Impact of cohesin complex gene mutations on clinical outcomes in Acute Myeloid Leukemia

Abstract Background: The cohesin complex is a tetramer that plays a key role in chromatin interactions, DNA loop formations, and regulation of gene transcription. Cohesin subunit mutations occur in epigenetic regulator genes SMC1A, SMC3, RAD21, & STAG2. These mutations are commonly found in myeloid malignancies, yet their prognostic significance has not been thoroughly investigated. We performed a comprehensive analysis of commonly mutated genes in the cohesin complex among a large population of adult patients with acute myeloid leukemia (AML). Methods: We conducted a single-institution retrospective cohort study of mutated cohesin genes among adult patients with newly diagnosed AML between 2015 and 2023. Gene mutation status for SMC1A, SMC3, RAD21, & STAG2 was determined by Next-Generation Sequencing. Patient and disease characteristics were summarized according to individual genes in the cohesin-altered pathway. Co-occurring mutations were tested using Fisher's exact test to compare mutation counts of other genes according to mutated (mt) vs wildtype (wt) status of each individual gene. Our main endpoints were overall survival (OS), event-free survival (EFS), and response rates. OS and EFS were estimated using multivariable Cox regression, while RR was evaluated using multivariable logistic regression (MV-LR). The MV models included age, gender, cytogenetics (per 2022 ELN risk classification), TP53 status, and comorbidities. AML response was calculated as composite complete response (CCR) defined as complete response (CR) or complete response with incomplete count recovery (CRi) to first-line treatment. Results: Between 1/2015 and 9/2023, 971 patients were treated for AML at the Cleveland Clinic in Ohio. Among those with known cohesin gene mutation status, the most frequent mutation was STAG2 (11%, n=47 of 443), followed by SMC1A (4%, n=17/439), SMC3 (3%, n=14/438), and RAD21 (2%, n=9/438). Patients with SMC1A-mt AML, compared to wt, were less likely to have high-risk cytogenetics (HRCy) (6% vs 32%, P=0.024), had lower peripheral blasts (PB) (17% vs 25%), and more pronounced neutropenia (0.4 vs 1.0 k/microL). Patients with SMC1A-mt AML had similar CCR rates to wt (OR 1.71, 95%CI 0.56 to 5.88). On MV-LR, patients with SMC1A-mt AML were more likely to achieve a cytogenetic response compared to wt (86% vs 57%, P=0.034). SMC1A was associated with similar OS (HR 1.05, 95%CI 0.56 to 1.92) and EFS (HR 0.96, 95%CI 0.52 to 1.77) compared to wt. 12-month OS and EFS were 59% and 35%, respectively, for SMC1A-mt AML. Patients with SMC3-mt AML, compared to wt, were less likely to have HRCy (7% vs 31%), had lower PB (21% vs 25%), and higher average leukocytosis (18 vs 6 k/microL). On MV-LR, patients with SMC3-mt AML had similar CCR rates compared to wt (OR 0.59, 95%CI 0.18 to 1.94). SMC1A was associated with similar OS (HR 1.38, 95%CI 0.70 to 2.72) and EFS (HR 1.08, 95%CI 0.55 to 2.12). 12-month OS and EFS were both 50% for SMC3-mt AML. Patients with RAD21-mt AML, compared to wt, were less likely to have HRCy (0% vs 31%), had higher PB (29% vs 25%), and lower platelet counts (37 vs 55 k/microL). On MV-LR, patients with RAD21-mt AML had higher CCR rates compared to wt (OR 1.67, 95%CI 0.40 to 8.61). RAD21 was associated with improved OS (HR 0.75, 95%CI 0.31 to 1.83) and EFS (HR 0.92, 95%CI 0.41 to 2.07). 12-month OS and EFS were both 56% for RAD21-mt AML. Patients with STAG2-mt AML, compared to wt, were less likely to have HRCy (11% vs 33%, P=0.002), less likely to have mutated TP53 (2.4% vs 20%, P=0.005), and had more pronounced leukopenia (2 vs 7 k/microL, P=0.002). On MV-LR, patients with STAG2-mt AML had similar CCR rates compared to wt (OR 0.84, 95%CI 0.41 to 1.72). STAG2 was associated with no change in OS (HR 0.99, 95%CI 0.67 to 1.45) or EFS (HR 1.0, 95%CI 0.68 to 1.45). 12-month OS and EFS were 48% and 35%, respectively, for STAG2-mt AML. Conclusion: In our large cohort of patients with AML, cohesin complex gene mutations had diverse clinical presentations and variable impacts on treatment response and survival outcomes. RAD21 showed a trend towards higher OS, and RAD21 and SMC1A showed a trend towards higher EFS. Interestingly, SMC1A-mt AML was associated with superior cytogenetic responses compared to wt. Given the variable clinical outcomes in cohesin-mutated AML, capitalizing on the understanding of the possible impact of targeted therapies on this pathway may have significant prognostic implications.