CUX1^mut Acute Myeloid Leukemia As a Distinct Biological Entity: An Analysis of Clinical Outcomes and Implications

1. Introduction

CUX1 is a tumor suppressor gene located on the long arm of chromosome 7. CUX1 mutations induce apoptosis evasion and are more commonly seen in therapy-related myeloid neoplasms. It is frequently mutated in myelodysplastic syndrome and less frequently in acute myeloid leukemia (AML). Preclinical investigations are ongoing to explore therapeutic approaches in CUX1-deficient leukemia cell lines. However, data on the clinical outcomes of patients with AML and mutated CUX1 are sparse. We aimed to characterize the biological and clinical outcomes of CUX1^mut AML.

2. Methods

We analyzed next-generation sequencing from 318 patients in the Project ERIS database with newly diagnosed AML treated from January 1, 2013 to April 18, 2023 at VCU Massey Comprehensive Cancer Center. We identified 12 patients with CUX1^mut AML and compared them to a cohort of 306 CUX1 wild-type historical controls. We recorded baseline patient-related and disease characteristics, including age, ECOG, Charlson comorbidity index (CCI) scores, molecular profiling and ELN 2022 cytogenetic risk, dates of regimen initiation, and survival. We used the D'Agostino & Pearson method for normality testing and the t-test or Mann-Whitney (as applicable) tests for between-group comparisons. Categorical comparisons used Fischer's exact test. We applied the Bonferroni correction if multiple comparisons were made. The Wilson-Brown method was used for 95% confidence intervals. We analyzed survival by the Kaplan-Meier method with significance determined by the log-rank test. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact.

3. Results

CUX1 mutations are found at a frequency of 3.9% (95% CI, 2.2-6.5) in AML. The median variant allele frequency of CUX1 mutations was 40.3% (range: 3.8-48.7), consistent with a heterozygous presentation. The median age at diagnosis of patients with CUX1^mut who received any anti-leukemic therapy was 57 years (range: 30-78 years), which was not significantly different from CUX1^wt at 65 years (range: 19-88, p = 0.312). Thirty-three (95% CI, 13.8-60.9) percent of patients had AML with myelodysplasia-related changes (AML-MRC) on the initial diagnostic bone marrow biopsy, compared with 29.2% (95% CI, 24.2-34.7, p=0.752) for CUX1^wt. CUX1^mut AML was found in cytogenetically normal specimens at a frequency of 30.0% compared with 49.3% for CUX1^wt (p = 0.337).

The most frequent cytogenetic abnormality in CUX1^mut AML was -7 (20.0%), followed by +8 (10.0%) and complex cytogenetics (10.0%). The most frequent cooperating molecular lesions were RUNX1, SRSF2, STAG2, FLT3-ITD, and NRAS (25.0% each). Patients with CUX1 mutations were nonsignificantly more likely to have ELN 2022 adverse-risk disease (odds ratio: 2.013, p = 0.379). In patients treated with intensive cytarabine-based inductions, the median overall survival was 26.3 months in the CUX1^mut group and 17.6 months in the CUX1^wt cohort, which was not significantly different (p = 0.501). Two patients with CUX1^mut AML were treated with first-line venetoclax and a hypomethylating agent. The overall survival was 12.7 months in one patient and not reached at a follow-up time of 20.2 months in the second.

4. Discussion

While definitive conclusions are limited by the rarity of the mutation, mutations in CUX1 are heterozygous and appear to be non-significantly more frequently associated with myelodysplastic-related changes and secondary-type mutations. These findings may explain a higher proportion of patients harboring CUX1 mutations that have ELN 2022 adverse-risk disease. While we did not detect any significant survival differences between patients with and without CUX1 mutations, larger cohorts are needed to confirm the prognostic impact of these rare mutations in AML.