Impact of Co-Mutations on Chemotherapy in NPM1^mut/FLT3-ITD^wt AML

Nucleophosmin 1 (NPM1) gene-mutated acute myeloid leukemia (NPM1^mut AML) is classified as a subtype with a favorable prognosis. However, some patients fail to achieve complete remission or relapse after intensified chemotherapy. Genetic abnormalities in concomitant mutations contribute to the heterogeneous prognosis of patients with NPM1^mut AML.

Quan Wu and the team aimed to focus on evaluating the influence of co-occurring genetic mutations, particularly in TET1/2, GATA2, and myelodysplasia (MDS)-related genes, on the chemotherapeutic outcomes of patients with NPM1^mut AML.

Researchers performed an inclusive analysis of 91 patients with NPM1-mutated and FLT3-ITD wild-type (NPM1^mut/FLT3-ITD^wt) AML with intermediate-risk karyotype to assess the impact of common genetic co-mutations on chemotherapeutic outcomes. Genetic profiling was conducted using next-generation sequencing (NGS) to identify the presence of co-mutations, particularly in TET1/2, GATA2, and MDS-related genes.

About 91 patients with NPM1-mutated and FLT3-ITD wild-type (NPM1^mut AML) were analyzed, revealing that TET1/2 mutations were the most prevalent co-mutation, present in 57.1% (52/91) of patients. This was followed by mutations in IDH1/2 (39.6%, 36/91), DNMT3A (38.5%, 35/91), myelodysplastic syndrome-related genes (MDS-related genes) including ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2 (38.5%, 35/91), FLT3-TKD (29.7%, 27/91), and GATA2 (14.3%, 13/91).

Patients with TET1/2 mutations (TET1/2mut) exhibited significantly worse relapse-free survival (RFS) with a median of 28.7 months compared to those without TET1/2 mutations (TET1/2^wt), who did not reach the median (P = 0.0382). However, no significant difference was observed in overall survival (OS) between the TET1/2^mut and TET1/2wt groups, with both groups having a median of not reached (NR) months (P = 0.3035).

The GATA2^mut subtype was associated with significantly inferior overall survival (median, 28 vs. NR months; P < 0.0010) and RFS (median, 24 vs. NR months; P = 0.0224) compared to GATA2^wt. Multivariate analysis indicated that GATA2^mut and MDS-related gene mutations were independently associated with worse survival outcomes.

The study concluded that mutations in TET1/2, GATA2, and MDS-related genes significantly influence the chemotherapeutic outcomes in patients with NPM1^mut AML. These findings hold important clinical implications for identifying patients at risk of adverse responses to frontline chemotherapy, offering a novel reference for further prognostic stratification in patients with NPM1^mut/FLT3-ITD^wt AML.

This study was funded by the National Natural Science Foundation of China (82170165); the Natural Science Foundation of Guangdong Province (2023A1515012401); and the Natural Science Foundation of Guangdong Province (2021A1515011437).

Source: https://pubmed.ncbi.nlm.nih.gov/39126219/

Wu Q, Zhang Y, Yuan B, et al. (2024). “Influence of genetic co-mutation on chemotherapeutic outcome in NPM1-mutated and FLT3-ITD wild-type AML patients.” Cancer Med. 2024 Aug;13(15):e70102. doi: 10.1002/cam4.70102. PMID: 39126219; PMCID: PMC11316012.