Impact of FLT3 Mutational Status as Prognostic Factor in Acute Myeloid Leukemia Patients from Argentina and Uruguay.
Authors: Giere Isabel , Chacon Angel , Uriarte Rosario , Lombardi Virginia , Fernandez Isolda , Reinoso Fernanda Garcia , Bonomi Rosana , Zubillaga Maria , Giordano Hugo , Pardo Laura , Sapia Sandra , Monreal Mariela , Martinez Lem , Pavlovsky Santiago 
Published: October 2019

Abstract
Background. There are known prognostic factors in Acute myeloid leukemia (AML) patients, being the cytogenetic analysis the strongest as single predictor of disease relapse or poor therapy response. Recently, alterations in FLT3 gene (Internal tandem duplications-ITD and D835/836 mutations) are frequently detected by PCR in 30–35% of AML patients (pts) and would be associated with aggressive disease. This study reports the molecular characterization of 82 AML pts from Argentina and Uruguay, mostly of Spanish-Italian origin, studied between 1996 to 2005.
Design and Methods. This study was based on 82 pts: 71 adults, median age 36 yrs, (range 25–80) and 11 children (median age: 11 yrs, range. 3–17 yrs). Cytogenetic risk was established in 77 pts by kariotyping, PCR and FISH: 49% (n=38) with low risk, 38% (n=29) with standard risk, and 13% (n=10)with high risk. The FAB distribution (n=75) was: M0=2,7% (n=2), M1= 6,7% (n=5); M2=17,3% (n=13); M3=46,7% (n=35); M4=16% (n=12); M5=6,7% (n=5); M6=4% (n=3). Clinical endpoints and follow up were available for 45 pts and 56 pts, respectively. A total of 42 pts achieved complete remission (CR), 12 pts had relapse of disease, 10 pts underwent early death without completing induction (ED pts), and 7 pts died after treatment. Prognostic factors considered were: Age > 55 years, WBC average, WBC > 100 x 106/L, % Blasts in bone marrow, Secondary etiology (therapy related/MDS). JM and TKD domain coding sequences were amplified by PCR for characterization of ITD and D835/836 mutations, respectively.
Results and Interpretation. FLT3 mutations could be demonstrated in 23% (19/82 pts): ITD =16% (13/82), D835/836 =7% (6/82). The median follow-up time was 36 months (range 1 – 96 m). A total of 48% (n=27) of pts. were still alive without relapse at the end of this study. Higher incidence of Flt3 mutations [ITD+ and D835/836+] were found in: 41,7% (n=5) of pts with no achievement of CR (n=12) Vs 7,1% (n=3) pts with CR (n=42) (p=0.01), and in 38% (n=5) of the death patients group (n=13) Vs. 7,4% (n=2) pts still alive without relapse (n=27) (p=0,027).The WBC average was significantly higher in the ITD+ group (69,38x106/L) Vs ITD(−) group (9,27x106/L) (p=0.001). ITD mutation was more frequent in pts with WBC >100x106/L (83,3%) Vs WBC <100x106/L (16,7%) (p=0.004). Higher incidence of FLT3 mutations [ITD+ and D835/836+] was found in ED pts (57,1%) Vs non ED pts (42,9%) (p=0.018). Early death was significantly more frequent in pts with secondary etiology of leukemia (57%) Vs those de novo AML (10,5%) (p=0.013). No association was found between FLT3 mutations and the other clinical variables. D835–836 mutation by its own was not associated with any variable.
Conclusions: The prevalence of FLT3 mutations in our study was lower, as previously reported data. FLT3 ITD (+) samples were associated with higher WBC count and WBC >100.106/L. Both type of FLT3 mutations (ITD and D835/836) were associated with early death in the cohort. This colaborative study showed that FLT3 mutational status had to be considered as important tool in prognosis of AML pts, however further follow up with larger number of pts is required to fully address its association with poor clinical outcome.