A New Stratification System for Adult AML That Includes FLT3-ITD as a Prognostic Factor-A JALSG Study.
Authors: Miyazaki Yasushi , Kiyoi Hitoshi , Kuriyama Kazutaka , Honda Sumihisa , Nishida Kazuhiro , Taniwaki Masafumi , Sakamaki Hisashi , Miyawaki Shuichi , Ohtake Shigeki , Naoe Tomoki , Ohno Ryuzo , Tomonaga Masao 
Published: October 2019

Abstract
Prognostic factors for patients with AML are commonly used to classify patients into different prognostic groups. Karyotype of AML cells is currently most powerful to predict prognosis as a single factor. However, almost half cases are usually categorized into the intermediate risk group, which necessitates further stratification of cases in this group. Internal tandem duplication of FLT3 gene (FLT3-ITD) is one of the most frequent genetic changes found in AML cells that relates to poor response to chemotherapy: FLT3-ITD is expected to be used for the stratification of AML cases. To test the value of FLT3-ITD as prognostic factor, using cases in Japan Adult Leukemia Study Group (JALSG) AML97 trial, we examined the significance of FLT3-ITD to predict the prognosis of patients with AML along with other factors such as karyotype. FLT3-ITD was tested in 263 cases in the AML97 trial, and karyotype of AML cells and the morphological diagnoses were centrally reviewed by committee members of JALSG without any other clinical data. Karyotype of AML cells (modified MRC method) created three distinct risk groups (5-year OS: favorable group, 69.0% [n=57]; intermediate risk group, 42.0% [n=184]; adverse risk group, 0% [n=18], p<0.0001), and the percentage of myeloperoxidase (MPO) positive blasts could also stratify cases into two groups (5-year OS: cases with MPO positive blasts >50% [high MPO group, MPO-H], 51.9% [n=229]; low MPO group [MPO-L], 32.9% [n=92], p=0.0058). These data recapitulated our previous observations in the JALSG-AML92 trial. FLT3-ITD divided cases into two groups showing significantly different prognoses; the 5-year overall survival (0S) was 23.0% (n=52) and 49.5% (n=211) in the FLT3-ITD positive and negative group, respectively (p<0.0001). By multivariate analysis, FLT3-ITD, karyotype of AML cells and performance status at diagnosis were selected as significant factors for OS but not the percentage of MPO positive blasts, age or initial WBC. Interestingly, however, there were significant inter-relationships among any two of four factors in the analysis; FLT3-ITD, the percentage of MPO positive blasts, karyotype and initial WBC. Based on these data, cases having normal karyotype (n=99) were further divided into four groups using FLT3-ITD and MPO group. ITD (−)&MPO-H group (n=47) showed 66.6% of 4-year OS that was comparable to that of the cases with favorable karyotype. The 4-year OS of ITD (−)&MPO-L group (n=27) was 42.5% whereas that of ITD (+) cases had worse prognoses (14.4% in MPO-L [n=15] and 10.0% in MPO-H group [n=10]). There was a statistically significant difference in 4-year OS of four groups (p<0.0001). These results suggested that the combination of FLT3-ITD and MPO group was useful to further stratify cases with normal karyptype dividing potential candidates for the inhibitors of FLT3-ITD from cases that chemotherapy would provide favorable outcome.