P734: clonal heirarchy and heterogeneity in stag2m myeloid neoplasms: the mayo clinic experience

Background:STAG2 is the most frequent cohesin complex gene mutated in myeloid neoplasms (MN). STAG2 mutations (STAG2m) mainly occur in MDS and AML. They rarely occur as isolated mutations and are often accompanied by ASXL1m, RUNX1m, BCORm. STAG2m have been recognized (WHO/ICC/ELN 2022) as markers of myelodysplasia-related AML and were incorporated in IPSS-M. Aims: In this study, we focus on clonal hierarchy in STAG2m MN. We hypothesize that STAG2m are more commonly secondary and that bi-allelic STAG2m portend a worse prognosis. Methods: A cohort of 96 STAG2m-harboring MN was retrospectively analyzed for clinical and genetic characteristics. MN classification was according to WHO 2016 criteria. Variant allele frequency (VAF) of STAG2m and co-mutations were used to stratify mutations into dominant (d) and secondary (s) (5% < most dominant VAF). STAG2m VAF was divided by 2 in males to account for X-linking. MN harboring multiple STAG2m or occurring in females with VAF> 50% or with -X were classified as multi-hit (mh). BlueSky Statistical Software was used for analysis. Results:STAG2m: STAG2m were mostly nonsense (n=51, 54%), most located in pArg259 (n=6) and pArg216 (n=4). AML cases had more pArg216 mutations (2/4). The most common co-mutations were ASXL1m (n=63, 66%), SRSF2m (n=37, 39%), TET2m (n=35, 37%), RUNX1m (n=30, 31%). Clonal architecture: Among 96 patients, the most common dominant mutations were STAG2m (n=38, 40%), SRSF2m (n=30, 31%), ASXL1m (n=30, 31%), TET2m (n=26, 27%). Those with STAG2md tended to be younger (69 years vs 73) males (87% vs 72%, p=0.09), more frequently AML (42% vs 21%, p=0.02). Other diagnoses included MDS (45% vs 60%) and MDS/MPN (8% vs 12%). There was no difference in (i) AML risk stratification between STAG2md and STAG2ms groups or (ii) frequency of therapy-related MN (tMN) (21% vs 14%, p=0.4). STAG2md carried fewer co-mutations (2 vs 3, p=0.009). SRSF2m and ASXL1m were less frequent in STAG2md (p<0.001 and p=0.002). STAG2md had lower OS than STAG2ms (15 months vs 32, p=0.01). Of STAG2md cases, 11 (29%) received HCT vs 13 (22%) in STAG2ms. Post-transplant survival (PTS) did not differ between the 2 groups (both not reached (NR), p=0.6). Patients with SRSF2md tended to have longer OS than those with SRSF2ms (NR vs 18 months, p=0.06). STAG2mmh: A total of 13 patients (14%) carried STAG2mmh, including 12 males with ≥2 STAG2m and 1 female with VAF>50% (no female had deletion X). Age and gender distribution did not differ between the STAG2mmh and single-hit (sh) groups, while tMN were more common among STAG2mmh (n=5, 39% vs n=11, 13%, p=0.02). MN diagnosis and AML/MDS risk stratification did not differ between STAG2mmh and STAG2msh. Four (31%) AML, 8 (62%) MDS and 1 (8%) MPN cases had STAG2mmh. STAG2mmh carried 4 co-mutations vs 3 in STAG2msh, potentially indicating a more heterogeneous clonal group. They co-occurred more with SRSF2m (69% vs 34%, p=0.01) and IDH2m (39% vs 15%, p=0.04). Only 1/13 cases had a STAG2md. Those with STAG2mmh had numerically longer OS (NR vs 16 months, p=0.1). PTS was 15 months vs NR in STAG2msh (p=0.9). Summary/Conclusion:STAG2m is a late-occurring secondary-type mutation associated with sAML or MDS-related AML. In our MN cohort, STAG2m was overall a secondary mutation. In AML, STAG2m was more commonly the dominant mutation, likely representing clonal expansion. As a dominant mutation, it was associated with fewer co-mutations and worse survival. For the first time, we show that STAG2mmh had more co-mutations and selectively favored SRSF2m and IDH2m. Although STAG2m has been linked to poor prognosis, a biallelic STAG2m was not linked to poorer survival in our study.Keywords: MDS, Myeloid malignancies, Gene mutation, Prognosis