Identification of Characteristics and Prognostic Impact of FUS-ERG and AML1-MTG16 Fusion Genes in Adult AML Patients

Background FUS-ERG and AML1-MTG16 are two rare fusion genes in acute myeloid leukemia (AML), characterized by similar karyotypic abnormalities, namely t(16;21)(p11;q22) and t(16;21)(q24;q22), respectively. A previous research has demonstrated that FUS-ERG represents a high-risk subtype associated with an extremely poor prognosis, while AML1-MTG16 has favorable outcomes in pediatric cohort. Despite this valuable insight, a comprehensive systematic review of these fusion genes in the adult population remains absent. Method In this study, we conducted an extensive collection of AML patients with FUS-ERG or AML1-MTG16 fusion genes, who were reported in Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer, PubMed and China national knowledge infrastructure (CNKI) from 1988 to 2023. Patients lacking detailed survival data or those who did not receive treatment were excluded. Additionally, patients diagnosed and treated in our institution between 2018 and 2023 were included if they were identified as carrying FUS-ERG or AML1-MTG16 fusion genes. The reference cohort comprised of 669 adult AML patients (excluding the t(16;21) cases and acute promyelocytic leukemia) admitted to our institution from 2016 to 2021. All patients within the cohort were classified into 3 categories based on the 2022 ELN genetic risk classification, namely favorable (F), intermediate (I) and adverse (A) risk. These patients were then compared with the FUS-ERG and AML1-MTG16 groups to explore their respective clinical features and prognosis. Results A total of 800 patients were included for analysis (Table 1). Patients with FUS-ERG (n=111) exhibited significant distinctions, including a younger onset age (34 years vs. 59 years), lower platelet count (30×10 9/L vs. 51×10 9/L), higher bone marrow blasts proportion (80.0% vs. 60.0%), a higher relapse rate (78.6% vs. 44.7%) and a higher incidence of trisomy 8 (16.4% vs. 9.0%), trisomy 10 (9.1% vs. 0.3%) and complex karyotype (37.8% vs. 11.6%), when compared to the reference cohort (p<0.01). Meanwhile, patients with AML1-MTG16 (n=20) primarily presented as the secondary AML (70.0%), and displayed a higher prevalence of trisomy 8 (40.0%) and complex karyotype (35.0%) than reference cohort (p<0.01). The FUS-ERG patients had a less median overall survival (OS) when compared to the reference cohort (13 vs. 35 months, p<0.001). The median OS in subgroups with ELN 2022 F-risk vs. ELN 2022 I-risk vs. FUS-ERG was not reached (NR) vs. 33.6 months vs. 13.0 months (p<0.001) and the median OS of FUS-ERG group was even inferior to ELN 2022 A-risk group (13.0 vs. 16.8 months, p=0.015). Furthermore, the FUS-ERG patients also displayed a less median disease-free survival (DFS) than the reference cohort (7.5 vs. 20.5 months, p<0.001). The median DFS in subgroups with F-risk vs. I-risk vs. A-risk vs. FUS-ERG was NR vs. 19.8 vs. 13.3 vs. 7.5 months (p<0.001). In contrast, patients with AML1-MTG16 had a median OS of 18.7 months and a median DFS of 16 months, presenting a relatively unfavorable OS trend and indistinctive DFS, when compared to the reference cohort (OS: p=0.083, DFS: p=0.612), F-risk (OS: p<0.001, DFS: p=0.128), I-risk (OS: p=0.162, DFS: p=0.835) and A-risk (OS: p=0.877, DFS: p=0.731). Moreover, the AML1-MTG16 group had a better DFS than the FUS-ERG group (14.0 vs. 7.5 months, p=0.016), but their OS was comparable (16.0 vs. 7.5 months, p=0.219). For adult patients with FUS-ERG (Table 2) multivariate analysis revealed that age >60 years (HR=2.96, 95%CI: 1.14-7.73, p=0.026), WBC >100×10 9/L (HR=2.98, 95%CI: 1.24-7.13, p=0.014) and the presence of monosomy (HR=2.61, 95%CI: 1.21-5.66, p=0.015) were independent risk factors for OS, while monosomy was associated with poor DFS (HR=3.72, 95%CI: 1.69-8.20, p=0.001). However, receiving HSCT could significantly improve both OS (HR=0.22, 95%CI: 0.11-0.42, p<0.001) and DFS (HR=0.31, 95%CI: 0.16-0.57, p<0.001). Pediatric FUS-ERG patients presented similar clinical features, exhibiting a better median OS (19.5 vs.13 months, p=0.014) and a comparable median DFS (9.5 vs. 7.5 months, p=0.496), when compared to the adult population. Conclusion Both FUS-ERG and AML1-MTG16 were identified as high-risk subgroups in adult AML anddiffered from the results in pediatric cohort. Several factors including age, WBC count, HSCT and monosomy influenced the prognosis of adult AML patients with FUS-ERG.