Therapy-Related Myeloid Neoplasms (T-MN) and Primary MDS (PMDS) Patients with Very Low (VL) or Low (L) IPSS-R Score Share Clinical and Biological Characteristics and Have Similar Outcome

Introduction: Myeloid neoplasms occurring after exposure to chemo- and/or radiotherapy, termed Therapy-related myeloid neoplasms (T-MN), are considered poor prognosis. This perception creates an inherent bias in treatment decision, resulting in either over- (allo-HSCT) or under-treatment (palliation) and exclusion from most clinical trials. The optimal T-MN treatment paradigm is unknown, partly because its mutational architecture is not well defined. Few small studies show mutations in only 50-60% (Ok, Leuk Res 2015; Lindsley, Blood 2015) of T-MN (compared to 80-90% in PMDS). This study compares the mutational architecture of T-MN and PMDS from the South Australian Myelodysplastic Syndrome registry. Methods: Demographic, clinical and laboratory data including cytogenetic profiles of 129 T-MN (95 T-MDS; 34 T-AML [≥20% blasts]) and 108 PMDS patients were analysed. Targeted Massively Parallel Sequencing of a custom panel of 43 myeloid neoplasms associated genes (all coding regions) was performed on diagnosis bone marrow samples. Mutations with VAF ≥3% were selected for further assessment. Overall survival (OS) was calculated from date of diagnosis to date of last follow-up or death and adjusted using time varying covariate to account for disease modifying therapy (DMT) exposure. Results: Compared to PMDS, T-MN patients were younger at diagnosis (71.1 vs 75.3 years, p Although the OS was poorer for T-MN than PMDS (10.6 vs 31.4 mo, p As expected, VL or Low risk T-MN patients were different from T-MN with intermediate, High or VH IPSS-R score (n=74) who showed higher frequency of high-risk karyotypes and poorer OS. Additionally, the mutation profile was also different between the two groups; TP53 mutations were less common while TET2, SF3B1, IDH2 mutations were significantly more frequent in low-risk T-MN. Conclusions: In our cohort, somatic mutations were seen in 93% of T-MN which is higher than published literature. TP53 and spliceosomal mutations were commonest in T-MN and PMDS, respectively. Although, the T-MN survival is poorer than PMDS, the subgroup with IPSS-R Very Low or Low risk mirrors clinical and genetic characteristics of PMDS and has similar outcome. Such patients should be managed at par with PMDS counterparts and, importantly, should not be excluded from appropriate clinical trials based on pre-MDS chemotherapy or radiotherapy exposure. Disclosures Hiwase: Novartis: Research Funding; Celgene: Research Funding.