A pilot randomized trial of supervised resistance training plus home-based activity in chronic lymphocytic leukaemia patients

Abstract

Chronic lymphocytic leukaemia (CLL) is frequently associated with frailty, impaired physical function, and reduced quality of life. Evidence on the role of exercise in this population is limited. This pilot randomised clinical trial evaluated the effects of a supervised resistance training programme, combined with a home-based physical activity plan, on frailty, body composition, strength, fatigue, quality of life, and mental health in patients with CLL receiving active treatment. Thirty-six patients were randomised to either a home-based physical activity group plus a supervised resistance training programme group (n = 18) or a home-based physical activity group (n = 14) for eight weeks. The primary outcome was frailty assessed with the Short Physical Performance Battery. Secondary outcomes included body composition, grip strength, fatigue, quality of life, anxiety and depression, and sleep quality. Non-parametric analyses were performed, and effect sizes calculated. No differences between-group were found in frailty. However, participants in the supervised group showed significant improvements in lean mass (p = 0.047), dominant hand grip strength (p = 0.004), cognitive fatigue (p = 0.008), and sleep disturbance (p = 0.010). Effect sizes were moderate for anxiety and sleep quality, and small for depression. Adherence exceeded 80% in both groups, and no adverse events related to exercise were reported. Supervised resistance training combined with home-based physical activity is feasible, safe, and well tolerated in patients with CLL. The intervention was associated with preliminary improvements in muscle mass, strength, fatigue, and sleep-related outcomes. Larger and longer trials are needed to confirm these findings.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-026-38721-2.

Introduction

Chronic lymphocytic leukemia (CLL) is the most common hematologic malignancy in adults in Western countries, with an estimated incidence of 4.2 cases per 100,000 individuals per year¹. This disease is characterized by malignant involvement of the bone marrow, peripheral blood, and lymphoid organs by mature clonal B cells. Although therapeutic advances have significantly improved prognosis, CLL remains an incurable and prolonged disease that markedly affects patients’ quality of life^2,3.

Most individuals diagnosed with CLL are older adults with multiple comorbidities and compromised functional status, which is associated with reduced overall survival in this population^4,5. These factors, combined with the burden of treatment and the clinical progression of the disease, contribute to the development of symptoms such as persistent fatigue, loss of muscle mass, decreased physical capacity, sleep disturbances, and mental health disorders including anxiety and depression^6–8. In this context, the comprehensive management of patients with CLL should include complementary strategies that promote both physical and mental health, beyond pharmacological disease control.

Several studies have demonstrated that regular participation in structured physical exercise can yield significant benefits in oncologic patients, improving quality of life, functional capacity, fatigue, and mental health outcomes^9–11. In the field of hematologic malignancies, there is growing evidence supporting the positive effects of exercise on fatigue, sarcopenia, and quality of life, particularly in patients undergoing hematopoietic stem cell transplantation or intensive treatment regimens^12,13. However, scientific evidence remains limited in the specific context of CLL, with few clinical trials evaluating tailored exercise interventions in this population. Recently, small pilot studies have suggested that physical exercise may alleviate symptoms and enhance quality of life in individuals with CLL^14,15.

Frailty has emerged as a clinically relevant variable in older adults with cancer¹⁶. This syndrome is increasingly recognized as a multidimensional biopsychosocial condition, not merely a cluster of physical deficits. It encompasses physical, psychological, cognitive, and social domains, and reflects a complex interplay of factors that contribute to an individual’s vulnerability and diminished physiological reserve¹⁷. Fatigue and insomnia are among the most frequently reported symptoms and are linked to a reduced likelihood of engaging in physical activity. Patients who maintain regular physical activity demonstrate higher quality of life, better physical and role functioning, and experience lower levels of fatigue, pain, and overall symptom burden compared to those who are insufficiently active. These findings highlight a critical need for targeted interventions aimed at promoting physical activity in individuals with CLL¹⁸. It is estimated that 60–70% of adults with CLL are classified as prefrail or frail—a significantly higher proportion than the 15–30% observed in the general older adult population¹⁹. The assessment and management of frailty in patients with CLL poses a clinical challenge in which physical exercise may play a valuable role as both a preventive and therapeutic tool.

