This systematic review sought to critically assess the available evidence on the relationship between physical activity (particularly HIIT and Resistance Training) and Chronic Lymphocytic Leukemia, regarding fitness, health-related quality of life and feasibility, and immunologic parameters. Only 6 papers met our search criterion, with 2 addressing the HIIT type of physical activity intervention.
Most of CLL studies were conducted throughout the last two decades, and before 2009 no intervention studies were reported, only observational using questionnaires and involving anthropometric parameters such as height, weight, waist and hip circumference, or the body mass index [42–44]. And because we are still in an early bird phase, many methodological problems are biasing results. An early meta-analysis in 2009, addressed resistance training in cancer survivors and displayed post training improvements in cardiopulmonary function from 6–39%, and increases in muscle strength between 11% and 110% [45]. We hypothesize this disparity may be explained by factors such as the contribution of learning effect, variability in strength exercises, intensities and duration of exercise programs, genetic differences, type and stage of cancer, diverse cancer treatments, the time elapsed since cancer diagnosis, etc. This shows the importance of knowing the progress path between sedentary behaviour and physical active behaviour, and the interconnection with patients physical active before and after diagnosis.
There is general agreement in the absence of adverse training effects on immunological, endocrinological, and hematopoietic variables, or lymphedema. Moreover, it seems that even high training intensities have been well-tolerated in cancer survivors [45].
A recent systematic review and meta-analysis confirmed that, in addition to clinical stage evaluation [46], the best practice to initial prognosis in CLL patients should include the CLL-IPI (chronic lymphocytic leukemia international prognostic index), which combines 5 parameters (age, clinical stage, TP53 status, IGHV mutational status and serum B2-microglobuli,) [47]. In the studies of our review, only Macdonald (2021) implemented CLL-IPI, while Artese (2022) and Courneya (2009) used Rai Staging.
The consistency of “best practice on evaluation” in the physical fitness evaluation is not met, leading to inconclusive data and poor strength evidence. Investigations until this date support intensive endurance exercise, known to induce lymphocyte apoptosis affecting the immune system [19]; regular resistance exercise, who can decrease oxidative stress which may lead to attenuate apoptosis related protein [20]; High-Intensity Interval Training (HIIT) suggesting that it may be able to delete mainly highly differentiated T cells, known to affect immunity to control latent infections [21]. However, for the same physical fitness outcomes, cardiovascular protocols differ in equipment (Treadmill or Recumbent Cycle ergometer), in intensity (90% VO2 reserve, or 90% HR reserve, or 65% Maximal Short Exercise Capacity, or HR maximal, or VO2 peak), on duration (20min interval training, 15-45min continuous, 30min continuous, 8min intervals), on recovery (60-90s active recovery, 30-60s active recovery, no recovery). Muscular protocols differ in resistance mode (major muscle groups using machines, or dumbbells, or calisthenic exercises), resistance intensity (70% of 1-RM for maximal repetitions, 80% of 1-RM for 6–8 repetitions, 65–80% 1-RM), duration of effort (2 sets of 10 repetitions, 2–3 sets of 6–8 repetitions, 2 sets of 20 repetitions), recovery (minimum of 90s between sets, or not described at all). For the goodness of proof, it is mandatory that gold-standard equipment’s are used, such as Isokinetic Dynamometers to evaluate muscular effort, Cardiopulmonary Exercise Test (CPET) with electrocardiogram to assess cardiac and pulmonary response, Dual-energy X-ray Absorptiometry (DEXA) to evaluate corporal composition.
In the studies with intervention protocols available, one was based only on recumbent cycle ergometer training, regarding heart rate reserve as modulator of intensity [38], three studies with HIIT exclusively during 30min, or with 1h combining 30min HIIT plus 30min resistance training [36, 37, 40], and another study using continuous cardiovascular training concomitant with resistance training [39]. However, because there is a combination of Continuous Cardiovascular (or HIIT) plus RT, we cannot fully establish a relation between resistance/strength training only, and cardiovascular only, or the combined effect of training in CLL patients, neither infer about the difference between endurance and strength training in resistance training protocols. Nevertheless, findings showed that more than 12-weeks of training, with more than 30 min. of HIIT combined with muscle endurance-based resistance training for treatment naïve CLL patients, is feasible and is associated with significant effects on muscle strength and normal immune cell functions [36, 37, 40].
