Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms

Abstract

The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data are limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 co-mutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria (median OS 1.16 vs. 1.27 years, P=0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P<0.001), while allogeneic stem cell transplant (alloSCT) improved survival (HR 0.38, P=0.04). However, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse (HR 88.0, P=0.02), whereas melphalan-based conditioning was associated with a decreased relapse risk (HR 0.02, P=0.01). We conclude that mBCOR is a high-risk feature across MDS/AML, and that alloSCT improves survival in this population.

Figure 1.

Genomic landscape of patients with BCOR mutations. (A) Oncoplot of patients with BCOR mutation; top 15 mutated genes are shown. (B) Top 10 genes with highest median variant allele frequency. (C) Lollipop plot showing various mutations across the BCOR gene. Mutations were most commonly frameshift or nonsense, and spread across the entire gene, without a specific hotspot region. (D) Specific cytogenetic abnormalities stratified by diagnoses: acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or others. Approximately half of the patients had normal karyotype, whereas complex karyotype or chromosome 17 abnormalities were seen in only a minority of patients. (E) Association of BCOR mutation with other genes among patients with MDS and AML. CK: complex karyotype; MK: monosomal karyotype; Ab: abnormal; Chr: chromosome; Diag: diagnosis; Mono: monosomy; N: number; NGS: next-generation sequencing; S: significant (P<0.05); T: trend (0.10 > P≥0.05; NS: not significant (P≥0.10); NA: not applicable.

Figure 2.

Clinical outcomes of patients with BCOR-mutated acute myeloid leukemia or myelodysplastic syndromes. Kaplan-Meier plots for survival since time of BCOR mutation (mBCOR) detection stratified by (A) disease type, (B) complex karyotype at next-generation sequencing (NGS), (C) age at NGS, and (D) presence/absence of high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria. (E and F) Overall survival of patients with mutated (m)BCOR versus wild-type (wt)BCOR, stratified by ELN 2017 risk category. Adv: adverse risk; AML: acute myeloid leukemia; Fav/Int: favorable / intermediate; MDS: myelodysplastic syndromes.

Figure 3.

Multivariate analysis of factors affecting post-next-generation sequencing survival in patients with mutated BCOR. adj: adjusted; HR: Hazard Ratio; NGS: next-generation sequencing; VAF: variant allele frequency.

Figure 4.

Outcomes of patients with BCOR-mutated acute myeloid leukemia / myelodysplastic syndromes undergoing allogeneic stem cell transplantation. (A) Overall survival after allogeneic stem cell transplantation (alloSCT). Follow-up data available in 26 patients. (B) Competing risk analysis showing cumulative incidence of non-relapse mortality (NRM) and relapse after alloSCT. (C). Multivariate competing risk analysis for relapse incidence at three years after alloSCT showing an overall adverse effect of RUNX1 mutation and a positive effect of melphalan-based conditioning. AML: acute myeloid leukemia; HR: Hazard Ratio; MDS: myelodysplastic syndromes.

Figure 5.

Factors influencing post-allogeneic stem cell transplantation survival in patients with mutated BCOR acute myeloid leukemia / myelodysplastic syndromes. Overall survival after allogeneic stem cell transplantation (alloSCT) stratified by: (A) disease type, (B) complex karyotype. (C) Multivariate analysis for 3-year post-alloSCT survival. AML: acute myeloid leukemia; HR: Hazard Ratio; MDS: myelodysplastic syndromes.