Abstract
Background: Apolipoprotein E (APOE) exists in three major isoforms—ε2, ε3, and ε4—which differentially influence tumor immunity by modulating antigen presentation, macrophage and T-cell activation, thereby shaping the tumor microenvironment in an isoform-specific manner. In acute myeloid leukemia (AML), population-based data have reported an adverse impact of the ε2 allele among patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) (Blood. 2025 Apr 24;145(17):1943-1956). However, the prognostic role of APOE genotypes during the chemotherapy period—particularly in consecutively treated cohorts—remains unclear. This study aimed to assess the prognostic significance of APOE genotypes in older adults with AML who receiving chemotherapy.
Methods: We retrospectively analyzed 136 consecutive patients aged ≥60 years, diagnosed with AML and received chemotherapy, either intensive chemotherapy or hypomethylating agent (HMA) plus venetoclax (VEN) as initial treatment, between December 2021 and February 2025. Patients were categorized by APOE allelic status. Clinical variables, including age, Hematopoietic Cell Transplantation–Comorbidity Index (HCT-CI) at diagnosis, European LeukemiaNet (ELN) 2022 risk classification, and treatment type, were assessed. Associations between APOE allelic status and both overall survival (OS) and chemotherapy response based on ELN 2022 criteria were evaluated.
Results: Among the 136 patients, 18 (13.2%) carried at least one ε2 allele (E2 group), 87 (64.0%) were ε3 homozygotes (E3 group), and 31 (22.8%) carried at least one ε4 allele (E4 group). The median age at diagnosis was 69 years (Interquartile range, IQR, 64–74) in the E2 group, 69 years (IQR, 64–75) in the E3 group, and 68 years (IQR, 64–74) in the E4 group. Regarding ELN 2022 risk classification, adverse risk was reported in 44.4%, 47.1%, and 48.4% of patients, respectively. As initial therapy, intensive chemotherapy was administered to 6 patients (46.2%) in the E2 group, 43 patients (44.3%) in the E3 group, and 10 patients (38.5%) in the E4 group, with the remainder receiving HMA plus VEN. No baseline variable showed a statistically significant difference in distribution among the three groups.
During follow-up, the median OS was 15.6 months (95% confidence interval, CI, 12.0–25.4) in the E3 homozygous group, 23.1 months (95% CI, 11.8–Not achieved [NA]) in the E2 group, and 9.1 months (95% CI, 5.8–18.8) in the E4 group (log-rank p = 0.016). The E4 group had the shortest median OS, whereas the E2 group showed a comparable median OS with the E3 group. In multivariable analysis adjusted for age, HCT-CI, ELN 2022 risk classification, and treatment type, the hazard ratios for the E2 and E4 groups compared with the E3 group were 0.95 (95% CI, 0.43–2.11) and 1.89 (95% CI, 1.15–3.10), respectively.
Based on the survival analysis results, we examined whether APOE ε4 carriage was associated with differences in chemotherapy response. Among patients who received intensive treatment, composite complete remission (CCR) was achieved in 63.3% in the non-E4 group (E2 or E3) and in 36.4% in the E4 group, with a borderline significant difference (p = 0.097). In the HMA/VEN group, this difference was more pronounced: CCR as the best response was observed in 67.2% in the non-ε4 group, compared with only 31.3% in the ε4 group (p = 0.019).
Among patients who underwent allo-HSCT (n = 59), post-transplant median OS was 23.1 months (95% CI, 23.1–NA) in the E2 group, 21.2 months (95% CI, 9.6–NA) in the E3 group, and 4.1 months (95% CI, 1.94–NA) in the E4 group (log-rank p = 0.061). When analyzed by E4 carriage status, the E4 group demonstrated significantly inferior post-transplant survival compared with the non-E4 group (log-rank p = 0.02).
Conclusion: In this consecutively treated cohort of older adults with AML, APOE ε4 carriage was associated with inferior OS and lower chemotherapy response rates, contrasting with findings from population-based data and transplant-focused study. The consecutive cohort design reduced selection bias, enhancing the reliability of these observations despite the modest sample size. Among patients undergoing allo-HSCT, ε4 carriage also predicted worse post-transplant survival. While the results warrant cautious interpretation, APOE genotype—particularly ε4 status—may hold prognostic significance in both chemotherapy and transplant settings, supporting the need for validation in larger prospective studies.
