Older Patients with Acute Myeloid Leukemia Have Distinct Mutational Landscape

Patients with acute myeloid leukemia (AML) aged 60 years or older exhibited a “markedly different” genetic mutation profile compared with younger patient populations enrolled in prior AML studies, according to an analysis of the Beat AML Master Clinical Trial presented at the 65th ASH Annual Meeting and Exposition in San Diego, California.

“The frequency of mutated TP53 was substantially higher in older AML patients, as was the occurrence of myelodysplasia-related gene mutations (eg, SRSF2, RUNX1, ASXL1, STAG2, U2AF1, SF3B1) and gene mutations in IDH1, IDH2, and TET2,” stated lead author Fieke Hoff, MD, PhD, of the UT Southwestern Medical Center in Dallas.

Conversely, NPM1 mutations were less frequent in older patients; however, the authors also reported that 46% of patients with AML older than 60 years of age exhibited mutations in FLT3, IDH1, IDH2, and NPM1, which could potentially be targets for directed therapies.

The analysis included 1,032 patients aged 60 years or older with newly diagnosed AML. The cohort was 42% female, was 79% Caucasian, and had a median age at diagnosis of 72 years (range, 60–92). Among 1,024 patients with available sequencing data, the median number of mutations was 11 (range, 3.0-28.0), and the most frequently mutated genes were as follows:

• DNMT3A (n=257; 25.1%)
• TP53 (n=255; 24.9%)
• TET2 (n=243; 23.7%)
• RUNX1 (n=225; 22.0%)
• SRSF2 (n=221; 21.6%)
• ASXL1 (n=216; 21.1%)
• NPM1 (n=206; 20.1%)
• FLT3 (n=205; 20.0%)
• IDH2 (n=190; 18.6%)
• NRAS (n=208; 16.9%)
• PTPN11 (n=104; 10.2%)
• STAG2 (n=101, 9.9%)
• IDH1 (n=99; 9.7%)

Co-occurring mutations with the strongest significance were FLT3 and NPM1 (n=103), STAG2 and ASXL1 (n=63), ASXL1 and RUNX1 (n=92), ASXL1 and SRSF2 (n=88), RUNX1 and SRSF2 (n=94), STAG2 and SRSF2 (n=51), and DNMT3A and NPM1 (n=92) (P<.01). Additionally, researchers identified FLT3-ITD in 98 of 810 (12.1%) patients who were tested.

“The high incidence of mutated TP53 and MDS-related gene mutations underscores the increased incidence of high-risk AML and the need for innovative personalized therapies in this older age group,” Dr. Hoff and colleagues concluded.

Reference

Woff F, Huang Y, Welkie R, et al. Genomic characterization of newly diagnosed acute myeloid leukemia in patients age 60 years and older; a report from the Beat AML Master Trial. Abstract #4296. Presented at the 65th ASH Annual Meeting and Exposition; December 9-12, 2023; San Diego, California.