Clinico-genomic characterization of RAS-mutant acute myeloid leukemia.

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• Somatic mutations in NRAS or KRAS are common in acute myeloid leukemia (AML).
• RAS mutations are late-occurring events in AML ontogeny with unclear prognostic significance.
• The prognostic impact of RAS mutations, particularly codon-level characteristics and response to chemotherapy, remains poorly understood in AML.

Purpose of the Study:

• To investigate the clinico-genomic profiling of RAS-mutant AML.
• To determine the prognostic significance of RAS mutations in AML, especially concerning chemotherapy response.
• To explore potential therapeutic strategies targeting the RAS pathway in AML.

Main Methods:

• Clinico-genomic profiling of 89 patients with RAS-mutant AML and 99 patients with RAS-wild-type AML.
• Analysis of overall survival (OS) based on RAS mutation status and treatment modalities.
• Evaluation of RAS mutation subgroups, hotspot codons, and variant allele frequencies.

Main Results:

• RAS-mutant AML showed significantly shorter median overall survival (OS) compared to RAS-wild-type AML (19.2 vs. 63.3 months).
• Patients with RAS mutations receiving cytarabine-based chemotherapy had shorter OS than RAS-wild-type AML (27.1 vs. 122.2 months).
• Within RAS-mutant AML, cytarabine-based therapy and hematopoietic cell transplantation (HCT) improved OS compared to hypomethylating agents or no HCT, respectively.

Conclusions:

• RAS mutations portend a poorer prognosis in AML, impacting survival outcomes.
• Cytarabine-based chemotherapy and HCT are associated with improved survival in RAS-mutant AML.
• Most RAS mutations in AML are subclonal and not targetable by current commercial RASG12C inhibitors, highlighting an unmet need for novel therapies.