Mutational Score May Improve Risk Stratification of Certain Patients With AML

While a widely used risk classification model has demonstrated reliability in predicting outcomes in younger patients with acute myeloid leukemia (AML) receiving intensive chemotherapy, an updated risk stratification tool that accounts for patients’ mutation profiles may be needed to reliably predict risk in older patients not fit for chemotherapy, as suggested in recent findings published in Blood Advances.^1,2

Risk stratification in AML could benefit from mutational scoring | image credit: faraktinov - stock.adobe.com

The researchers suggest refining the 2022 European LeukemiaNet (ELN) classification model for patients aged 60 years or older receiving lower intensity treatment (LIT), including the adoption of a mutation score that accounts for certain gene mutations, such as IDH2, indicative of prognosis.

“Treatment decision-making is heavily influenced by prognostic risk stratification and genomics, particularly in this older patient population as most will not go onto hematopoietic stem cell transplantation,” explained the researchers. “Because 78% of the older patients given LIT is classified as adverse-risk by 2022 ELN, we investigated the impact of molecular abnormalities to improve the ability to risk stratify ND AML patients ≥ 60 years with adverse-risk AML receiving LIT.”

The approval of venetoclax (Venclexta) with azacitadine (Vidaza) has established LIT as a cornerstone of AML treatment for newly diagnosed patients who are ineligible for intensive chemotherapy. Among these patients with more difficult-to-treat disease, being able to identify biomarkers associated with favorable, or unfavorable, outcomes can help drive more informed and optimized treatment decisions.

Researchers of this new analysis pulled data from 595 patients aged 60 years or older with newly diagnosed (ND) AML. Survival analysis showed that the 2022 risk stratification was reliable in accurately classifying patients with poor OS (P < .001). However, the risk stratification tool could not reliably distinguish patients with favorable or intermediate risk (P < .71).

This finding, said the researchers, was consistent with previous research showing there was no significant difference in OS among patients treated with a hypomethylating agent (HMA) or HMA + venetoclax based on 2022 ELN risk assessment (P = 0.926 and P = 0.498, respectively).³

Based on 2022 ELN risk stratification, 11% (n = 66) of patients were classified as having favorable risk and 11% (n = 66) as having intermediate risk; 78% (n = 465) of patients were classified as having adverse risk, up from 70% based on ELN 2017. Overall, 88% of patients were classified the same between the 2 risk stratification tools.²

Patients included in the study had varying mutational profiles. TP53, RUNX1, and ASXL1 were strongly associated with adverse risk, while NPM1 had the strongest correlation with favorable risk. Mutations associated with intermediate risk included DNMT3A and IDH2. In multivariable analyses, IDH2 showed to be an independent favorable prognostic marker (HR 0.65; 95% CI 0.46-0.94). Notably, this association occurred despite treatment with an IDH inhibitor and was not associated with differences in outcomes for patients with the mutation (HR: 0.62; 95% CI 0.31-1.23).

The researchers found that using a mutation score to determine risk, calculated based on a patient’s mutational profile, improved OS discrimination.

“We redefined risk for older ND AML and propose refined Beat-AML-favorable (22% of patients), Beat-AML-intermediate (41%), and Beat-AML-adverse-risk (37%) groups with improved discrimination for OS (2-year OS: 48% vs 33% vs 11%, respectively; P < 0.001),” described the researchers.

References:

1. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345-1377. doi:10.1182/blood.2022016867
2. Hoff FW, Blum WG, Huang Y, et al. Beat-AML 2024 ELN-refined risk stratification for older adults with newly diagnosed AML given lower-intensity therapy. Blood Adv. Published online August 9, 2024. doi:10.1182/bloodadvances.2024013685
3. Park S, Kim TY, Cho B-S, et al. Prognostic value of European LeukemiaNet 2022 criteria and genomic clusters using machine learning in older adults with acute myeloid leukemia. 2024;109(4):1095-1106. doi: 10.3324/haematol.2023.283606