G6PD Deficiency Linked to Better Outcomes in Ven-Aza–Treated Patients With AML

An observational study recently published in Cancer highlights a notable correlation between glucose-6-phosphate dehydrogenase (G6PD) deficiency and improved clinical outcomes among patients with acute myeloid leukemia (AML) treated with venetoclax (Venclexta) plus azacitidine (Vidaza) (ven-aza).¹

The retrospective study, conducted at Rabin Medical Center in Israel, aimed to investigate a hypothesis that decreased activity of G6PD, the rate-limiting enzyme of the pentose-phosphate pathway (PPP), may enhance sensitivity to venetoclax-based therapy. Given that venetoclax induces apoptosis through BCL-2 inhibition and mitochondrial priming, investigators postulated that impaired NADPH production in G6PD-deficient cells could exacerbate oxidative damage and augment therapeutic response.

The study analyzed a cohort of 73 adult patients with newly diagnosed AML who received ven-aza as first-line therapy, 20.5% of whom were G6PD-deficient, 15.1% considered borderline deficient, and the remaining 64.4% having normal G6PD activity.

Findings: Enhanced Response and Survival

The analysis found that patients with G6PD deficiency experienced significantly improved response and survival outcomes compared with those with normal or borderline G6PD activity.

Patients with G6PD deficiency achieved higher response rates, with a composite complete remission rate of 93% vs 69% in the normal/borderline group. In addition to deeper remissions, G6PD-deficient patients saw superior survival outcomes compared with patients with normal activity (HR, 0.417; 95% CI, 0.181-0.965; P =.043).

The findings underscore a compelling biologic link at the intersection of metabolic processes and therapeutic efficacy, supporting G6PD deficiency as a potential biomarker of therapeutic response to ven-aza, according to authors Buchrits et al.

“Our findings highlight the potential role of metabolic vulnerabilities in modulating treatment response in AML and provide a novel clinical marker to predict response and survival,” they wrote.¹

Clinical Implications for AML Management

Ven-aza, initially approved by the FDA in 2018 for treatment of AML in patients aged 75 and older,² became the standard of care for older patients or those ineligible for intensive chemotherapy following the landmark phase 3 VIALE-A trial (NCT02993523). While ven-aza demonstrated superior outcomes over azacitidine monotherapy in the trial,³ identifying which patients will achieve durable responses remains a persistent challenge in clinical practice.

The study raises the question of whether G6PD testing—already a routine and inexpensive assay—should be integrated into the prognostic workup for all patients with AML starting venetoclax-based regimens. Furthermore, the data suggest that pharmacologic inhibition of G6PD or other nodes of the PPP could potentially be used as a sensitizing strategy for patients with normal enzyme activity, though this would require careful management to avoid systemic toxicity.

REFERENCES

1. Buchrits S, Rozental A, Korngold N, et al. Glucose‐6‐phosphate dehydrogenase deficiency is associated with improved survival in patients with acute myeloid leukemia treated with venetoclax and azacitidine. Cancer. 2026;132(3). doi:10.1002/cncr.70265

2. FDA approves venetoclax in combination for AML in adults. News release. US FDA. Updated December 14, 2018. Accessed February 11, 2026. https://tinyurl.com/bder6wpn

3. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Eng J Med. 2020;383(7):617-629. doi:10.1056/nejmoa2012971