Characteristics and Outcomes of Patients with BCOR Mutated Myeloid Neoplasms

Introduction: The BCL6 corepressor (BCOR) is a tumor suppressor gene located on chromosome X at the Xp11.4 locus. Approximately 5% of patients with myeloid neoplasms (MN) have a mutation in the BCOR gene (mBCOR). The updated WHO guidelines recommend considering the presence of mBCOR in patients with ≥20% bone marrow blast percentage, as a defining feature of AML, myelodysplasia related (AML-MR). However, the impact of mBCOR on characteristics and treatment outcomes of patients with mBCOR across the spectrum of myeloid neoplasms (MN) has not been studied.

Methods: After IRB approval, patients with pathogenic mBCOR were identified. Disease characteristics and treatment outcomes were reviewed for patients with MDS or AML. Risk stratification of AML and MDS was done using European Leukemia Network 2017 (ELN 2017) and revised-international prognostic scoring system (IPSS-R), respectively. Kaplan-Meier and log-rank methods were used to evaluate overall survival (OS). Cox-proportional hazard was used for multivariate analysis for overall survival at 5 years. Variables with P < 0.1 were included in the multivariate analysis.

Results: A total of 122 patients (83, 68% males) were found to harbor a pathogenic mBCOR. Thirty-one (25.4%) had AML, 55 (45.1%) had MDS, 11 (9%) had a myeloproliferative neoplasm, and 5 (4.1%) had aplastic anemia. Median age at diagnosis was 69 years (IQR: 63-77 years) with a median hemoglobin of 9 g/dL (IQR 8-10.9 g/dL), median neutrophil count 0.99x10⁹ cells/L (IQR 0.31-2.15 x10³), and median platelet count 80x10⁹ /L (IQR 40-129). Median OS after diagnosis was 2.5 years (95% CI: 1.91-3.12) for the entire cohort, 2.6 years (95% CI 1.91-3.56) for patients with MDS and 1.1 years (95% CI 0.69-3.75 years) for patients with AML. Median variance allele frequency (VAF) of mBCOR was 34.5% (IQR 17.25-59.75%). Only five (4%) patients were found to have two mBCOR. The most common were frameshift mutations (70, 57.4%), followed by nonsense (38, 31%) and splice-site mutations (13, 10.7%). The most common co-mutations associated with the BCOR mutation were RUNX1 (43, 35.2%, patients), U2AF1 (35, 28.7%), DNMT3A (30, 24.6%), and ASXL1 (27, 22.1%, patients).

Among patients with AML (median age: 68 years (IQR: 65-81 years)), 1 (3.4%) had favorable risk, 13 (44.8%) had intermediate risk disease and 15 (51.7%) had adverse risk disease. There was no difference in OS among patients with favorable or intermediate risk disease compared to those with high-risk disease (median OS 1.5 vs. 0.7 years, P = 0.4).

Among the 55 patients with MDS (median age: 70 years (IQR: 65-77 years)), 20 (37%) had MDS-EB2 and 15 (27.8%) had MDS-EB1. Eleven patients (20%) had low or very low risk disease, 13 (23.6%) had intermediate risk disease, and 25 (45.5%) of patients had high or very-high risk disease by IPSS-R. The median OS was 4.9 years among those with very low or low risk disease vs. 2.9 years among those with intermediate risk disease and 1.6 years among those with high or very high-risk disease (P = 0.02). OS was not significantly different among patients with AML compared to those with MDS-EB (median OS 1.1 vs. 1.9 years, P = 0.37) (Figure 1).

Thirty (24.6%) patients underwent allogeneic stem cell transplant (alloSCT) (median age 65 years, IQR: 57-68 years). Those who underwent alloSCT had significantly improved OS compared to those without alloSCT (3.8 vs. 1.5 years, P = .001). This improvement in survival was primarily seen among patients with AML (NA vs. 0.64 years, P = 0.0002) with a trend of improvement among patients with MDS (3.21 vs. 1.91 years, P = 0.12). Multivariate analysis showed that presence of KRAS (HR 6.71, 95%CI 1.43-31.50, P = 0.02) or complex karyotype (CK) (HR 3.6, 95%CI 1.04-12.41, P = 0.04) were associated with a significantly decreased survival, whereas alloSCT had a positive effect on survival (HR 0.28, 95%CI 0.13-0.60, P = 0.001) (Table 1).

Conclusions: Survival in mBCOR patients was similar regardless of MDS or AML phenotype at diagnosis. The presence of KRAS co-mutation and CK were associated with inferior survival. In contrast, alloSCT was associated with improved outcomes, with the impact being most notable in AML.

Shah:Astellas: Research Funding; Celgene: Research Funding; Marker Therapeutics: Research Funding. He:Kura Oncology, Inc: Consultancy. Mangaonkar:Bristol Myers Squibb: Research Funding. Patnaik:Kura Oncology, Stem Line Pharmaceuticals: Research Funding. Al-Kali:Astex: Other: research support to institution.