In this context, the present study was designed to analyse the effects of a supervised resistance training program, combined with a home-based physical activity component, on quality of life, mental health and frailty in patients with CLL undergoing active treatment. This pilot randomized clinical trial aims to provide preliminary evidence on the feasibility and effectiveness of such an intervention in a population that is both understudied and clinically vulnerable.

The main objective of the study was to evaluate the effects of a supervised therapeutic exercise program, focused on strength training, on frailty in patients undergoing treatment for CLL.

Secondary objectives were to explore the effects of the intervention on body composition, muscle strength, fatigue, health-related quality of life, psychological well-being (anxiety and depression), and sleep quality in patients undergoing treatment for CLL.

Materials and methods

Study design

This is a phase 3, randomized, open-label, controlled, unicentric study. The study received approval from the Ethics Committee of the University of Salamanca (record number 2024/11) and was conducted in accordance with the Declaration of Helsinki. The clinical trial was registered in ClinicalTrials.gov (19/02/2025 registration number NCT06654206).

Participants

The study recruited patients currently receiving treatment for CLL at Salamanca University Hospital, according to the following inclusion and exclusion criteria:

Inclusion criteria:

• Participants were diagnosed with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and were receiving active treatment.

• Participants had not engaged in regular physical activity during the previous 8 weeks. Regular physical activity was defined as participation in structured or moderate-to-vigorous exercise at least twice per week, assessed by self-report at baseline. This criterion was applied to minimize baseline heterogeneity and potential confounding effects related to prior training adaptations.

• Participants had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1.

• Participants provided written informed consent prior to study participation.

Exclusion criteria:

• Participants presented medical contraindications to physical exercise, including severe musculoskeletal disorders, serious cardiovascular diseases, bone metastases, or other conditions as determined by a healthcare professional.

• Participants were unable to complete the baseline assessment or had difficulty performing basic exercises.

• Other circumstances were identified by the researchers as potentially interfering with the objectives or conduct of the study.

Intervention

A total of 40 individuals were enrolled in the study and gave informed consent. Participants were then randomly assigned to one of two groups: Home-based physical activity group plus a supervised resistance training programme group (n = 20), or a home-based physical activity group (n = 20). Baseline data were collected from all participants prior to the start of the interventions.

The supervised group followed a resistance training programme twice weekly for eight weeks, in combination with the home-based physical activity plan. All supervised sessions were led by a physiotherapist. The comparison group participated solely in the home-based physical activity plan for the same duration. All participants received weekly telephone calls to monitor adherence.

Both interventions are described in detail in the publication of the protocol²⁰ and have also been added as supplementary material 1.

Variable and outcomes: type and measurement

Primary variable and outcome

Frailty

Frailty was assessed using the Short Physical Performance Battery (SPPB) scale²¹. This questionnaire includes three components: a balance test, gait speed, and a chair stand test. The scale has a maximum score of 12 points, with higher scores reflecting better physical function.

Secondary variable and outcomes

Body composition

Data on various body composition variables were collected. Height was measured using a stadiometer, while the remaining variables were obtained through electrical bioimpedance using the TANITA BC-418^® device. Collected variables included total body weight and appendicular skeletal muscle mass (ASM), defined as the sum of muscle mass from all four limbs. The appendicular muscle mass index (ASMI) was calculated using the height-adjusted formula (ASM/height²)²². Additional parameters assessed included visceral fat, body fat percentage (BF%), and body mass index (BMI).

To ensure accuracy, all participants were weighed barefoot and wearing minimal clothing, thereby reducing measurement variability and improving the reliability of the body composition data²³.

