Analysis of Genetic Mutation of the Elderly Patients with Acute Myeloid Leukemia
Authors: Fujiwara Yusuke , Yamaguchi Hiroki , Marumo Atsushi , Omori Ikuko , Yamanaka Satoshi , Terada Kazuki , Yui Shunsuke , Fukunaga Keiko , Ryotokuji Takeshi , Hirakawa Tsuneaki , Okabe Masahiro , Wakita Satoshi , Osaki Yoshiki , Arai Kunihito , Kitano Tomoaki , Kosaka Fumiko , Tamai Hayato , Okamoto Muneo , Nakayama Kazutaka , Inokuchi Koiti 
Published: October 2019

Abstract
Backgrounds: Acute myeloid leukemia (AML) is a heterogeneous disease whose onset involves a variety of chromosomal abnormalities and genetic mutations. To improve the outcome of AML treatment, it is very important to establish a prognosis from cytogenetic and genetic analysis and provide accordingly differentiated treatment. However, the treatment strategy has not been clear in elderly patients with AML due to intolerance of treatment and its adverse characteristics such as concomitant comorbidity and poor performance status. To clarify the prognostic impact of genetic abnormalities in elderly AML, we conducted a comprehensive analysis of recurrently mutated 28 genes in AML.
Method: We retrospectively analyzed newly diagnosed 128 AML patients excluding M3 who were more than 65 years old at Nippon Medical School Hospital or its associated facilities between 1990 and 2014. Mutation analyses were performed by direct sequence analysis, Mutation Biased PCR, direct sequence analysis, and the next-generation sequencer Ion PGMTM.
Results: Average age was 70.5 years (65-91years). The patients from 65 years old to 74 years old (early elderly) were 92 (71.9%)cases, the patients 75 years or older (late elderly) were 36 (28.1%)cases. Chromosomal analysis according to the prognostic risk classification of the Eastern Cooperative Oncology Group (ECOG) classified into 14 of the favorable cytogenetic risk group (10.9%), 80 of the intermediate cytogenetic risk group (62.5%), and 24 of the poor cytogenetic risk group (18.8%). Gene mutations were observed in 112 cases (87.5%). The most frequent gene mutations were NPM1 (89 cases/28.9%), FLT3/ITD (25 cases/19.5%), TET2 (20 cases/15.6%), and DNMT3A (19 cases/14.8%). CEBPA double mutation was detected at low frequency in elderly patients (younger patients: 15/311 (4.8%) vs elderly patients: 1/128 (0.8%)). There were no significant differences in gene mutations between early elderly and late elderly patients). Of 102 patients who received induction therapy, 52 patients (51.0%) achieved first hematological complete remission (CR), but primary refractory and early death were observed in 50 patients (49.0%). There was no significant difference in CR rate between the two groups in the early elderly patients and late elderly patients (early elderly: 53.8% vs late elderly: 41.7%. p= 0.354). In addition, there was no difference in CR rate in the standard chemotherapy and low dose chemotherapy group (standard chemotherapy: 48.7% vs low dose chemotherapy: 38.9%. p= 0.601). Median overall survival (OS) was 287days, OS at 3years was 35.9%. Prognostic stratification was possible for CR rate on the chromosomal classification (favorable cytogenetic risk 92.9%, intermediate cytogenetic risk 50.0%, poor cytogenetic risk 12.5%, p< 0.001). For total cohort of patients, rates of relapse free survival (RFS) at 3 years are significantly lower in patients with FLT3ITD (p=0.006) and TP53 abnormality (p< 0.001) compared to without it. Rates of overall survival (OS) at 3 years are significantly lower in patients with DNMT3A mutation (p=0.004), FLT3ITD (p=0.003), and TP53 abnormality compared to without it. Also late elderly patients (p=0.010) and high white blood cell count (≥ 20,000/μl) (p=0.023) were powerful factors for unfavorable prognosis. In stratified analysis of FLT3ITD-negative cases aged below 75 years with intermediate cytogenetic prognosis, TP53 abnormality was associated with unfavorable prognosis (RFS: p=0.062, OS: p< 0.001). Finally multivariate analysis demonstrated that FLT3ITD (p=0.014) and TP53 abnormality (p=0.015) were an independent poor prognostic factor for RFS, and poor cytogenetic risk (p=0.002), Flt3ITD (p=0.014), TP53 abnormality (p=0.015), and DNMT3A mutation (p=0.001) were an independent poor prognostic factor for OS.
Conclusions: Our results suggest that the genetic abnormalities have a prognostic importance in elderly patients, as well as younger patients with AML. FLT3ITD mutation is an important factor for unfavorable prognosis, but going forward TP53 mutation may also serve as a clinically important gene mutation marker in elderly patients with AML.

Disclosures
No relevant conflicts of interest to declare.