosis. It should be noted that MDS-MLD and -EB-1 patients with low and intermediate risk in IPSS-R were included in FLT3-ITD mutation group, and showed poor prognosis. Further analysis is necessary to investigate if FLT3-ITD mutation plays a significant role in risk classification in MDS patients.