Strength

Upper limb strength was assessed. Grip strength was measured using a Jamar^® hydraulic dynamometer (J00105, Lafayette Instrument Company, USA), considered the gold standard for this purpose (40). Both hands were assessed following the Southampton Protocol²⁴. Participants were seated in a chair with a backrest, and the procedure was explained prior to testing. Each hand underwent three consecutive trials, with each contraction lasting 5 s and a 10-second rest between attempts. Verbal encouragement was provided to maximise effort.

Participants maintained a standardised posture during the test: seated with the shoulder adducted and neutrally rotated, elbow flexed at 90°, forearm in a neutral position, and wrist slightly extended (0°–30°). The second position on the Jamar^® device was used for all participants, except for those with smaller hands, who were tested using the first position; this was recorded accordingly. All grip strength measurements were carried out by the same evaluator. The maximum value across the three trials for each hand was selected for analysis.

Fatigue

Fatigue was evaluated using the 12-item EORTC QLQ-FA12²⁵, which consists of 12 items, each with four response options scoring from 1 to 4. In line with the scoring procedures of the EORTC QLQ-C30, FA12 scores are transformed to a 0–100 scale, with higher scores indicating greater levels of fatigue.

Health-related quality of life

Quality of life was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ). The core questionnaire, EORTC QLQ-C30, is a well-established instrument for evaluating quality of life in individuals with cancer²⁶. It comprises 30 items, with 24 distributed across five functional domains: physical, role, emotional, cognitive, and social functioning. Additionally, it contains three symptom scales—fatigue, pain, and nausea/vomiting—as well as a global health status scale. Six further items address other symptoms such as dyspnoea, appetite loss, sleep disturbance, constipation, and diarrhoea, along with the perceived financial impact of the disease. Responses were given on a four-point Likert scale (‘not at all’, ‘a little’, ‘quite a bit’, ‘very much’), except for the global health and quality of life items, which used a seven-point scale. On the functional and global health scales, higher scores represented better quality of life, whereas higher scores on the symptom scales indicated a greater burden of symptoms.

To assess disease-specific quality of life in patients with chronic lymphocytic leukaemia (CLL), the EORTC QLQ-CLL17 was also administered. This 17-item questionnaire is divided into three subscales: symptom burden from disease and/or treatment (six items), physical condition and fatigue (four items), and emotional concerns related to health or function (seven items, including two conditional questions). These conditional items, addressing work or education, were only answered when applicable. All items were rated on a four-point scale ranging from ‘not at all’ to ‘very much’, based on the participant’s experience during the previous week²⁷. Scoring for the QLQ-CLL17 followed the standard EORTC procedure, with subscale scores calculated and converted to a 0–100 scale. Higher scores across subscales and items reflected more severe symptoms or greater perceived problems.

Anxiety and depression

Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS), a validated and reliable tool applicable to a wide range of populations²⁸. The scale consists of 14 items—seven measuring anxiety (subscale A) and seven measuring depression (subscale D). Each item was scored on a scale from 0 to 3, generating two separate scores, one for each subscale.

Sleep quality

Patient sleep quality was measured using the Athens Insomnia Scale (AIS), a self-report questionnaire comprising eight items, originally developed by Soldatos and validated for use in the Spanish population²⁹. The first five items addressed “sleep disturbances”, specifically difficulties with sleep onset, nocturnal awakenings, early morning awakening, total sleep duration, and overall sleep quality. These corresponded to criterion “A” for the diagnosis of insomnia in the ICD-10 classification of mental and behavioural disorders. The remaining three items assessed the “daytime consequences” of poor sleep, including general well-being, physical and mental functioning, and daytime sleepiness, in line with criterion “C” of the ICD-10. Each item was rated on a four-point Likert scale (0 = “no problem” to 3 = “severe problem”), producing a total score ranging from 0 to 24. Higher scores indicated greater impairment, with a cut-off of ≥ 6 suggesting the presence of insomnia³⁰.

