Safety and Feasibility of a 16-Week Progressive Exercise Intervention in Treatment Naïve Chronic Lymphocytic Leukaemia
Authors: Brown Frankie F , Oliver Rebecca , Causer Adam J , Collier-Bain Harrison D , Emery Annabelle , Eddy Rachel , Dutton David , Crowe Josephine , Augustine Daniel , Graby John , Rees Dan , Rothschild Rodriguez Daniela , Peacock Oliver , Moore Sally , Murray James , Turner James E , Campbell John P 
Published: December 2023

A growing body of evidence from preclinical and human epidemiology studies of multiple cancer types indicate that physical activity can delay or avert the outgrowth of cancer, in a mechanistic process that may involve exercise-induced alterations to anti-cancer immunity. Many Chronic Lymphocytic leukaemia (CLL) patients present with asymptomatic, early-stage disease that is monitored until disease progression. Thus, exercise may be an effective way to manage disease burden and delay progression in treatment naïve CLL. The primary objective of this pilot study was to investigate the safety and feasibility of an exercise programme in people with treatment naïve CLL, and preliminarily explore the effects of exercise training on CLL counts, body composition, cardiorespiratory fitness, and immune cell phenotypes including T-cells.

We approached N = 100 treatment naïve CLL patients (Binet stage A and B) (Figure 1). Trial uptake was 40%, thus n = 40 participants with treatment naïve CLL were screened. After assessing suitability for exercise (e.g., resting electrocardiogram and other safety tests), n = 11 participants were excluded - the majority of these, n = 9, were due to the presence of cardiac abnormalities. Consequently, n = 28 participants were randomised into a 16-week, home-based, supervised, personalised, progressive exercise intervention ( n = 14: mean ± SD: age = 62 ± 12 years) or 16-weeks of usual care, control group ( n = 14: mean ± SD: age = 61 ± 10 years). The overall retention rate was 86%, with 79% of the exercise group and 93% of the control group completing the trial. Adherence to the exercise intervention was 92 ± 8%. One serious adverse event was reported (hospitalisation for pneumonia) that was unrelated to the trial and one adverse event was reported (syncope following exercise) that was related to the trial. Together, this evidence indicates that exercise training is both safe and feasible in people with treatment naïve CLL who passed pre-trial screening.

The exercise intervention elicited a 2% increase in DEXA-derived lean mass in the exercise group compared to a 0.4% decrease in the control group ( p = .01) (Table 1). DEXA-derived total body fat percentage decreased by 4% and 1% and fat mass decreased by 3% and 2% ( p &lt; .05) respectively in the exercise and control groups but there was no significant difference between the groups ( p &gt; 0.05). Resting systolic and diastolic blood pressure was lower at post-intervention in both groups ( p &lt; .05); the exercise group reduced systolic and diastolic blood pressure by 5% and 2% respectively and the control group reduced by 6% and 7% respectively, but there was no significant difference between groups ( p&gt;0.05) suggesting the observed changes could be the result of “white coat hypertension” pre-intervention. Additionally, no changes were observed for whole-body mass, BMI, bone mineral density, resting heart rate, or measures of cardiorespiratory fitness (all p&gt;0.05).

This trial provided a unique opportunity to investigate the effects of regular exercise on neoplastic activity in humans (i.e., CLL counts) without the confounding presence of anti-cancer therapy. Resting blood samples collected pre- and post-intervention were analysed by flow cytometry to enumerate CD5 +CD19 + CLL cells clonally restricted to kappa or lambda. No differences were observed for clonal CLL cells over time or between conditions ( p&gt;0.05) (Table 1). We also analysed resting blood samples collected pre- and post-intervention by flow cytometry to enumerate T cell subsets. No statistically significant changes were observed between conditions pre-intervention to post-intervention for CD4 + or CD8 + T-cell subsets including, naïve (CD27 +CD45RA +), stem cell-like memory (CD27 +CD45RA +CD127 +CD95 +), central memory (CD27 +CD45RA -), effector memory (CD27 -CD45RA -), EMRAs (CD27 -CD45RA +) or exhausted T-cells (PD1 +, Tim3 +) or FoxP3 T-regulatory cells (CD4 +CD127 lowCD25 +FoxP3 +) (all p&gt;0.05).

Our results show that exercise is safe and feasible in people with treatment naïve CLL who passed pre-trial screening. In addition, exercise training increased lean mass. No changes were observed to CLL cells. The latter finding is unsurprising given the poorly immunogenic profile of CLL.