Response predictors and clonal evolution during thalidomide therapy in myelodysplastic neoplasms with increased blasts

Abstract Therapeutic options remain limited for patients with myelodysplastic neoplasms (MDS) with increased blasts who are ineligible for, intolerant of or decline hypomethylating agents (HMAs). We retrospectively investigated the efficacy, predictors of response, survival outcomes and clonal evolution of thalidomide in 56 patients with MDS and increased blasts. Among 50 evaluable patients, the overall response rate was 52.0%, and treatment was well tolerated without grade ≥ 3 non-hematologic adverse events. Multivariable analyses identified male sex, lower baseline lymphocyte count, and higher platelet count as independent predictors of treatment response. Patients who achieved a treatment response experienced significantly longer overall survival (OS) and leukemia-free survival (LFS). Older age, higher IPSS-R category, and STAG2 mutation independently predicted inferior OS, whereas SF3B1 mutation was associated with favorable LFS. Serial molecular analyses demonstrated persistent clonal evolution in 58.3% of patients, predominantly through acquisition of new mutations, with ASXL1 emerging as the most frequently acquired mutation. Overall, thalidomide demonstrated clinical activity with acceptable tolerability in selected patients. Persistent clonal evolution despite morphologic response suggests that the therapeutic benefit of thalidomide reflects disease control rather than eradication of the founding malignant clone, supporting longitudinal molecular monitoring for treatment assessment.