Adult Acute Myeloid Leukemia with fus::ERG fusion: A national, retrospective, multi-center study

Abstract Introduction: Acute myeloid leukemia (AML) with t(16;21)(p11;q22)/FUS::ERG demonstrate poor outcomes even after allogeneic hematopoietic cell transplantation (allo-HCT). Up to now, most studies were from pediatric patients. Therefore, it is necessary to investigate the clinicopathological features, genomic and transcriptomic landscape, as well as treatment outcomes in a larger cohort to gain an in-depth understanding of adult patients. Methods: We initiated a retrospective study of FUS::ERG AML aged≥14 years in Chinese TROPHY group (Institutional Review Boards, No. 2025436). Patients diagnosed between May 2012 and May 2024 with complete medical records were enrolled. Patients were identified by reviewing karyotypes, PCR or RNA sequencing (RNA-Seq) results. The 2-year overall survival (OS), event free survival (EFS) and relapses were estimated using Kaplan–Meier curves and compared using log-rank test. The Prentice, Williams and Peterson total time (PWP-TT) model was used for analysis of recurrent time-to-event data, with results presented as hazard ratios (HR) and 95% confidence intervals (CI) for risk factors (considering age, gender, 2022 ELN risk stratification, and allo-HCT) regarding relapse. Data of 899 patients diagnosed in Ruijin Hospital with RNA-seq were provided as a reference cohort. Results: A total of 104 adult FUS::ERG AML were identified. Cytogenetic information was available in 101 patients, NGS were available in 64, and RNA-Seq data were available in 25. The median age was 35 (range: 14-73) years old, 13 patients aged older than 60 and 60 patients were male. Patients showed high WBC (median: 12.9×109/L) and bone marrow blast counts (median: 72%) at diagnosis. M5 (51%) was the predominant FAB subtype. Most leukemic blasts (80/82) were CD56 positive, and 31.2% (24/77) were classified as harboring RAM phenotype. Complex karyotypes were found in 41.3% of patients. PTPN11, RUNX1, and NRAS are the most prevalent somatic mutations. Ninety-two patients were stratified according to 2022 ELN recommendation with 56 (60.9%) cases in adverse-risk group. Ninety-one patients were eligible for intensive chemotherapy, 8 received low intensity induction, and 5 received supportive care. After two courses of induction, 83 (83.8%) patients achieved morphology complete remission (CR). The long-term survival of the entire cohort was dismal, with estimated 2-year probability of relapse, EFS, and OS of 77.2%, 18.7%, and 38.1%, respectively. Fifty-five patients underwent allo-HCT in first CR, 3 in second CR, and 7 with active disease. In CR1 cohort, both 2-year OS (allo-HCT: 59.1%, 95% CI: 46.2-75.5%; chemo: 5.1%, 95% CI: 0.8- 33.7%, P<0.0001) and EFS (allo-HCT: 34.1%, 95% CI: 22.7-51.2%; chemo: 0%, P<0.0001) were improved significantly with allo-HCT. The PWP-TT model revealed higher risk of relapse in patients aged≥60 years (HR: 8.1, 95% CI: 2.7–23.7, P<0.001), and allo-HCT can significantly reduce disease recurrence (HR: 6.5; 95% CI, 3.8–11.4, P<0.001). Compared to the reference cohort, FUS::ERG AML demonstrated similar long-term survival to that of the ELN adverse-risk group. Transcriptome-based analysis clustered all 25 cases together and classified into the myelodysplasia-related/-like subtype. Differential expression gene analysis revealed that insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) expression was significantly upregulated in FUS::ERG fusion AML comparing to reference cohort. Kyoto Encyclopedia of Genes and Genomes analysis showed enrichment of Rap1 and MAPK signaling pathway. Meanwhile, Gene Ontology analysis indicated that immune function-related pathways were significantly down-regulated, including immune system process, immune response, regulation of immune system, histocompatibility complex (MHC) protein complex binding, antigen binding and immune receptor activity. Elevated levels of IGF2BP1 correlated with loss of MHC class II expression (HLA-DR, -DQ, -DP, -DM, -DO) alongside suppression of most immune stimulators (CD28, CD80, CD86, KLRK1 and TNFSF/TNFRSF). Of note, the transcript level of TGFβ1 showed a significant elevation which is positively correlated with increase in IGF2BP1. Conclusions: We presented the largest comprehensive evidence to characterize a rare subtype of adult AML with FUS::ERG fusion which demonstrate poor outcomes with high relapse rate even after allo-HCT. Immune-evasion phenotype driven by IGF2BP1 overexpression may be the key factor contributing to the poor prognosis.