EACR25-0515

Fuelling the fight: The Impact of a Ketogenic Diet on Chemotherapy-induced DNA damage in Acute Leukemia

G. Rajakumar1,2, M. Lasta Cagigas1,3, T. Pelaia4, R. Hayward5, K. Skarratt5, A. Ardjmand5, L. Fontana6,7,8, S. Fuller1,9
1Nepean Clinical School, The University of Sydney, Faculty of Medicine and Health, Sydney, Australia
2Charles Perkins Centre, The University of Sydney, Faculty of Medicine and Health, Sydney, Australia
3Faculty of Medicine and Health, Sydney,
4University of Sydney, Faculty of Engineering, Sydney, Australia
5Nepean Clinical School, University of Sydney, Faculty of Medicine and Health, Sydney, Australia
6Charles Perkins Centre, University of Sydney, Faculty of Medicine and Health, Sydney, Australia
7Department of Endocrinology, Sydney, Australia, Brescia University School of Medicine
8Department of Clinical and Experimental Sciences, Bresca, Italy,
9Department of Haematology, Sydney, Australia,
Introduction:

Acute Myeloid leukemia (AML) is an aggressive bone marrow malignancy that requires chemotherapy treatment. However, about 50% of patients relapse, due to the ability of leukemic cells to proliferate despite dysfunctional DNA damage repair mechanisms, coupled with resistance to apoptosis and escape from immune surveillance. Additionally, dysfunctional leukemia cells and chemotherapy toxicity compromises the immune system, frequently resulting in life-threatening infections. Preclinical data from multiple cancer models suggest that ketogenic diets (KD) administered as an adjuvant to chemotherapy can reduce cancer cell proliferation, increase apoptosis, and deprive cancer cells of glucose. Aim: (1) To examine the effects of a KD administered during chemotherapy on markers of apoptosis and DNA damage and repair in leukemic cells from patients with AML. (2) To evaluate the impact of a KD on glucose levels and infections during chemotherapy and the following period of neutropenia.

Material and method:

Leukemic cells were isolated from the peripheral blood of patients with AML participating in a KD study. Participants were randomized to receive a control diet (n = 6) or a KD (n = 10) during chemotherapy. Samples were collected before, during, and after treatment. Apoptosis and DNA damage and repair were assessed using flow cytometry. Blood glucose and infections were measured.

Result and discussion:

The KD group had stable glucose levels during treatment, while the control group had high and unstable levels. Preliminary data showed a trend toward reduced infection rates during hospitalization with the KD (~20-40% reduction). During chemotherapy, the KD group showed lower levels of DNA repair markers (Chk1 p317, p<0.01 and p-ATM, p<0.01) in leukemic cells, despite similar levels of DNA damage markers (yH2AX, p=0.31) and no significant differences in apoptosis between the groups. The control group showed a decrease in DNA repair markers (p-ATM) in non-malignant T-cells from baseline to post-chemotherapy (p<0.01), while the ketogenic group showed a trend toward an increase (p=0.23).

Conclusion:

A KD administered as an adjuvant to chemotherapy in patients with AML may protect against infection and chemotherapy-induced T-cell damage by enhancing DNA repair, while potentially limiting DNA repair in leukemic cells. Further clinical and mechanistic studies in larger cohorts are warranted.