DNMT3A and NPM1 co-mutations in Acute Myeloid Leukemia (AML): A genomic landscape study

Abstract Background: Independent genomic alterations (GA) in the DNMT3A and NPM1 genes occur frequently in AML. While NPM1 mutation carries favorable prognosis in AML and has emerged as a target for anti-menin based treatments, co-mutation with DNMT3A, a recognized adverse prognostic factor also under investigation as a therapy target, seems to impact survival in this subset of AML. Little is currently known of AML cases where both genes are altered. We aimed to study the GA in AML patients with NPM1 and DNMT3A co-mutation to better understand the genomic profile in this group. Methods: 3,165 cases of AML underwent comprehensive genomic profiling using the Foundation One Heme combined hybrid capture based DNA and RNA sequencing assay. All classes of GA were evaluated. Results: 244 (7.7%) AML cases feature co-mutations in both DNMT3A and NPM1 (Co-mut+). The Co-mut+ AML patients were older (60 vs 56 yrs; p<.0001), more frequently female (55.7% vs 41.7%; p<.0001) and of European ancestry (77.0% vs 65.5%; p<.0001) and less frequently admixed American ancestry (7.0% vs 18.2%; p<.0001). Individual GA more frequently identified in Co-mut+ cases included FLT3 (63.1% vs 14.8%; p<.0001), IDH1 (13.5% vs 6.8%; p<.0001), IDH2 (13.5% vs 6.6%; p=.0007), PTPN11 (18.4% vs 8.0%; p<.0001), and TET2 18.0% vs 12.2%; p=.016). Myelodysplastic related mutations were more frequently seen in the DNMT3A/NPM1 wild type (DNMT3A/NPM1wt) and included ASXL1 (17.9% vs 0.8%; p=.011), BCOR (5.5% vs 0.8; p<.0001), RUNX1 (22.4% vs 2%; p<.0001), SRSF2 (12.5% vs 1.6%; p<.0001), STAG2 (6.8% vs 0.0%; p<.0001), and U2AF1 (5.7% vs 2%; p=.016). TP53 was less common with Co-mut+ (3.7% vs 18.7%; p<.0001). Conclusions: The DNMT3A/NPM1 Co-mut+ is seen in 7.7% AML cases and have a unique genomic signature that preserves other established AML therapy targets including FLT3 and IDH1/2. Myelodysplastic related mutations and TP53 are more commonly seen in DNMT3A/NPM1wt. Further studies of this relatively rare AML genotype with unique opportunities for targeted therapy drug combinations appears warranted.