Therapy‐related myeloid neoplasms with normal karyotype show distinct genomic and clinical characteristics compared to their counterparts with abnormal karyotype

Therapy-related myeloid neoplasms (t-MNs) are a complication of treatment with cytotoxic chemotherapy and/or radiation therapy. The majority of t-MNs show chromosomal abnormalities associated with myelodysplastic syndrome (MDS) or KMT2A rearrangements and are characterized by poor clinical outcomes. A small but substantial subset of patients have normal karyotype (NK) and their clinical characteristics and mutational profiles are not well studied. We retrospectively studied patients diagnosed with t-MN at three institutions and compared the mutational profile and survival data between t-MNs with NK and t-MNs with abnormal karyotype (AK). A total of 204 patients with t-MN were identified including 158 with AK and 46 with NK. NK t-MNs, compared to AK, were enriched for mutations in TET2 (p < 0.0001), NPM1 (p < 0.0001), ASXL1 (p = 0.0003), SRSF2 (p < 0.0001), RUNX1 (p = 0.0336) and STAG2 (p = 0.0099) and showed a significantly lower frequency of TP53 mutations (p < 0.0001). Overall survival (OS) was significantly lower in AK t-MNs as compared to NK cases (p = 0.0094). In our study, NK t-MNs showed a significantly better OS, a higher prevalence of MN-associated mutations and a lower frequency of TP53 mutations compared to their AK counterparts. The distinct clinical and mutational profile of NK t-MNs merits a separate classification.