Sample size

The sample size was calculated based on functional capacity, measured using the Short Physical Performance Battery (SPPB), which yields scores ranging from 0 to 12 points²¹. According to previous studies involving similar populations, a minimum detectable change of 1.34 points has been identified as clinically meaningful, helping to avoid the detection of trivial or irrelevant differences (Perera et al., 2006). In comparable interventions lasting less than 12 weeks, the standard deviation of SPPB scores has been reported to range between 1 and 1.5 points^31,32.

Based on these parameters, detecting a difference of 1.34 points with an assumed standard deviation of 1.3, an alpha risk of 0.05, and a statistical power of 80%, required 18 participants per group. A 15% dropout rate was also factored into this estimate. The sample size calculation was conducted using GRANMO software, version 7.12.

Allocation and randomization

The randomisation for this clinical trial was performed using Microsoft Excel 2020, which produced a list of random numbers for assigning participants. Each individual received a unique number from this list: those with odd numbers were placed in the supervised resistance training plus home-based physical activity group, while those with even numbers were assigned to the home-based physical activity group. This approach provided a random and balanced allocation between groups, helping to minimise bias and strengthen the reliability of the trial outcomes. The procedure was carried out by a staff member from the Haematology Department at the Hospital Universitario de Salamanca who had no involvement in the research.

Blinding

Given the study design, blinding of participants and evaluators to the intervention was not feasible. However, to maintain objectivity, statistical analysis was carried out by an independent statistician who was unaware of the participants’ group assignments.

Statistical methods

Means and standard deviations were computed for quantitative sociodemographic variables, while percentages were reported for qualitative ones. Group differences in sociodemographic characteristics were assessed using independent samples t-tests. The Kolmogorov-Smirnov test was applied to check for normality. Associations between sociodemographic variables and intervention groups were examined using the Chi-squared test.

For the EORTC QLQ-C30, QLQ-CLL17, QLQ-FA12, HADS, Atenas scale, hand grip, frailty and anthropometric instruments, medians and their 95% confidence intervals³³ were calculated for each subscale and overall scale within each intervention group. Medians were chosen as descriptive statistics due to non-normal distribution of scores and high within-group variability. Change was assessed as the difference between pre- and post-intervention scores for each scale or subscale. The Mann-Whitney U test³⁴ was used to compare both pre-intervention scores and change scores between groups.

The difference in medians (supervised group minus home-based group) was used to estimate the magnitude of change for each scale or subscale (see supplementary material 2). To quantify effect size, the rank-biserial correlation derived from the Mann-Whitney U test was calculated. This standardised measure ranges from − 1 to 1, with values below 0.125 indicating a small effect, between 0.125 and 0.465 a moderate effect, and above 0.465 a large effect³⁵. A significance level of 0.05 was used, with 95% confidence intervals reported. All statistical analyses were conducted using Jamovi software, version 2.6³⁶.

Results

Patients baseline characteristics

A total of 40 patients were assessed for eligibility. Four patients declined to participate before randomization, and therefore 36 participants were randomized. Of these, 18 were allocated to the home-based physical activity promotion group and 18 to the home-based physical activity plus supervised resistance training group. During follow-up, no participants were lost in the home-based group, whereas four participants in the supervised resistance training group were lost to follow-up for reasons unrelated to the intervention. Consequently, the final analyzed sample consisted of 18 participants in the home-based group and 14 participants in the supervised group (Fig. 1).

Fig. 1.

Flowchart.

The demographic characteristics of the two groups are detailed in Table 1. The mean age was comparable between the home-based physical activity group plus a supervised resistance training programme (73 range 46–88 years) and the home-based physical activity group (73 range 55–88 years), with no statistically significant difference. Similarly, the mean BMI was 26,8 range 19,5–31,5 kg/m² in the supervised and 25,2 range 20,8–30,5 kg/m² in the home-based group, with no significant difference observed between them.

Table 1.

Baseline characteristics.

