[Analysis of the association between pre- and post-treatment genetic mutation status and treatment efficacy and survival in patients with newly diagnosed myelodysplastic syndromes with excess blasts receiving hypomethylating agent therapy].

<b>Objective:</b> To investigate the association between pre- and post-treatment gene mutation profiles and clinical outcomes (treatment response and prognosis) in patients with myelodysplastic syndromes with excess blasts (MDS-EB) receiving hypomethylating agent (HMA) monotherapy. <b>Methods:</b> The clinical characteristics, treatment efficacy, and survival outcomes of 69 treatment-naive patients with MDS-EB who underwent next-generation sequencing (NGS) before treatment and completed at least 4 cycles of HMA monotherapy at the Institute of Hematology & Blood Diseases Hospital, CAMS & PUMC, between June 2016 and September 2023, were retrospectively analyzed. <b>Results:</b> ① The cohort comprised 47 males and 22 females with a median age of 62 years (range: 41-80). Thirty-nine patients were classified as MDS-EB1 and 30 as MDS-EB2. The median number of treatment cycles was 6 (range: 4-35). The median follow-up duration was 22 months (range: 5-72), and the median overall survival (OS) was 32 months (95% <i>CI</i>: 27-43). ② The presence of DTA (DNMT3A, TET2, or ASXL1) mutations, signaling pathway mutations, transcription factor mutations, or splicing factor mutations before HMA treatment showed no significant association with the best response within 4 treatment cycles, duration of response (DOR), or OS. TP53 mutation status was significantly associated with DOR and shorter OS. The median DOR was 3 months (95% <i>CI</i>: 1-10) for patients with biallelic TP53 mutations, 10 months (95% <i>CI</i>: 3-34) for those with monoallelic TP53 mutations, and 16 months (95% <i>CI</i>: 8-27) in patients without TP53 mutations (<i>P</i>=0.032). The median OS was 16 months (95% <i>CI</i>: 7-38), 15 months (95% <i>CI</i>: 6-40), and 35 months (95% <i>CI</i>: 14-91), respectively (<i>P</i><0.001). ③ Neither the Revised International Prognostic Scoring System (IPSS-R) nor the Molecular International Prognostic Scoring System (IPSS-M) could predict the best response within 4 treatment cycles or DOR in patients receiving HMA therapy. ④ Among patients without TP53 mutations, the median OS was 55 months (95% <i>CI</i>: 9-106) for the major clone significant clearance group (<i>n</i>=14) and 31 months (95% <i>CI</i>: 16-184) for the major clone non-significant clearance group (<i>n</i>=10) (<i>P</i>=0.013). For patients who responded to HMA treatment and had significant major clone clearance, the 3-year OS rate reached (77.8±13.9) %. <b>Conclusion:</b> For MDS-EB patients receiving HMA monotherapy, single gene mutations, IPSS-R, and IPSS-M could not effectively predict treatment outcomes before therapy. However, for patients without TP53 mutations, monitoring the degree of major clone clearance by NGS during treatment may predict the long-term efficacy in MDS patients receiving HMA therapy.