Rebalancing systemic and cellular energy dysmetabolism in Chronic Lymphocytic Leukemia through exercise training

Introduction : Chronic lymphocytic leukaemia (CLL) cells abnormally express lipoprotein lipase (LPL), an enzyme typically restricted to adipocytes and myocytes for lipid-mediated energy utilisation. This enables CLL cells to store and utilise lipids, potentially competing with or diverting resources from healthy tissues. In vitro studies suggest that reducing fatty acid availability may limit CLL proliferation; however, little is known about how patients can modulate this process in vivo . Exercise training offers a systemic, non-pharmacological approach to counter metabolic dysregulation, with potential benefits for tumour control and overall health. Methods : We conducted a 12-week exercise trial involving five treatment-naive (TN-CLL) and five previously treated (Td-CLL) patients. We assessed the metabolic fate of ingested lipids before (Baseline) and after (Post-Intervention) the program. Patients consumed a meal containing 200mg palmitic acid tracer ( 13 CPA), and blood samples were collected hourly for 3 hours (T 0h -T 3h ). We assessed 13 CPA enrichment in plasma triacylglycerol (TAG) and non-esterified fatty acids (NEFA), and total fatty acids in immune cells (PBMC) using mass spectrometry, and data were analysed using RM-ANOVA. Results : Post-meal ingestion, 13 CPA enrichment in plasma TAG and NEFA increased steadily from T 1h -T 3h (p<0.001). At Baseline T 3h , TN-CLL exhibited higher plasma 13 CPA-TAG and unlabelled PA-TAG incorporation than Td-CLL (p<0.001). Post-Intervention T 3h , TN-CLL 13 CPA-TAG levels decreased (p<0.05) and were no longer significantly different than Td-CLL. TN-CLL 13 CPA-NEFA enrichment increased post-Intervention compared to Td-CLL (p<0.05), suggesting enhanced 13 CPA-TAG hydrolysis. Similarly, 13 CPA uptake into PBMCs, which was higher in TN-CLL at Baseline T 3h (p<0.05), reduced Post-intervention. Conclusion : This pilot study demonstrates the feasibility of stable isotope tracing to assess in vivo lipid uptake in CLL. Exercise training in TN-CLL patients reduced lipid uptake, suggesting a shift towards a more balanced and healthier metabolic profile. Further research is needed to determine whether exercise can disrupt the lipid dependence of CLL cells.