Physiological Fitness and the Pathophysiology of Chronic Lymphocytic Leukemia (CLL)

Abstract

Chronic lymphocytic leukemia (CLL) is associated with physical dysfunction and low overall fitness that predicts poor survival following the commencement of treatment. However, it remains unknown whether higher fitness provides antioncogenic effects. We identified ten fit (CLL-FIT) and ten less fit (CLL-UNFIT) treatment-naïve CLL patients from 144 patients who completed a set of physical fitness and performance tests. Patient plasma was used to determine its effects on an in vitro 5-day growth/viability of three B-cell cell lines (OSU-CLL, Daudi, and Farage). Plasma exosomal miRNA profiles, circulating lipids, lipoproteins, inflammation levels, and immune cell phenotypes were also assessed. CLL-FIT was associated with fewer viable OSU-CLL cells at Day 1 (p = 0.003), Day 4 (p = 0.001), and Day 5 (p = 0.009). No differences between the groups were observed for Daudi and Farage cells. Of 455 distinct exosomal miRNAs identified, 32 miRNAs were significantly different between the groups. Of these, 14 miRNAs had ≤−1 or ≥1 log2 fold differences. CLL-FIT patients had five exosomal miRNAs with lower expression and nine miRNAs with higher expression. CLL-FIT patients had higher HDL cholesterol, lower inflammation, and lower levels of triglyceride components (all p < 0.05). CLL-FIT patients had lower frequencies of low-differentiated NKG2+/CD158a/bneg (p = 0.015 and p = 0.014) and higher frequencies of NKG2Aneg/CD158b+ mature NK cells (p = 0.047). The absolute number of lymphocytes, including CD19+/CD5+ CLL-cells, was similar between the groups (p = 0.359). Higher physical fitness in CLL patients is associated with altered CLL-like cell line growth in vitro and with altered circulating and cellular factors indicative of better immune functions and tumor control.

A pilot study of high-intensity interval training in older adults with treatment naïve chronic lymphocytic leukemia

“…That said, in women undergoing breast cancer therapy 38 or following therapy 39 , HIIT did not increase cardiorespiratory fitness. As such, CLL may have a yet unknown effect on the ability to promote large cardiorespiratory fitness changes and future studies should aim to determine the role of CLL on metabolic energy utilization central to cardiorespiratory fitness adaptation 40 .…”

Associations of clinical and circulating metabolic biomarkers with low physical fitness and function in adults with chronic lymphocytic leukemia

“…One potential mechanism of cancer cachexia is the hyperactivation and expression of LPL, which, if pharmaceutically reduced, modulates metabolic dysregulation, leading to solid tumor cachexia (51). Since CLL is a chronic, often slow-progressing cancer, it is plausible that some of the We also observed that treatment-naïve CLL patients with higher physical fitness levels have circulating blood factors that reduce the growth of a CLL-like cell line (21). Specifically, higher fitness was associated with higher HDL levels and lower triglyceride levels.…”

“…Following 12 weeks of aerobic plus resistance exercise training, we observed significant increases in CLL patients’ muscle strength, and these strength changes were associated with lower numbers of circulating CLL cells ( 52 ). We also observed that treatment-naïve CLL patients with higher physical fitness levels have circulating blood factors that reduce the growth of a CLL-like cell line ( 21 ). Specifically, higher fitness was associated with higher HDL levels and lower triglyceride levels.…”

“…We have described physical performance and fitness measures previously ( 21 ). Briefly, patients completed a short battery of standardized physical performance tests conducted by trained specialists.…”

“…We have described blood sampling and NMR assessments previously ( 21 ). Briefly, approximately 20 ml of blood was collected into vacutainers containing either EDTA or heparin as an anticoagulant.…”