[High-Risk Factors for Transformation to Acute Myeloid Leukemia in Patients with Higher-Risk Myelodysplastic...

To investigate the high-risk factors for transformation to acute myeloid leukemia (AML) in patients with higher-risk myelodysplastic syndromes (MDS) undergoing hypomethylating agents (HMA).

A retrospective analysis was conducted on higher-risk MDS patients who received at least two cycles of HMA-based therapy and had complete clinical data at the Affiliated Hospital of Qingdao University between January 2016 and May 2025. The clinical and molecular characteristics at initial diagnosis were analyzed to identify risk factors for leukemic transformation.

With a median leukemia-free survival (LFS) of 14.3 months (range: 1.5-125.6 months), 39 patients (31.2%) experienced transformation to AML. Compared to the non-transformation group, the transformation group had a significantly higher percentage of bone marrow blasts (10.7% vs. 7.7%, P=0.002), a higher red blood cell count (2.62×10¹²/L vs. 2.30×10¹²/L, P=0.047), and a higher lactate dehydrogenase level (341.5 U/L vs. 279.5 U/L, P=0.013). Significant differences were also observed in the distribution of WHO classification subtypes (P=0.018) and treatment regimens (P=0.029) between the two groups. At diagnosis, the transformation group exhibited a higher TP53 variant allele frequency (VAF, P=0.016) and higher mutation rates of TP53 (P=0.012) and NRAS (P=0.009). Multivariate Cox regression analysis identified the percentage of bone marrow blasts and mutations in TP53 and NRAS were independent risk factors for leukemic transformation in MDS. Furthermore, bone marrow fibrosis grade, the RUNX1 mutation rate, and complex karyotype were independent risk factors for overall survival.

The bone marrow blast percentage, TP53 and NRAS mutations are independent risk factors for AML transformation in higher-risk MDS patients undergoing HMA therapy, while bone marrow fibrosis grade, the RUNX1 mutation rate, and complex karyotype are independent prognostic factors for OS.