Corroborated from current knowledge, urges the need to clarify the exercise characteristics and outcomes regarding HIIT, resistance training (also between strength and endurance approaches) and combined training in CLL patients. The difference between muscular endurance training (more repetitions, and fatigue resistance to exercise) and maximum strength training (increment in muscle strength and/or muscle hypertrophy) must also be assessed. Most studies use DEXA and BIA for body composition analysis, which are indirect measures, insensitive to changes in muscle size, that consequently would keep very small changes from muscle hypertrophy adaptations undetected [48]. As described elsewhere [49, 50], when volume is equated, resistance training frequency does not significantly or meaningfully impact muscle hypertrophy. However, higher training frequencies can help to accumulate more significant volumes of training, which may enhance hypertrophic response.
The studies obtained in this review shows a preference for low-moderate intensities, or endurance effort on resistance training (65–70% of 1-RM), but as literature suggest, exercise-induced myokines production have a critical role in increasing cytotoxicity and the infiltration of immune cells into the tumour [25]. When comparing Aerobic Only, Strength Only and Both Guidelines, the Hazard Ratio for All-Cause Mortality was lower when combining Both Guidelines, but when alone, Strength training was better than Aerobic; in the case of cardiovascular disease mortality, Both Guidelines combined are still the better choice to a lower hazard ratio; but in cancer mortality, Strength Only training shows to be the better option compared to combined guidelines [51]. There are no studies addressing the use of strength training on CLL patients but given the fact that one of the most evident symptoms as the disease progresses are fatigue and shortness of breath during regular physical activity, it seems reasonable that a strength training is better tolerated than a cardiovascular training. Confirming the feasibility and success of this type/mode of training should be engaged in future studies.
It is also important to objectively assess the daily lifestyle of patients to establish a possible etiology of CLL, implementing the accelerometry technology, to ensure correct lifestyle patterns recommendations, and make a connection point with anatomic/morphologic data (muscular mass, body fat percentage, weight, blood, and cardiovascular parameters), and physical condition (VO2, strength, flexibility, mobility, and more).
Despite the medical conservative approach in leukemic patients regarding exercise prescription, leading Exercise Oncologists suggest that all cancer patients should avoid inactivity and engage in safe exercise training [52]. It was reported in a small cohort with 12 patients with hematologic disease (7 patients with Acute Myeloid Leukemia, 1 Acute Lymphoblastic Leukemia and 4 Non-Hodgkin’s Lymphoma) receiving high-dose chemotherapy, that none of the patients with thrombocyte counts below 10.000/µl suffered bleeding and no patient with haemoglobin counts below 8 g/dl suffered critical tachycardias, showing that physical exercise in patients with severe cytopenia is safe and results in increased physical performance and unchanged quality of life [53]. Also in the studies we collected, the feasibility of the intervention protocols were always highly rated, with 99 ± 3,6% attendance and 148,5 ± 5,4 min/week of exercise and with 100% safety [36, 37, 40]; with 91% attendance with 88 ± 17 min/week (Furzer et al., 2016); with small adverse events related with intervention protocol such as back, hip and knee pain (Courneya et al., 2009) but without impairment of patients maintenance on the protocol.
Considering immunologic outcomes, only two small pilot studies compared disease parameters. One revealed a significant effect on NK-cells, including increased absolute counts, cytotoxic function, as well as increased perforin and granzyme B expression, mimicking the response to exercise in subjects without cancer [36] while the other enlightened an increased ratio CD4:CD8 T-cell, and reduced proportion of T-cells subsets [35]. Although these results should be treated with care since a control group is missing, and patients received treatment before or during intervention with medication known to alter T-cell phenotype and function, this relationship between exercise and immune outcomes should be further explored in future studies. As reported elsewhere [54], exercise is an effective modulator in sustaining proliferative signalling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, exercise and tumour-promoting inflammation and reprogramming energy metabolism, evading immune destruction, with myokines playing a significant role in the prevention of cancer proliferation. The effect of exercise in these hallmarks of cancer should be evaluated in CLL cells.