A comprehensive analysis of the largest database of myelodysplastic syndromes (MDS) patients treated with hypomethylating agents (HMAs) has revealed significant variations in treatment outcomes based on cytogenetic risk profiles, according to research presented at the 2024 American Society of Hematology (ASH) Annual Meeting.
The study, examining 1,450 patients, demonstrated striking differences in survival rates across various cytogenetic complexity groups. Patients with very complex karyotype (VCK) MDS showed a median overall survival (mOS) of 12.6 months, while those with complex karyotype (CK) achieved 19.9 months, and non-complex karyotype (NCK) patients reached 36.1 months.
Impact of TP53 Mutations on Treatment Response
The research highlighted the critical role of TP53 mutations in treatment outcomes. Among patients with TP53 mutations, those with VCK MDS experienced significantly shorter survival (12.2 months) compared to NCK patients (24.2 months). The study revealed a notably higher prevalence of TP53 mutations in VCK MDS patients (75%) compared to CK (40%) and NCK (7%) groups.
Treatment protocols primarily involved azacytidine (71%), decitabine (14%), HMA combined with venetoclax (6%), or other HMA combinations (9%).
Novel Insights into HMA Response Mechanisms
A parallel investigation presented at ASH employed advanced single-cell sequencing technologies to understand HMA treatment response mechanisms. The research team conducted detailed clonal dissection during treatment, revealing important insights into therapy resistance.
The study utilized both short-read and long-read sequencing to analyze hematopoietic stem cells and progenitor cells (HSCPs) from bone biopsies. Significant findings included the induction of interferon pathway gene expression and broad splicing alterations in primitive HSCPs.
Therapeutic Implications and Future Directions
Analysis of samples from 346 patients using a deep-learning platform identified hundreds of high-confidence immunotarget candidates. Particularly noteworthy were targets occurring in over 15% of patients, especially those specific to patients with splicing factor mutations such as SF3B1 and K700E.
The research demonstrated that azacytidine treatment could partially restore normal gene expression and splicing patterns in HSPCs of low-risk MDS patients, suggesting potential therapeutic strategies for improving treatment outcomes.
These findings represent a significant advance in understanding MDS treatment response patterns and offer new directions for developing targeted therapeutic approaches, particularly for patients with complex cytogenetic profiles who currently face poorer outcomes.
