Patients with acute myeloid leukemia and RAS mutations benefit most from postremission high-dose cytarabine: a Cancer and Leukemia Group B study

Abstract

Purpose: RAS mutations occur in 12% to 27% of patients with acute myeloid leukemia (AML) and enhance sensitivity to cytarabine in vitro. We examined whether RAS mutations impact response to cytarabine in vivo.

Patients and methods: One hundred eighty-five patients with AML achieving complete remission on Cancer and Leukemia Group B study 8525 and randomly assigned to one of three doses of cytarabine postremission were screened for RAS mutations. We assessed the impact of cytarabine dose on cumulative incidence of relapse (CIR) of patients with (mutRAS) and without (wild-type; wtRAS) RAS mutations.

Results: Thirty-four patients (18%) had RAS mutations. With 12.9 years median follow-up, the 10-year CIR was similar for mutRAS and wtRAS patients (65% v 73%; P = .31). However, mutRAS patients receiving high-dose cytarabine consolidation (HDAC; 3 g/m(2) every 12 hours on days 1, 3, and 5 or 400 mg/m(2)/d x 5 days) had the lowest 10-year CIR, 45%, compared with 68% for wtRAS patients receiving HDAC and 80% and 100%, respectively, for wtRAS and mutRAS patients receiving low-dose cytarabine (LDAC; 100 mg/m(2)/d x 5 days; overall comparison, P < .001). Multivariable analysis revealed an interaction of cytarabine dose and RAS status (P = .06). After adjusting for this interaction and cytogenetics (core binding factor [CBF] AML v non-CBF AML), wtRAS patients receiving HDAC had lower relapse risk than wtRAS patients receiving LDAC (hazard ratio [HR] = 0.67; P = .04); however, mutRAS patients receiving HDAC had greater reduction in relapse risk (HR = 0.28; P = .002) compared with mutRAS patients treated with LDAC.

Conclusion: AML patients carrying mutRAS benefit from higher cytarabine doses more than wtRAS patients. This seems to be the first example of an activating oncogene mutation favorably modifying response to higher drug doses in AML.

Fig A1.

Cumulative incidence of relapse of 185 patients with acute myeloid leukemia according to RAS mutation status (mutRAS, mutated RAS; wtRAS, wild-type RAS).

Fig 1.

Outcome of 185 patients with acute myeloid leukemia (AML) according to RAS mutation status (mutRAS, mutated RAS; wtRAS, wild-type RAS) and random assignment to consolidation treatment with high-dose cytarabine (HDAC) or low-dose cytarabine (LDAC). (A) Cumulative incidence of relapse of all patients included in this study. (B) Survival of all patients included in this study. (C) Cumulative incidence of relapse of patients with non–core binding factor AML (ie, those who did not harbor t(8;21)/RUNX1-RUNX1T1 or inv(16)/t(16;16)/CBFB-MYH11).

Fig 2.

Forest plots summarizing the multivariable models for cumulative incidence of relapse of (A) all 185 patients with acute myeloid leukemia (AML) and (B) 150 patients with non–core binding factor AML. The hazard ratios (HRs) with 95% CIs for each variable in the model are shown. HRs less than 1 indicate lower risk for relapse for the first category listed. mutRAS, mutated RAS; wtRAS, wild-type RAS; HDAC, high-dose cytarabine; LDAC, low-dose cytarabine.

Fig 3.

Predicted cumulative incidence of relapse of patients with acute myeloid leukemia receiving high-dose cytarabine (HDAC) and low-dose cytarabine (LDAC) postremission therapy according to RAS mutation status (mutated or wild-type) adjusting for core binding factor status. (A) Patients with RAS mutation. Model was based on 22 patients on the HDAC arm and 12 patients on the LDAC arm. (B) Patients with wild-type RAS. Model was based on 95 patients on the HDAC arm and 56 patients on the LDAC arm.