KRAS突变状态严重决定了KMT2A重排急性髓系白血病患者的临床结局。

KRAS mutation status critically determines the clinical outcome of patients with KMT2A-rearranged acute myeloid leukemia.

作者信息

Wu Yibo, Yuan Xiaolin, Lai Xiaoyu, Liu Lizhen, Liang Yue, Yang Luxin, Zhu Panpan, Shi Jimin, Yu Jian, Zhao Yanmin, Zheng Weiyan, Sun Jie, Zhu Yuanyuan, Wu Wenjun, Cai Zhen, Huang He, Pei Shanshan, Luo Yi

机构信息

Bone Marrow Transplantation Center of the First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.

Institute of Hematology, Zhejiang University, Hangzhou, China.

出版信息

Cancer. 2025 Jul 1;131(13):e35941. doi: 10.1002/cncr.35941.

DOI:10.1002/cncr.35941

PMID:40530668

Abstract

BACKGROUND

KMT2A(11q23)-rearranged acute myeloid leukemia (KMT2A-r AML) represents a clinically aggressive subtype with heterogeneous outcomes. Current evidence remains inconclusive regarding the prognostic relevance of fusion partners in 11q23/KMT2A-rearranged AML. The comprehensive mutational landscape and prognostic implications of co-occurring driver mutations remain poorly characterized.

METHODS

A comprehensive clinicogenomic analysis of 159 de novo KMT2A-r AML patients was conducted to assess the correlation between molecular profiles and clinical outcomes.

RESULTS

Notably, the KMT2A::MLLT4 subgroup exhibited significantly higher KRAS mutation frequencies compared to other rearrangement groups (p < .05). Survival analysis revealed that the KMT2A::MLLT4 cohort demonstrated trends toward inferior overall survival (OS) and increased cumulative incidence of relapse (CIR) relative to other rearrangement subgroups. Stratified by mutational status, patients with KRAS mutations exhibited significantly inferior 2-year OS rates (24.6% vs. 50.5%; p = .001) and higher 2-year CIR (56.3% vs. 34.6%; p = .018) compared to KRAS wild-type counterparts. This adverse prognostic association remained in the transplanted cohort (OS: 32.3% vs. 73.5%; p < .001; CIR: 73.6% vs. 23.0%; p < .001). In contrast, mutations in NRAS, FLT3 did not demonstrate statistically significant associations with OS or CIR in either the overall cohort or transplant subgroup. Multivariable Cox regression confirmed KRAS mutation as an independent adverse prognostic factor for both 2-year OS (hazard ratio [HR], 0.51; 95% CI, 0.31-0.84; p = .008) and CIR (HR, 1.80; 95% CI, 1.04-3.12; p = .037) in the overall cohort. This association persisted in the transplanted patients subgroup (OS: HR, 0.18; 95% CI, 0.06-0.52; p = .001; CIR: HR, 3.89; 95% CI, 1.05-14.37; p = .042).

CONCLUSIONS

These results demonstrate the independent prognostic value of KRAS mutations across treatment modalities, including both conventional chemotherapy and hematopoietic stem cell transplantation.

摘要

背景

KMT2A（11q23）重排的急性髓系白血病（KMT2A-r AML）是一种临床侵袭性亚型，预后各异。目前关于11q23/KMT2A重排AML中融合伴侣的预后相关性的证据仍不明确。同时发生的驱动基因突变的综合突变图谱和预后意义仍未得到充分描述。

方法

对159例初发KMT2A-r AML患者进行了全面的临床基因组分析，以评估分子特征与临床结局之间的相关性。

结果

值得注意的是，与其他重排组相比，KMT2A::MLLT4亚组的KRAS突变频率显著更高（p <.05）。生存分析显示，与其他重排亚组相比，KMT2A::MLLT4队列的总生存期（OS）有较差趋势，复发累积发生率（CIR）增加。按突变状态分层，与KRAS野生型患者相比，KRAS突变患者的2年OS率显著更低（24.6%对50.5%；p =.001），2年CIR更高（56.3%对34.6%；p =.018）。这种不良预后关联在移植队列中仍然存在（OS：32.3%对73.5%；p <.001；CIR：73.6%对23.0%；p <.001）。相比之下，NRAS、FLT3突变在整个队列或移植亚组中均未显示与OS或CIR有统计学显著关联。多变量Cox回归证实，KRAS突变是整个队列中2年OS（风险比[HR]，0.51；95%置信区间，0.31 - 0.84；p =.008）和CIR（HR，1.80；95%置信区间，1.04 - 3.12；p =.037）的独立不良预后因素。这种关联在移植患者亚组中持续存在（OS：HR，0.18；95%置信区间，0.06 - 0.52；p =.001；CIR：HR，3.89；95%置信区间，1.05 - 14.37；p =.042）。