The Association of FAT1 Mutations with Therapeutic Outcomes in AML, Especially in Receiving Venetoclax Combination

Tao Wang ¹ 俊霞 黄 ² Yongqian Jia ¹ Jun-Ting Li ³ Mou WeiWei ^4* Guang Lu ^1,4*

• ¹ Department of Hematology and Research Laboratory of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
• ² Department of Hematology, Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
• ³ School of Medicine, Shanghai Jiao Tong University, Shanghai, China
• ⁴ Department of Hematology, Shengli Oilfield Central Hospital, Dongying, China

The role of FAT1 mutations in acute myeloid leukemia (AML) remains unclear, particularly regarding their impact on the chemosensitivity of AML patients. To elucidate the effect of FAT1 mutations on the therapeutic outcomes and prognosis of AML patients, we conducted this study.wild-type patients (p < 0.001). Further analysis of the 83 patients in the LAML-KR cohort with complete clinical data showed that the mutation rates of P53, DNMT3A, FLT3, and NPM1 genes (including synonymous mutations) were higher in the FAT1 mutant group than in the wild-type group (p < 0.05). In our retrospective Venetoclax-AML cohort (n = 108), the nonsynonymous mutation rate of the FAT1 gene was approximately 13% (14/108), which was higher than the mutation rate in the public LAML-KR cohort. Moreover, only the P53 mutation rate was higher in FAT1 mutant patients (p < 0.01), while the mutation rates of DNMT3A, FLT3, and NPM1 genes showed no significant difference between FAT1 mutant and wild-type patients (p > 0.05).In both the LAML-KR and Venetoclax-AML cohorts, FAT1 mutant patients showed better initial induction chemotherapy outcomes compared to wild-type patients. However, in the LAML-KR cohort, there was no improvement in overall survival (OS) for FAT1 mutant patients (median survival time: 34.6 months vs. 41.7 months, p = 0.6757), whereas there was a trend toward improved progression-free survival (PFS) in the Venetoclax-AML cohort (p = 0.103).Interestingly, further analysis of P53 mutant patients (n = 17) in the Venetoclax-AML cohort revealed that FAT1 mutant patients had better initial induction chemotherapy outcomes and a trend toward improved PFS compared to wild-type patients (p = 0.1381).AML patients with FAT1 mutations have better initial induction chemotherapy efficacy with venetoclax-based regimens compared to wild-type patients, and there is a trend towards improved PFS. This may be related to the improved efficacy and prognosis in P53 mutation-positive patients.