Title:
The prognostic impact of K-RAS mutations in adult acute myeloid leukemia patients treated with high-dose cytarabine.

Abstract:
Activating point mutation of the RAS gene has been generally accepted as an oncogenic event in a variety of malignancies. It represents one of the most common genetic alterations in acute myeloid leukemia (AML). However, little is known about its clinical relevance in the treatment outcome for this leukemia.
This study aimed to clarify the biologic and prognostic impact of K-RAS mutations in relation to the dose of cytarabine (ara-C) used in postinduction consolidation chemotherapy in adult AML patients.
The study comprised of 71 de novo AML patients with male/ female ratio 1.4:1; their ages ranged from 21-59 years with a median of 37 years. They were subjected to full clinical evaluation, routine laboratory investigations, cytogenetic studies by G-banding (Giemsa staining), and K-RAS mutation detection using real-time polymerase chain reaction. The patients were randomized into two groups according to the ara-C dose used in consolidation treatment, the high the dose ara-C (HDAC) group receiving 400 mg ara-C and-low-dose ara-C (LDAC) group receiving 100 mg ara-C; they were followed over a period of five years.
Mutations in the K-RAS gene (mutRAS) were detected in 23 patients (32%) with the remaining 48 patients (68%) having wild-type RAS (wtRAS). The percent of blast cells was significantly lower in mutRAS compared to wtRAS patients (P ≤ 0.001) while M4 subtype of AML and Inv(16) frequencies were significantly higher in mutRAS compared to wtRAS patients (P = 0.015) and (P = 0.003), respectively. The patients were followed up for a median of 43 months (range 11-57 months). There was no significant difference in overall survival (OS) between mutRAS and wtRAS (P = 0.326). Within the mutRAS patients treated with HDAC, cumulative OS was significantly higher than those treated with LDAC (P = 0.001). This was not the case in the wtRAS group (P = 0.285). There was no significant difference in disease-free survival (DFS) between mutRAS and wtRAS groups (P = 0.923). mutRAS patients treated with HDAC had a statistically higher cumulative DFS than mutRAS patients treated with LDAC (P = 0.001). Patients with wtRAS also benefited from HDAC, but to a lesser extent. Among patients with wtRAS, those treated with HDAC showed higher cumulative and median DFS than patients treated with LDAC (P = 0.031).
It was concluded that adult AML patients carrying mutations in the K-RAS gene benefit from higher ara-C doses more than wtRAS patients, so pretreatment mutation detection could be an important predictor for treatment strategy and survival of adult AML patients. These findings counter the prevailing bias that oncogene mutations lead to more aggressive behavior in human malignancies.