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Therapy-related myeloid neoplasms (t-MN) are an aggressive and heterogeneous group of myeloid disorders with no established guidelines for frontline treatment. This retrospective study of 53 consecutive t-MN patients at our institution evaluated the influence of clinical features, treatment approaches, and prognostic indicators on clinical outcomes of t-MN. The 1-year, 3-year, and 5-year overall survival (OS) rates were 61.0%, 50.0%, and 36.0%, respectively. Multivariate analysis revealed that age ≥ 60 (p = 0.009), TP53 (p = 0.040) and RAS mutations (p = 0.018) were associated with inferior OS. After induction therapy, patients who received a venetoclax-based regimen (venetoclax group) had an overall response rate (ORR) of 96.2%, compared with 63.6% in the chemotherapy group (p = 0.007). The venetoclax group tended to have better OS and DFS than the chemotherapy group (p = 0.052 and p = 0.078). Importantly, ORR rates and OS were higher in some subgroups of the venetoclax group, especially in patients over 60 years old and patients with intermediate/adverse risk. This study demonstrates the feasibility of venetoclax-based combination regimens for the treatment of t-MN and may influence decision-making for frontline therapy.