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Implications of RAS mutational status in subsets of patients with newly diagnosed acute myeloid leukemia across
Daniel Rivera1, Kunhwa Kim1, Rashmi Kanagal-Shamanna2
1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Abstract:
Activating mutations in RAS have been reported in about 10-15% of patients with AML; previous studies have not identified a prognostic significance. However, RAS mutations have emerged as a potential resistance mechanism to treatment with inhibitors of FLT3, IDH, and BCL2. We aimed to determine the characteristics and outcomes of patients with RAS-mutated (RAS-mut) AML across therapy subsets of 1410 patients newly diagnosed (ND AML). RAS-mut was observed in 273 (20%) patients. Overall, patients with RAS-mut AML had an estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p = .01. Among patients with RAS-mut, favorable karyotype and concomitant NPM1 mutations were associated with a higher CR/CRi rate, OR 23.2 (95% CI: 2.7-192.7; p < .001) and OR 2.8 (95% CI: 1.1-6.9; p = .02), respectively, while secondary and treated secondary (ts)-AML were associated with low response rates, OR 0.34 (95% CI: 0.1-0.9; p = .04) and OR 0.22 (95% CI: 0.09-0.5; p = .001), respectively. Intensive chemotherapy was associated with high response rates OR 5.9 (95% CI: 2.9-12.2; p < .001). Better median OS was observed among those with favorable karyotype, HR 0.28 (95% CI: 0.1-0.6; p = .002), and those treated with intensive chemotherapy, HR 0.42 (95% CI: 0.2-0.6 p < .001). Conversely, ts- AML and co-occurrence of mutations in TP53 were associated with poor median OS; HR 2.3 (95% CI: 1.4-3.9; p = .001) and HR 1.7 (95% CI: 0.9-3.1; p = .06), respectively. The addition of venetoclax was associated with a non-significant improvement in CR/CRi and OS.
Insights
RAS mutations in acute myeloid leukemia (AML) are linked to better survival rates, especially with intensive chemotherapy. Favorable karyotype also improves outcomes in RAS-mutated AML patients.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Activating RAS mutations occur in 10-15% of acute myeloid leukemia (AML) patients, with prior studies lacking consensus on their prognostic significance.
- RAS mutations are implicated as a potential mechanism of resistance to targeted therapies like FLT3, IDH, and BCL2 inhibitors.
Purpose of the Study:
- To investigate the characteristics and clinical outcomes of patients with RAS-mutated (RAS-mut) AML.
- To analyze the impact of RAS mutations across different therapeutic subsets in newly diagnosed AML (ND AML).
Main Methods:
- Retrospective analysis of 1410 newly diagnosed AML patients.
- Evaluation of RAS mutation status in relation to cytogenetic and molecular features, treatment response, and overall survival (OS).
Main Results:
- RAS mutations were identified in 20% (273/1410) of ND AML patients.
- Patients with RAS-mut AML demonstrated a significantly higher 3-year survival rate (38%) compared to RAS wild-type (RAS-wt) AML (28%, p=0.01).
- Favorable karyotype and concomitant NPM1 mutations were associated with improved CR/CRi rates in RAS-mut AML, while secondary and treated secondary AML (ts-AML) showed lower response rates. Intensive chemotherapy correlated with high response rates and better median OS. Conversely, ts-AML and TP53 co-mutations were linked to poorer median OS.
Conclusions:
- RAS mutations in AML are associated with a better prognosis than previously thought, particularly when treated with intensive chemotherapy.
- Specific genetic factors like favorable karyotype and NPM1 mutations further enhance outcomes in RAS-mut AML, whereas secondary AML and TP53 co-mutations portend a worse prognosis.
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