Gene Mutations Linked to Adverse Outcomes in AML/MDS

New research strengthens a possible link between genetic mutations and clinical outcomes in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), according to a study published in Haematologica.¹

The BCL6-corepressor gene (BCOR) is a tumor-suppressor gene located on the X chromosome. Several previous studies have revealed an association between somatic BCOR mutations and AML. However, the study authors were concerned that BCOR-mutated AML and MDS have generally been studied in combination with other gene mutations, so outcomes for these patients could not be evaluated. Moreover, research into BCOR-mutated AML/MDS has been limited by small sample size. Evidence suggests that only about 5% of patients with myeloid neoplasms have a mutation in BCOR.

They wanted to better understand the impact of the BCOR mutation in patients with AML and MDS, which led them to conduct a large, single-institution retrospective analysis.

An enhanced image of a genetic mutation

Image credit: lya - stock.adobe.com

“Our research aimed to evaluate the genetic and clinical features, and factors predicting outcomes of patients with BCOR-mutated acute myeloid leukemia and myelodysplastic syndrome,” the authors wrote

They began by identifying patients with World Health Organization–defined myeloid neoplasms, including AML and MDS, with a BCOR mutation on next-generation sequencing (NGS) performed between October 2015 and August 2021 on peripheral bone or bone marrow aspirate. Patients were entered into the study at the time of NGS testing. They then reviewed patient demographics, disease characteristics at time of diagnosis and NGS testing, comutations, treatment-related variables, and survival outcomes. Because the BCOR gene is located on the X chromosome, the variant allele frequency of the BCOR mutation was gender adjusted.

Ninety-nine patients with BCOR-mutated myeloid disorders were identified: 36 (36.4%) patients with AML and 63 (63.6%) patients with MDS. Their median age was 71.5 years, and 70.7% were male patients. A control group consisted of 155 patients with AML, 105 patients with MDS, and 15 others; the median age at study entry was 65 for participants with AML and 74 years for MDS. A total of 153 patients (58.8%) were male patients.

Disease risk stratification for patients with AML showed 1 (2.8%), 14 (38.9%), 19 (52.8%), and 2 (5.6%) patients had favorable, intermediate, adverse, or missing risk, respectively. Among patients with MDS, 43 (68.3%) had intermediate or higher risk by International Prognostic Scoring System (IPSS-R), 20 (31.7%) had MDS-IB1 (increased blasts of 5%-9% in bone marrow or 2%-4% in peripheral blood), and 23 (36.5%) had MDS-IB2 (10%-19% in bone marrow, 19% in peripheral blood, or presence of Auer Rods in blasts).^1,2 Survival outcomes were calculated from timepoint of study entry, unless mentioned otherwise.

Thirty patients underwent allogenic stem cell transplant (alloSCT) after study entry: 10 (33%), 17 (56.7%), 2 (6.7%), and 1 (3.3%), had AML, MDS, myeloproliferative neoplasms, and chronic myelomonocytic leukemia, respectively. At the time of transplant, 15 (55.6%) patients were in complete remission, 11 (40.7%) had persistent disease, and disease status was not known for 1 patient. Their median age was 65.6 years.

The investigators also assessed post-alloSCT outcomes. Median follow-up time after alloSCT was 2.5 years (95% CI, 1.8-4.0 years). Melphalan-based conditioning decreased relapse risk (HR, 0.02; 95% CI, 0.001-0.40; P = 0.01), while RUNX1 comutation increased risk of posttransplant relapse (HR, 88.0; 95% CI, 1.98-3918; P0.02). The survival rate at 3 years was 61.1%.

Most study patients (96.4%) had a single BCOR mutation. However, the researchers identified 144 BCOR variants. BCOR-mutated MDS/AML was highly associated with RUNX1 and U2AF1 comutations.

With regards to overall survival (OS), the authors highlighted these findings:

• Median survival for the entire cohort was 15 months
• Survival was lower in patients with AML compared with MDS, but the difference was not statistically significant
• Complex karyotype and age 70 years or older were associated with worse survival
• Patients with a BCOR mutation had similar survival regardless of the presence of additional high-risk comutations
• The median OS from diagnosis among patients with NGS at diagnosis was similar to those who had NGS performed after treatment

Lastly, the results indicate that 8 (29.6%) deaths were reported within 3 years after transplant; 3 patients died after disease relapse and 5 deaths were attributed to nonrelapse mortality (NRM). The cumulative incidence of NRM was 32.7% and relapse incidence 3 years after transplant was 24.1%. There was no significant difference in 3-year NRM and relapse in patients with AML or MDS.

This study had several limitations. Given the rarity of BCOR mutations, small sample size will be a limitation of any single-institutional study, the authors explained. Additionally, NGS testing was done at different timepoints.

Still, the authors believe theirs may be the largest study specifically evaluating the impact of the BCOR mutation across patients with AML and MDS.

“Our study shows that patients with [BCOR-mutated] AML/MDS have poor prognosis, and it was seen across all subgroups of patients,” the authors stressed. “However, our study also confirms that alloSCT is associated with improved outcomes,” they said. “These patients should be evaluated for alloSCT at the earliest convenience,” the authors concluded.

References

1. Baranwal A, Gurney M, Basmaci R, et al. Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms. Haematologica. Published online February 1, 2024. doi:10.3324/haematol.2023.284185
2. Foster M. Myelodysplastic syndromes staging. Medscape. November 3, 2022. Accessed February 28, 2024. https://emedicine.medscape.com/article/2007806-overview?form=fpf