Survival outcomes and therapy response in <i>RAS</i> -mutated myeloid malignancies.

Abstract

e18515 Background: RAS proteins are GTP-binding proteins that act as molecular switches to regulate cell signal transduction. Mutations in these proteins are some of the most common oncogenes, affecting nearly 19% of cancers. They are known to confer more aggressive phenotypes and have impacted the choice of chemotherapy in solid tumors. However, RAS mutation status is not incorporated into myeloid malignancy prognostication systems, such as the 2022 European LeukemiaNet. Therefore, we sought to better characterize its impact on overall survival and chemotherapy response. Methods: We conducted a single-center, retrospective analysis, which included 118 patients with myeloid malignancy and RAS mutations identified from bone marrow between 2014 to 2024. An additional 118 patients with myeloid malignancy and wild-type (WT) RAS were included as a control. The primary endpoint was overall survival at the defined time point, while the secondary endpoint was remission achievement. Results: The RAS -mutant group was 61% male and 81% Non-Hispanic White, with median age of 66 years (range 2 – 90). The majority (78%) had acute myeloid leukemia (AML). The RAS -WT group was 59% male and 92% Non-Hispanic White, with median age of 63 years (range 6 months – 92). Most patients (89%) had AML. The median survival in RAS -mutants was significantly shorter at 21 months compared to 76 months for RAS -WT (log-rank test, p = 0.0039). Among patients treated with cytarabine-based induction chemotherapy, RAS -mutants had significantly shorter median survival of 29 months compared to 136 months for RAS -WT (log-rank test, p &lt; 0.0001). Among those receiving a stem cell transplant, RAS -mutants had significantly shorter median survival of 39 months versus 235 months for RAS -WT (log-rank test, p &lt; 0.0001). Within the RAS -mutant group, patients treated with cytarabine-based induction chemotherapy had significantly longer median survival of 30 months versus 16 months for the group treated with hypomethylating agents (HMA) (log-rank test, p = 0.04). Patients with RAS mutations were then divided into three groups: NRAS (65 patients), KRAS (33 patients), and double-mutants (20 patients). Their median age, gender, and races were comparable. There was no significant difference in overall survival between the three groups, whether measured from time of diagnosis or time of RAS mutation appearance (log-rank test, p = 0.41). Conclusions: In patients with myeloid malignancy, RAS mutations are associated with shorter median overall survival compared to RAS -WT. This difference remains significant in those treated with cytarabine-based induction chemotherapy. Our data suggests that RAS mutations confer poor prognosis despite intensive initial therapy. Additionally, cytarabine-based induction chemotherapy appears superior to HMA in this population. Finally, there was no difference in survival between patients with single-hit or double-hit RAS mutations.