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

Abstract EN

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 there is still controversy about its clinical relevance on the treatment outcome of this leukemia.

Objective : 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 post induction consolidation chemotherapy in adult AML patients.

Patients and Methods : the study comprised 71de novo AML patients with a male: Female ratio of 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 and K-RAS mutation detection using real-time PCR.

The patients were randomized into 2 groups (gps) according to the ara-C dose used in consolidation treatment, HDAC gp receiving 400 mg ara-C and LDAC gp receiving 100 mg ara-C.

They were followed over a period of 5 years.

Results : Mutations in the K-RAS gene (mutRAS) were detected in 23 patients (32 %) with the remaining 48 patients (68 %) having wild type RAS (wtRAS).

Blast cell percentage was significantly lower in mutRAS compared to wtRAS patients (p ≤ 0.001).

The M4 subtype of AML and cases with Inv 16 showed significantly higher frequencies in mutRAS compared to wtRAS patients, (p = 0.015, 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 patients (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).

Conclusion : Adult AML patients carrying mutations in the K-RAS gene benefit from higher cytarabine 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.