KMT2A (MLL1) Rearrangements in Hematolymphoid Malignancies: A Genomic Landscape Study

Background: KMT2A (MLL1) gene is altered in a variety of hematolymphoid neoplasms and solid tumors. In acute myelocytic leukemia, the interactions between KMT2A gene fusion proteins and menin have been linked to leukemogenesis and represent new potential targets for anti-tumor therapies.

Methods: 4,190 cases of AML underwent comprehensive genomic profiling using the Foundation One Heme combined hybrid capture based DNA and RNA sequencing assay. All classes of genomic alterations (GA) were evaluated. The tumor mutation burden (TMB) and microsatellite stability (MSS) status were determined from the sequencing data.

Results: Of the 4,190 AML cases, there were 43.1% female and 56.9% male patients with a median age of 62 years. 520 (12.4%) of the AML cases featured a GA in the KMT2A gene 99.1% of which were large rearrangements (KMT2Ara). The KMT2Ara AML cases had a median age of 62 years and were 41.7% female and 58.3% male gender. In contrast, the KMT2A not rearranged (KMT2Anra) cases had a similar mean age and gender distribution. Of the KMT2Ara cases there were 43.1% KMT2A duplications, 52.7% fusions and 4.2% not otherwise specified rearrangements. 0.9% of the KMT2A altered AML cases were short variant mutations. There were no KMT2A (0%) amplifications or deletions. GA enriched in the KMT2Ara vs the KMT2Anra AML cases included significantly increased frequencies of GA in FLT3 (27.3% vs 19.9%; p=.0001), KRAS (16.0% vs 8.0%; P<.0001) (overall; 1.1% KRAS G12C) and IDH2 (16.0% vs 7.2%; p<.0001) and significantly decreased frequencies in GA in RUNX1 (15.8% vs 19.6%; p=.05), ASXL1 (10.5% vs 16.1%; p=.0008) and TET2 (10.1% vs 16.3%; p=.0002). Similar GA frequencies in NRAS (17.2% vs 17.7%) DNMT3A (16.0% vs 16.4%) and WT1 (10.7% vs 10.1%) were not significant. The median TMB in the KMT2Ara and KMT2Anra cases was identical at 0.8 mutations/Mb with only 0.2% of both groups having a TMB of > 10 mutations/Mb. All (100%) of KMT2Ara and KMT2Anra AML cases were MS stable.

Conclusions: Rearrangements in the KMT2A gene in AML are common and may emerge as a new target of therapy for AML patients. This genomic landscape study reveals significant differences in import GA associated with AML in KMT2Ara and KMT2Anra cases.

Ross:Foundation Medicine: Current Employment; Roche Holdings: Current equity holder in publicly-traded company; Tango Therapuetics: Consultancy, Current equity holder in publicly-traded company.