Molecular Characterization of Normal Karyotype Acute Myeloid Leukemia: Role of the NPM1 Mutations May Be Different in Different Races.

Recent advances in molecular characterization of acute myeloid leukemia (AML) have led to molecular classification of normal karyotype (NK) AML. Mutations of the NPM1 gene showed a good response to induction therapy and had a favorable prognosis, especially in the absence of a FLT3-ITD mutation, in the studies of NK AML. However, most studies regarding the NPM1 gene mutations have come from the Western countries. Thus we investigated role of the NPM1 mutations in Korean patients with NK AML.

Inclusion criteria of this retrospective study was the followings: a new patient (1) with NK AML, (2) receiving standard induction chemotherapy ('7+3' regimen), and (3) with DNA from leukemic blasts at diagnosis being available. Polymorphisms of 4 genes (GSTT1, GSTM1, GSTA1, MDR1 [C3435T]) and mutations of 2 genes (FLT3, NPM1) were analyzed using PCR (GSTT1, GSTM1, FLT3-ITD), RFLP (GSTA1, MDR1 [C3435T]), and direct sequencing (NPM1). Clinico-laboratory data were retrieved from the Asan Medical Center Leukemia Registry.

This study included a total of 102 patients who were newly diagnosed as NK AML in the Asan Medical Center, Seoul, Korea between May 1999 and December 2006. Median age of the patients, 63 males and 39 females, was 44 years (range, 15-80). Null genotype of GSTM1 and GSTT1 was observed in 41.2% and 52.0% of the patients, respectively. Genotype of GSTA1 was CC in 75.3% and CT in 24.7%, and C3435T polymorphism of MDR1 gene was CC in 52.2%, CT in 39.1% and TT in 8.7%. FLT3-ITD was detected in 22.8% and NPM1 was mutated in 36.5%. Baseline clinico-laboratory data were not significantly different according to the genotype or mutational status of the genes except significantly higher leukocyte counts at diagnosis in patients with FLT3-ITD compared to those without the mutation (mean, 77000/mcL vs. 33000/mcL, P=0.019). For total patients, the rate of complete remission (CR) was 78.9%, and survival probabilities at 5-year were 39.9% for overall survival (OS), 57.9% for relapse-free survival (RFS), and 42.5% for event-free survival (EFS). Table 1 shows the clinical outcomes according to the polymorphism or mutation of the genes analyzed in this study. Multivariate analyses demonstrated independently significant prognostic factors for clinical outcomes of NK AML as followings: (1) for the induction of CR, no independently significant factor, (2) for OS, age (year, < 60 vs. 60 or more, 45.4% vs. 15.4%, RR 2.710, P=0.003) and FLT3-ITD (absent vs. present, 43.1% vs. 30.4%, RR 1.947, P=0.025), (3) for RFS, age (year, < 60 vs. 60 or more, 64.7% vs. 11.4%, RR 6.333, P<0.001), FLT3-ITD (absent vs. present, 43.1% vs. 30.4%, RR 3.658, P=0.002), and uric acid level (mg/dL, < 7.0 vs. 7.0 or more, 61.2% vs. 34.3%, RR 2.833, P=0.027), and (4) for EFS, age (year, < 60 vs. 60 or more, 47.8% vs. 9.1%, RR 3.422, P=0.003), FLT3-ITD (absent vs. present, 46.0% vs. 31.6%, RR 2.655, P=0.005), and C3435T of MDR1 (CC vs. CT/TT, 29.1% vs. 56.3%, RR 0.449, P=0.013).

Mutations of the NPM1 gene did not show significant impact on clinical outcomes in Korean patients with NK AML, whereas presence of a FLT3-ITD mutation was significantly associated with inferior survivals. Clinical significance of genetic alterations in NK AML might be different in different races and the racial differences should be considered before molecular classification is established in NK AML.

Lee:Janssen Korea: Consultancy, Honoraria.