Evaluating the effects of a Ketogenic Diet on chemotherapy-induced DNA damage, Cellular Senescence, Apoptosis and chemotoxicity in Acute Myeloid Leukaemia (AML) patients.

Abstract

Introduction: Acute myeloid leukaemia (AML) is an aggressive blood cancer typically treated with intensive chemotherapy, which non-selectively damages healthy tissues, causing severe side effects. Key treatment challenges include infections, resistance, and relapse, driven by immune-metabolic dysfunction and disrupted DNA damage response (DDR), apoptosis, and senescence. Ketogenic diets (KDs), which reduce glucose availability and enhance immunity, have shown promise in preclinical cancer models, but their role in AML remains unclear.

Aim: This first-in-human study investigates the effects of a KD alongside chemotherapy in newly diagnosed AML patients. It also explores DDR, apoptosis, and senescence- molecular drivers of disease and immune evasion.

Methods: A systematic review/meta-analysis assessed KD effects on insulin-like growth factor 1 (IGF-1), insulin, and glucose. A pilot randomised clinical trial was then conducted in AML patients receiving induction chemotherapy, comparing standard care vs. a KD. Glucose, ketones, and adverse events were monitored. Peripheral blood mononuclear cells were analysed via flow cytometry for DDR (γH2AX, ATM, p-ATM, 53BP1, CHK1 p317), apoptosis (Annexin V/PI), and senescence (p16, p21).

Results: The meta-analysis showed KD reduced IGF-1 by 19.7%, insulin by 29%, and glucose by 6%. KD patients had more stable glucose and elevated ketones during treatment. KD did not affect remission rates. AML blasts from KD patients showed significantly lower DDR markers p-ATM and CHK1 p317. No differences were seen in γH2AX, 53BP1, or ATM. Apoptosis and senescence in blasts were unaffected. In T-cells, KD reduced apoptosis and maintained p-ATM levels during/after chemotherapy.

Conclusion: KD was safe and did not impair remission. It modulated DDR signaling in AML blasts and T-cells, suggesting a dual role—suppressing pro-survival pathways in cancer while protecting immune function. Larger studies are needed to further explore these findings.