Background:

Activating mutations of NRAS and KRAS genes are common in newly diagnosed acute myeloid leukemia (AML), occurring in 11-16% and 4-5% of patients, respectively. RAS mutations are frequently acquired at time of progression from MDS to AML and are associated with poor survival. Next generation sequencing (NGS) at diagnosis and during complete remission has shown that RAS mutations have high clearance rates with induction chemotherapy. In the CALGB 8525 study, RAS-mutant younger patients (age <60 years) randomized to treatment with high-dose cytarabine consolidation had a lower 10-year cumulative incidence of relapse when compared to RAS WT patients. We performed a single center retrospective study to determine the outcomes of NRAS and KRAS mutated AML in patients receiving induction chemotherapy.

Methods:

We retrospectively reviewed the charts of patients with newly diagnosed AML treated at Memorial Sloan Kettering Cancer Center between January 1, 2014 to May 15, 2019. Patients with pathologic confirmation of AML and treatment with induction chemotherapy were included. Age < 18 years old, treatment with a pediatric induction regimen, a diagnosis of biphenotypic AML, unknown RAS mutation status at diagnosis, or treatment an outside institution were criteria for exclusion. All patients underwent NGS from a diagnostic bone marrow aspirate (BMA) with MiSeq or MSK-IMPACT platforms. Mutations present with a variant allele frequency (VAF) ≥ 1% were retained. Response was evaluated per ELN 2017 criteria. Immunophenotypic MRD was identified in BMA by multiparameter flow cytometry. Any level of residual disease was considered MRD+. Baseline characteristics were evaluated by Fisher's exact test and Wilcoxon rank sum tests. Kaplan-Meier estimates were used to summarize OS and EFS. Multivariable cox regression, including time-dependent variables was performed on univariate factors with p<0.05.

Results:

202 patients, including 162 WT and 40 RAS mutant met inclusion criteria for further analysis. Mutations in NRAS and KRAS occurred in 14%, and 8% of patients, respectively with 6 patients having co-occurring NRAS and KRAS mutations. At baseline, the RAS mutant AML cohort had a significantly greater proportion of patients with AML-MRC and a trend toward fewer patients receiving allogeneic stem cell transplant. (Table 1.) Cytogenetic abnormalities were similar among RAS and WT patients. Sequencing at diagnosis revealed an increased frequency of FLT3 TKD, RUNX1, TET2, WT1, and ETV6 mutations and a decreased frequency of FLT3-ITD and TP53 mutations in the RAS mutant cohort. Response rates and MRD negative remission rates to induction chemotherapy were similar between RAS and WT AML patients (Table 2). With a median follow up of 25 months among survivors, RAS mutant AML was associated with a significant decrease in median EFS (4.9 vs. 11.4 months, p< 0.01) and a near significant decrease in median OS (12 vs. 30.1 months, p=0.057) (Figure 1 and 2). After controlling for variables with p<0.05 on univariate analysis including age, prior myeloid malignancy, AML classification, ELN risk, transplantation, and re-induction, RAS mutation was independently associated with an increased risk of death (HR 1.85, p=0.016) and decreased EFS (HR 2.19, p< 0.01) on multivariate analyses (Tables 3 and 4). Among 77 patients with paired sequencing at diagnosis and at time of CR or CRi, all RAS mutations (n=17) were cleared (Figure 3). Additionally, other RAS pathway mutations had high clearance rates including PTPN11 (n=8, 100%), NF1 (n=3, 100%, and CBL …