Variable	Home-based physical activity group (n = 18)		Home-based physical activity group plus a supervised resistance training programme group (n = 14)
	No.	%	No.	%
Age (years)
Mean	73		73
Range	46–88		55–88
Male	11	61	11	79
Female	7	39	3	21
Weight (kg)
Mean	71,2		69,8
Range	43,8–85,9		47,3–92,2
BMI (kg/m2)
Mean	26,8		25,2
Range	19,5–31,5		20,8–30,5
Lines of treatment
Mean	1		1
Range	1–5		1–6
Current treatment
BTKi	12	67	13	93
BTKi+BCL2i	3	17	0	0
BCL2i (+/- anti-CD20)	3	17	1	7
IGHV status
Unmutated	13	72	11	79
Mutated	5	28	3	21
del17p
Yes	1	6	1	7
No	17	94	13	93
mutTP53
Yes	1	94	1	7
No	17	6	13	93
Years since diagnosis
Mean	18		12
Range	1–22		4–28

BCL2i: BCL2 inhibitor; BTKi: BTK inhibitor, mutTP53: TP53 mutation.

Changes in frailty and anthropometric variables

No significant differences were found in the pre-post changes between the groups in relation to frailty. Of the anthropometric variables, statistically significant differences were found between the groups for the pre-post differences on the lean mass (Table 2).

Table 2.

Changes in frailty and anthropometric variables.

Variable	p-value	Median difference (95%CI)	Effect size
SPPB
Balance	0.572	0.00 (-0.656 to 0.656)	0.10
Velocity	0.885	0.00 (-0.474 to 0.474)	-0.03
Stand and sit	0.549	0.00 (-1.492 to 1.492)	-0.13
Total	0.696	1.00 (-0.492 to 2.492)	0.09
TANITA
% Fat mass	0.290	-0.70 (-2.9088 to 1.509)	-0.236
Kg Fat mass	0.525	-0.35 (0.09856 to 0.286)	-0.144
Lean mass	0.047	1.35 (-0.0990 to 2.799)	0.440
Visceral fat	0.303	0.00 (-0.6561 to 0.656)	-0.213
ASM	0.051	0.45 (-0.1469 to 1.047)	0.431
ASMI	0.657	0.1625 (-0.3184 to 0.643)	0.102

Significant values are in [bold].

SPPB, Short Physical Performance Battery; ASM, appendicular skeletal muscle mass; ASMI, appendicular skeletal muscle mass index; BMI, body mass index.

Changes in strength

The intervention groups were homogeneous with regards to pretest measures on hand grip test. Statistically significant differences were found between for the pre-post differences on grip strength in the dominant hand (Table 3).

Table 3.

Changes in hand grip test.

Variable	p-value	Median difference (95%CI)	Effect size
Strength
Handgrip dominant	0.004	3.227 (1.118 to 5.336)	-0.368
Handgrip non dominant	0.120	1.589 (-0.442 to 3.619)	-0.155

Significant values are in [bold].

Changes in fatigue

The intervention groups were homogeneous with regards to pretest measures on all subscales of the QLQ-FA12. Statistically significant differences were found between the home-based physical activity group plus a supervised resistance training programme groups for the pre-post differences on the cognitive fatigue subscale of the QLQ-FA12 (Table 4). This result should be interpreted with caution, because the significance is due to a few individuals who score very high while the rest score zero (Fig. 2).

Table 4.

Changes in fatigue.

Variable	p-value	Median difference (95%CI)	Effect size
FACTI
Physical fatigue	0.932	-3.33 (-14.576 to 7.91)	-0.02
Emotional fatigue	1.000	0.00 (-11.673 to 11.67)	0.01
Cognitive fatigue	0.008	0.00 (-10.933 to 10.93)	-0.46
Interference with daily life	0.208	0.00 (-21.871 to 21.87)	-0.24
Social sequelae	0.154	0.00 (0.00 to 0.00)	-0.17

Significant values are in [bold].

Fig. 2.

