The Mutated of KRASgene Determine the Fate of KMT2A-Rearranged AML Patients
Authors: Wu Yibo , Yuan Xiaolin , Lai Xiaoyu , Liu Lizhen , Shi Jimin , Zheng Weiyan , Yu Jian , Zhao Yanmin , Sun Jie , Ye Xiujin , Cai Zhen , Huang He , Pei Shanshan , Luo Yi 
Published: December 2024

Backgrounds:
KMT2A(11q23)-rearranged acute myeloid leukemia (KMT2A-r AML) is a highly refractory and deadly subtype of AML. KMT2A is rearranged in approximately 10% of all leukemia, 3% to 7% of adult de novo AML patients. It was a genetically and clinically heterogeneous disease. Previous studies have suggested that patient prognosis is associated with the 11q23/KMT2A fusion partner. Compared with other AML subtypes, mutations in genes of the RAS pathway were most frequent in KMT2A-r AML. There were conflicting results about prognostic value of fusion partner in 11q23/KMT2A-rearranged AML. Little is known about the comprehensive mutational landscape and prognostic significance of driver mutations.
Methods:
We conducted a comprehensive analysis of patients with de novo KMT2Ar AML treated at our institution to characterize their genomic and phenotypic characteristics and determine the association of these variables with prognosis and response to therapy.
R esults:
A total of 180 patients were enrolled from 2019 to 2024. Most morphology of blast cells were M5(73.89%) in FAB classification at diagnosis. With MLLT3, MLLT4, MLL-ELL, PTD and MLLT10 being the most frequent fusion partners. 63(35.0%) patients were KMT2A-MLLT3, 35 (19.4%) patients were KMT2A-MLLT4, 29(16.1%) patients were KMT2A-ELL, 21(11.7%) patients were KMT2A-KMT2A, 10(5.6%) patients were KMT2A-MLLT10. The most occurred frequences of mutated genes were FLT3(21.67%), KRAS(21.37%), NRAS(17.56%),TET2(16.79%),RUNX1(15.27%),GATA2(7.22%), DNMT3A(6.67%), ASXL1(6.67%), TTN(6.67%), U2AF1(6.11%), PTPN11(5.56%), CBL(5.00%), STAG2(5.00%). When we classified patients into 5 groups according to different fusion partners, The KRAS mutated frequences were significant higher in KMT2A-MLLT4 (37.14%) than others.
KMT2A-MLLT4 group had the trends of lower overall survival (OS) than others. The 2-year OS was 46.2%, 33.3%, 61.2%, 45.8% and 42.6% in KMT2A-MLLT3, KMT2A-MLLT4, KMT2A-ELL, KMT2A-KMT2A and others respectively (P=0.113). The 2-year cumulative incidence of relapse (CIR) was 33.5%, 42.9%, 36.7%, 25.5%, 47.9% in KMT2A-MLLT3, KMT2A-MLLT4, KMT2A-ELL, KMT2A-KMT2A and others respectively (P=0.900). KRAS mutated patients had significantly worse 2-year OS and higher 2-year CIR than WT patients (24.6% vs. 50.9%, P&lt;0.001; 56.3% vs. 34.3%, P=0.015). However, NRAS, FLT3 and TET2 gene mutations didn't significantly impact OS and CIR in the entire group.
In allo-HSCT cohort, KMT2A-MLLT4 group had lower 2-year OS trends than KMT2A-MLLT3, KMT2A-ELL, KMT2A-KMT2A and others (52.2% vs. 63.1% vs. 85.7% vs. 66.7% vs. 66.3%, P=0.169). KMT2A-MLLT4 group had highest 2-year CIR than KMT2A-MLLT3, KMT2A-ELL, KMT2A-KMT2A and others (71.2% vs. 22.9% vs. 7.1% vs. 14.3% vs. 27.7%, P=0.065). KRAS mutated patients had significantly lower 2-year OS and higher 2-year CIR than WT patients after transplantation (32.3% vs. 72.9%, P&lt;0.001; 73.6% vs. 23.1%, P&lt;0.001). However, NRAS, FLT3 and TET2 gene mutations didn't significantly impact both OS and CIR in transplant cohort. In the entire cohort or allo-HSCT cohort, there was both no significantly difference of OS and CIR between ELN 2022 intermediate risk group and ELN2022 high risk group in KMT2A-r AML patients.
We put KRAS, TET2, FLT3, fusion partners, pre-HSCT MRD, patient age, WBC at diagnosis, transplant type into multivariable analysis for OS and CIR. KRAS was the independent factor impact the 2-year OS and 2-year CIR both in entire group (HR=0.501(95%CI:0.305-0.823),P=0.006; HR=1.815(95%CI:1.049-3.140),P=0.033) and transplant group (HR=0.178(95%CI:0.0.062-0.516), P=0.001; HR=3.980(95%CI:1.062-14.910), P=0.040).
C onclusions:
KMT2A-MLLT4 group had the trends of lower OS and higher CIR than other fusion partners. We also confirmed the independent prognostic influence of KRAS mutation on the clinical outcome both in chemotherapy and HSCT treatment. 11q23/KMT2A-rearranged AML with KRAS mutation should be classified into high risk classification, which need further mechanism research and innovative treatment in the future.
Keywords: 11q23/KMT2A, acute myeloid leukemia, KRAS, prognosis