Insight

Talha Badar

Apr 28, 2024, 11:34

Talha Badar: Clinical significance of RAS mutation in AML

Talha Badar, Assistant Professor at Mayo Clinic Comprehensive Cancer Center, shared a post on X:

“RAS oncogenes are mutated in ∼10% to 15% of AML cases. These include activating mutations in NRAS, KRAS, PTPN11, and NF1, leading to proliferative signaling through the RAS/RAF/MEK/extracellular signal-regulated kinase pathway.

The prognostic significance of RAS mutation in AML is debatable, acquisition of RAS mutation at the time of MDS transformation to AML is associated with poor OS, 6 months.

In one large retrospective study on 273 AML pts with RASm. Estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p = .01. Co-mutation with NPM1 favorable outcome. Co-mutation with TP53 poorer outcome.

Ven plus intensive chemotherapy or IC alone tends to have a better outcome. Response to Ven + HMA is sub-optimal at 45%.

Therapeutic targets for RAS-mutant leukemias, such as MEK, extracellular signal-regulated kinase, PI3K, and MTOR inhibitors have been complicated by the rapid development of resistance or activation of bypass pathways with monotherapy.

Salirasib, oral RAS inhibitor in hem malignancies. In a phase I study, 17 RR leukemia pts were treated, and no DLT was encountered. G1/2 diarrhea was the only frequent nonhematologic toxicity observed in 82%. Eight (47%) patients (4 MDS, 2 AML, 1 CMML, and 1 CML) had hematological improvement. The response lasted for a median of 10 weeks (range 5-115). The study was discontinued because of financial constraints.

Ven + HMA with oral MEKi (Trametinib) for RASm AML. In the phase II study, 16 pts RR AML were treated with this triplet. (13/17 received HMA + VEN prior). ORR 25%, mOS 2.4 months.

So, RAS mutation is frequently observed in AML (10-20%). Not considered an adverse risk as per ELN 2022. Response to Ven + HMA are sub-optimal, Intensive chemo tends to have a better outcome. RAS-targeted therapy has not shown much promise due to the rapid development of resistance. Acquisition at the progression from MDS to AML confers poorer outcome.”

Talha Badar