Median values and their difference between the two groups for the cognitive fatigue subscale of the QLQ-FA12. The 95% confidence intervals (95% CI) and individual data points are shown to illustrate the distribution and variability of responses within each group and to support an exploratory interpretation of these findings, rather than indicating definitive group-level effects.

Changes in health-related quality of life

The intervention groups were comparable at baseline across all subscales of the QLQ-C30 and QLQ-CLL17. Statistically significant differences were found between the home-based physical activity group plus a supervised resistance training programme groups for the pre-post differences on the sleep disturbance subscale of the QLQ-CLL17 (Table 5). This result should also be interpreted with caution, as in QLQ-FA12 described above (Fig. 3). In the subscale financial impact all participants answered the same (0) because the treatment they received is part of the public health system in Spain.

Table 5.

Changes in HRQoL.

Variable	p-value	Median difference (95%CI)	Effect size
EORTC QLQ C30
Functional
Physical	0.069	-10 (-19.946 to -0.0539)	-0.09
Role	0.829	0.00 (-10.936 to 10.9357)	-0.05
Cognitive	0.303	0.00 (-10.936 to 10.9357)	0.20
Emotional	0.325	4.17 (-6.769 to 15.1024)	0.21
Social	0.842	0.00 (0 to 0)	0.04
Global health status	0.441	-10 (-29.471 to 12.8041)	-0.17
Symptom
Fatigue	0.861	-5.56 (-6.118 to 17.2288)	0.04
Nausea and vomiting	0.050	0.00 (-7.895 to 7.8953)	-0.34
Pain	0.581	0.00 (0 to 0)	-0.11
Dyspnoea	0.535	0.00 (0 to 0)	0.09
Sleep disturbance	0.010	0.00 (-15.13 to 15.13)	-0.49
Appetite loss	0.769	0.00 (0 to 0)	-0.05
Constipation	0.614	0.00 (-15.13 to 15.13)	-0.10
Diarrhoea	0.599	0.00 (-15.79 to 15.79)	0.10
EORTC QLQ CLL17
Symptom burden	0.765	5.56 (-1.735 to 12.85)	0.07
Physical condition/ fatigue	0.686	-8.33 (-22.159 to 5.490)	-0.08
Worries/fears about health and functioning	0.814	3.81 (-7.455 to 15.0740)	0.06

Significant values are in [bold].

Fig. 3.

Median values and their difference between the two groups for the sleep disturbance subscale of the QLQ-CLL17. The 95% confidence intervals (95% CI) and individual data points are shown to illustrate the distribution and variability of responses within each group and to support an exploratory interpretation of these findings, rather than indicating definitive group-level effects.

Changes in anxiety, depression and sleep quality

No significant differences were found in the pre-post changes between the groups in relation to the HADS and Atenas scale (Table 6). Effect sizes were low (depression) to moderate (anxiety and sleep quality).

Table 6.

Changes Un anxiety, depression and sleep quality.

Variable	p-value	Median difference (95%CI)	Effect size
HADS
HADS- Anxiety	0.084	-2.500 (-5.6518 to 0.652)	-0.380
HADS-Depression	1.000	0.500 (-0.8123 to 1.812)	0.00
HADS- Total	0.097	-2.500 (-6.4369 to 1.437)	-0.366
Atenas scale
Sleep quality	0.381	-0.500(-2.834 to 1.83)	-0.194

Adherence to the exercise programmes ranged from 80 to 100% among all participants. Only days on which participants had completed the full training programme, including the 60-minute walk, were counted.

Discussion

This pilot randomized clinical trial compared the feasibility and safety of two physical exercise-based rehabilitation interventions in patients with CLL undergoing active treatment. Participants assigned to the supervised resistance training plus home-based physical activity group demonstrated high adherence to the intervention, and no exercise-related adverse events were reported. These findings support the safety and feasibility of the proposed intervention in this population and are consistent with previous literature in patients with hematologic malignancies^37–39.

