Therapy-related myeloid neoplasms (T-MN) are poorly characterized secondary hematological malignancies following chemotherapy/radiotherapy exposure. We compared the clinical and mutational characteristics of T-MN (n = 129) and primary myelodysplastic syndrome (P-MDS, n = 108) patients. Although the somatic mutation frequency was similar between T-MN and P-MDS patients (93% in both groups), the pattern was distinct. TP53 mutations were more frequent in T-MN (29.5 vs. 7%), while spliceosomal complex mutations were more common in P-MDS (56.5 vs. 25.6%). In contrast to P-MDS, the ring sideroblasts (RS) phenotype was not associated with better survival in T-MN, most probably due to genetic association with TP53 mutations. SF3B1 was mutated in 96% of P-MDS with ≥15% RS, but in only 32% T-MN. TP53 mutations were detected in 92% T-MN with ≥15% RS and SF3B1 wild-type cases. Interestingly, T-MN and P-MDS patients with “Very low” or “Low” Revised International Prognostic Scoring System (IPSS-R) showed similar biological and clinical characteristics. In a Cox regression analysis, TP53 mutation was a poor prognostic factor in T-MN, independent of IPSS-R cytogenetics, disease-modifying therapy, and NRAS mutation. Our data have direct implications for T-MN management and provide evidence that, in addition to conventional disease parameters, mutational analysis should be incorporated in T-MN risk stratification.
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This work was supported by the Royal Adelaide Hospital Research Committee, Contributing Hematologists Committee, and Royal Adelaide Hospital.
DS: planned and performed mutational analysis, analyzed data, and wrote the manuscript. LYAW: processed samples, analyzed data, and edited the manuscript. MMK and RC: analyzed data and edited the manuscript. JG, AWS, JF, and PP-SW: analyzed bioinformatics data and provided critical comments. MB, WTP, and SH: processed samples and analyzed data. SE: provided statistical advice. SM and PA: analyzed data and provided critical comments. SB and ALB: provided critical comments and edited the manuscript. NS and RG: provided clinical information and critical comments. TK, LBT, PGB, IDL, RJD: provided critical comments. JPM: provided critical comments and edited the manuscript. HSS: developed the project, analyzed data, and edited the manuscript. CNH: developed the project, analyzed data, and edited the manuscript. DKH: developed the project, analyzed data, and edited the manuscript.