Exercise and Chronic Lymphocytic Leukemia (CLL) - Relationships Among Physical Activity, Fitness, & Inflammation, and Their Impacts on CLL Patients

Introduction Exercise has potent immune enhancing and anti-inflammatory effects in healthy adults, and is increasingly recognized as a beneficial adjunct to cancer care. Increased maximal aerobic fitness (VO_2peak) is a gold standard measure that predicts better outcomes in patients with breast, prostate, and brain cancer. However, in patients with chronic lymphocytic leukemia (CLL), little is known regarding the physiologic and immune/inflammatory impact of physical fitness. GlycA is a recently identified robust inflammatory biomarker that is associated with increased risk for cardiovascular disease, all-cause mortality, diabetes, and is an independent predictor of colorectal cancer outcomes. Further, GlycA levels can be reduced by exercise training. We postulated that GlycA can serve as a marker of disease-associated inflammation and physical fitness in CLL. Our objectives were 1) to determine the feasibility of measuring physical activity and fitness in CLL patients during a standard clinical visit, and 2) to evaluate the associations between physical fitness, chronic inflammation assessed by GlycA levels, and hematologic parameters in untreated CLL patients.

Methods During a routine clinical visit, CLL patients completed the validated activity surveys "Incidental and Planned Activity Questionnaire" (IPAQ) and the age-defined "Stanford Brief Activity Survey" (SBAS). Physical function was assessed in a subset of patients by determining grip strength, 6 minute walk test (6MWT), and the short physical performance battery (SPPB). Predicted aerobic fitness (VO_2peak) was calculated from a validated algorithm using the 6MWT, age, body weight, resting heart rate, and gender. Complete blood counts with leukocyte differentials, plasma GlycA, and VO_2peak function were assessed in all untreated patients who had physical function testing. Given the heterogeneity of CLL, reporting of relationships with VO_2peak, function, and GlycA will focus on treatment naïve patients. We used linear regression and Spearman's correlations to determine relationships among outcomes.

Results The IPAQ and SBAS surveys both had 90% validity and full completion (n = 141, see table 1 for details). Activity results from all patients were 60% to 70% of age-predicted normative values. Specifically, 48% of patients were inactive or engaged in light activities and 28% moderate intensity activities (by SBAS), with 0 to 129 hours/week of total incidental and planned activity (by IPAQ). The surveys were positively associated with each other (r=0.303, p<0.001).

In a 5-month period, 108 patients completed physical fitness testing. The distance covered in the 6MWT was 464±99 meters, grip strength was 35±14 kg, SPPB was 10.8±1.8 (range 4 - 12), and predicted VO_2peak was 29±6 mL/kg/min. VO_2peak was 64±13% of normative values, and this was positively associated with the SPPB (r=0.336, p<0.001) and SBAS (r=0. 416, p<0.001).

After controlling for age and body mass index in untreated patients who completed physical fitness testing (n=40), higher VO_2peak was significantly associated with lower levels of GlycA (r=-0.474, p=0.002), and a lower neutrophil: lymphocyte ratio (r=-0.397, p=0.012). Higher GlycA was associated with higher neutrophil counts (r=0.592, p<0.001). Higher VO_2peak was significantly associated with lower platelet counts (r=-0.471, p=0.002), but not with lymphocyte counts (r=0.294, p=0.066), neutrophil counts (r=-0.216, p=0.186), or hemoglobin (r=0.133, p=0.402).

Conclusion We found that assessing the physical activity and fitness of CLL patients in a clinical setting is feasible. The majority of CLL patients were less active than age-matched normal individuals, and that higher aerobic fitness was associated with lower GlycA, supporting recent findings that GlycA is associated with physical activity levels. Since GlycA is a marker for inflammation, this supports that physical activity may lower clinically relevant inflammation in CLL patients. Regardless of the absolute lymphocyte count, if patients were more physically fit, there was no evidence of inflammation as defined by elevated GlycA and neutrophil count. In summary, we demonstrated that many untreated patients with CLL are physically inactive and have relatively high levels of inflammation by GlycA. Further work will determine if exercise intervention in CLL patients will improve their CLL disease severity and long-term health.

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