The results of this pilot randomized clinical trial indicate that a supervised resistance training program combined with home-based physical activity is feasible and well tolerated in patients with CLL and may be associated with favorable trends in several physical and patient-reported outcomes. In particular, improvements were observed in body composition and dominant hand grip strength, suggesting a potential positive effect on muscular function. Although no statistically significant between-group differences were found in frailty as assessed by the SPPB, participants in the supervised group showed significant within-group gains in lean mass and grip strength. Trends toward improvements in fatigue, anxiety, and sleep-related outcomes were also observed; however, these findings did not consistently reach statistical significance and were characterized by substantial inter-individual variability. Therefore, these results should be interpreted cautiously and considered preliminary and exploratory, given the small sample size of this pilot study.

It is important to acknowledge that, although frailty was conceptualized as a multidimensional construct in the Introduction, the primary outcome measure used in this study—the Short Physical Performance Battery (SPPB)—primarily assesses physical performance. Consequently, it does not capture other relevant dimensions of frailty, such as psychological, cognitive, or social domains. The absence of statistically significant between-group differences in SPPB scores should therefore not be interpreted as evidence that the intervention had no effect on frailty-related processes more broadly. Potential effects on non-physical domains of frailty may have occurred but were not directly assessed in this trial.

These outcomes align with previous research in other hematologic malignancies, where resistance training has been associated with improvements in muscle mass and strength, even in settings of immunosuppression or intensive treatment^37,39–42. In CLL, where loss of lean mass and physical inactivity are common, such improvements may have important implications for maintaining autonomy, preventing falls, and reducing the risk of functional decline and future disability.

The study did not include any intervention regarding the participants’ diet during the intervention period. Specialized dietary advice could have led to improved results in terms of the patients’ body composition.

Regarding mental health and symptom-related outcomes, exploratory improvements were observed in cognitive fatigue and sleep-related measures. Although these results should be cautiously interpreted due to intra-individual variability and the limited sample size, they support the hypothesis that exercise can modulate common neuropsychological symptoms in oncology patients—possibly through neuroendocrine, anti-inflammatory, or circadian rhythm mechanisms. These findings are consistent with prior studies conducted in hematologic cancer populations^43,44.

Although no statistically significant differences were found between groups for most dimensions of the EORTC QLQ-C30, favorable trends were observed in the physical and emotional functioning subscales among participants in the intervention group, these results should be interpreted with caution as this is a pilot study with a small sample size. It is possible that the 8-week program duration was insufficient to produce substantial improvements in broader aspects of perceived well-being. Nevertheless, the observed effect sizes—particularly in mood and sleep-related outcomes—suggest a potentially beneficial impact that may be reinforced with longer interventions. Previous studies have reported greater improvements in quality of life^14,40,44, likely due to longer exercise durations. However, other studies have found similar results to this study^39,43.

Anxiety and depression scores, assessed using the HADS, did not show statistically significant differences between groups. This may be due to a low baseline prevalence of clinically relevant symptoms in the sample, limiting the room for measurable improvement. Although the results should be interpreted with caution, moderate effect sizes were observed for anxiety and sleep quality, reinforcing the relevance of physical exercise as a complementary strategy in the management of emotional distress in CLL—once again in line with previous evidence^39–41.

Implications of the study

The findings of this pilot randomised clinical trial have important implications for the clinical management of patients with chronic lymphocytic leukemia. First, the study shows that supervised resistance training, when combined with a home-based physical activity programme, is both feasible and safe for patients undergoing active treatment. High adherence rates (80–100%), together with the absence of exercise-related adverse events, reinforce the suitability of structured exercise interventions as an integral component of supportive care in hematological oncology.

Second, the improvements observed in lean mass, grip strength, cognitive fatigue, and sleep quality suggest that exercise may mitigate some of the most frequent and burdensome consequences of both disease and treatment. These results should be interpreted cautiously and considered preliminary and exploratory, given the small sample size of this pilot study, helping to perform more extensive clinical trials in the future.

