Glucose-6-phosphate dehydrogenase deficiency is associated with improved survival in patients with acute myeloid leukemia treated with venetoclax and azacitidine.

[BACKGROUND] Glucose-6-phosphate dehydrogenase (G6PD) deficiency impairs cellular redox balance through reduced NADPH production and is the most common enzymatic disorder-causing anemia. Venetoclax combined with azacitidine (Ven-Aza) targets leukemic stem cells by disrupting oxidative phosphorylation and inducing mitochondrial stress. This study hypothesized that G6PD deficiency may enhance the efficacy of Ven-Aza in acute myeloid leukemia (AML) by reducing leukemic cell metabolic resilience.

[METHODS] The authors studied 73 consecutive patients with newly diagnosed (ND) AML treated with Ven-Aza. G6PD activity was systematically assessed at diagnosis in all patients and categorized as normal (n = 47), borderline (n = 11), or deficient (n = 15).

[RESULTS] Composite complete remission rates were 93% in the G6PD deficient group versus 69% in the normal/borderline group (p = .03). Patients with G6PD deficiency had a significantly longer median overall survival (23.8 months; 95% confidence interval [CI], 8.9-38.7), as compared to 8.96 months (95% CI, 2.9-15.0) in the normal/borderline group (p = .034). In multivariate analysis, G6PD-deficiency was associated with improved survival as compared to patients with normal G6PD activity (hazard ratio, 0.417; 95% CI, 0.181-0.965, p = .043). No significant differences were observed across groups in rates of febrile neutropenia, pneumonia, sepsis, or grade 3-4 cytopenia.

[CONCLUSION] G6PD deficiency is associated with higher response rates and improved survival in patients with ND-AML treated with Ven-Aza. These findings support G6PD deficiency as a potential biomarker of therapeutic sensitivity to Ven-AZA and may uncover metabolic vulnerabilities in AML with potential therapeutic implications.