Thirdly, the study supports the value of a multidimensional approach to care, in which physical exercise can contribute not only to improving muscle function, but also to broader aspects such as quality of life, mental health and sleep. This perspective is consistent with current trends in oncology that advocate for holistic, patient-centred interventions.

Finally, the results provide preliminary evidence that can inform the design of larger and more definitive trials to establish clear exercise guidelines for patients with CLL. The integration of exercise-based rehabilitation into standard clinical practice may represent a paradigm shift in supportive cancer care, complementing pharmacological strategies with interventions that address both physical and psychosocial needs.

Limitations and future directions

The main limitations of this study include the small sample size, which reduces statistical power to detect group differences. Additionally, the lack of blinding among participants and evaluators may introduce bias. The intervention focused solely on resistance training, without incorporating aerobic or flexibility components that might have influenced other health domains. Specific, specialized dietary guidelines could have led to improved results in the patients’ body composition. No other interventions as massage or psychological intervention were assessed. Additionally, participant attrition after randomization, which occurred exclusively in the supervised group, resulted in an unbalanced and reduced final sample size. This may have further limited the statistical power to detect between-group differences. Finally, the short duration of the program limits our ability to assess more robust or sustained long-term effects.

Despite these limitations, this study provides preliminary evidence supporting the feasibility and utility of implementing supervised exercise programs in patients with CLL. The randomized design, use of validated assessment tools, and multidimensional evaluation approach strengthen the validity of our findings. Future studies with larger sample sizes, longer follow-up, and multimodal exercise protocols are needed to establish specific recommendations for this clinical population.

Conclusion

This pilot randomized trial primarily demonstrates the feasibility and safety of a supervised resistance training program in patients with CLL undergoing active treatment. Although no statistically significant between-group differences were observed in the primary outcome of frailty, preliminary and exploratory improvements were observed in muscle mass, strength, fatigue, and sleep-related outcomes. These findings should be interpreted cautiously and considered hypothesis-generating, warranting confirmation in adequately powered trials.

These findings suggest that physical exercise may play an important role as a supportive care strategy in this population, contributing to the maintenance of physical function and psychological well-being. Integrating structured exercise interventions into the multidisciplinary management of CLL may improve patients’ quality of life and help mitigate adverse effects associated with treatment and disease progression.

Further studies with larger sample sizes, longer durations, and extended follow-up are needed to confirm these findings and to define clinical recommendations regarding the most appropriate type, intensity, and frequency of exercise for this population.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

Juan Luis Sánchez-González (JLSG), Eduardo José Fernández-Rodríguez (EJFR), Roberto Méndez-Sánchez (RMS), Luis Polo-Ferrero (LPF), Ana Silvia Puente-González (ASPG), Cristina de Ramón (CdR), Sara Marcos-Asensio (SMA), Patricia Blázquez-Benito (PBB), Mónica Baile-González (MBG), Almudena Navarro-Bailón (ANB), Fermín Sánchez-Guijo (FSG), Javier Martín-Vallejo (JMV), Jesus Perez (JP) and Carlos Martín-Sánchez (CMS).Conceptualization: JLSG, EJFR, RMS, LPF, ASPG, CdR, ANB and CMS, Methodology: JLSG, RMS, CMS and JMV, Investigation: JLSG, EJFR, RMS, LPF, ASPG, CdR, ANB, SMA, PBB and CMS Results and statistics: JMV Visualization: FSG, MNG, SMA, PBB and JP. Funding adquisition: JLSG, EJFR, RMS, LPF, ASPG, CdR, ANB and CMS Writing – original draft: JLSG and CMS, Writing – review & editing: ANB and JP.

Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by Colegio Profesional de Fisioterapeutas de Castilla y León, Spain (CPFCYL), S/2024/01503 CO.

Data availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Ethics approval

The studies involving humans were approved by this study involving human participants has been reviewed and approved by the Research Ethics Committee for Medicinal Products of the University Hospital of Salamanca (record number2024/11). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.