Review Reports - The Role of Daily Activity in Risk and Survival Outcomes for Chronic Lymphocytic Leukemia Patients: Baseline Insights from the ADRENALINE Pilot Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I'm attaching a Word document with some comments. I think the main point to improve is the neatness of the text (font size, format, order, etc.).

Comments for author File: Comments.pdf

Author Response

Dear Reviewers, in the attached file, I will respond to each of your questions/comments. For easy reading, I will make my explanations in line with the text of your comments, in blue color and after “R.:”. Thank you for all your precious feedback.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Can you specify what meand value in brackets in lines 107-111? Is it SD?

Is there any graph/table to show correlation B2-microglobulin with Lean Mass and MVPA? Probably it should be in Table3.

Author Response

Dear Reviewer, in the attached file, I will respond to each of your questions/comments. For easy reading, I will make my explanations in line with the text of your comments, in blue color and after “R.:”. Thank you for all your precious feedback.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This study brings valuable and much-needed insights into the relationship between physical activity and health status in patients with Chronic Lymphocytic Leukemia (CLL) who are in the “watch and wait” phase.

Originality and Scientific Relevance
The chosen topic is highly relevant, considering the lack of objective data regarding physical activity in treatment-naïve CLL patients. The study successfully integrated physiological assessments with quality of life evaluations.
Robust Methodological Design
The study followed clear methodological rigor, with well-defined inclusion/exclusion criteria, objective fitness testing (accelerometry, VO2peak, and muscular strength), and appropriate statistical analysis.
Detailed Results Presentation
The results are clearly presented using relevant tables and figures, and the correlations between physical activity and physiological or immunological parameters offer a strong foundation for future research.

Suggestions for Improvement

1. Justification of Limitations and Generalizability

Although the small sample size (n=11) is acknowledged, the implications of this limitation on the external validity of the conclusions should be discussed more clearly. For example:

Line 286-288: “...data presented in the present study establishes a baseline analysis...” – It would be helpful to more clearly state that while these results are not generalizable, they provide a valuable basis for future studies with larger samples.

2. Clarification of Objectives and Hypotheses

The objectives in the Introduction section are vague and scattered (lines 94–98). A clearer and more concise reformulation is recommended, such as

To explore the relationship between daily physical activity levels and hematological, immunological, and functional parameters.
To evaluate the subjective perception of physical capacity and quality of life
To investigate whether time of day influences physical activity patterns in patients with CLL.

This would enhance the alignment between the aims, methods, and interpretation of results.

3. Better Balance Between Data and Conclusions

The conclusions regarding the benefits of strength training (lines 470–475) are promising but should be framed more cautiously. While strong correlations between muscle mass and strength were observed, it is important to emphasize that the study did not directly test an exercise program.

Suggested clarification: "While our findings show strong associations between lean mass and strength, further intervention-based studies are needed to confirm the clinical relevance of strength training in CLL management."

4. More Effective Use of Figures and Tables

Figure 2 is relevant for illustrating diurnal physical activity patterns but would benefit from a clearer explanation of the differences between sexes and time periods with increased activity.
Table 1 is very dense. Consider splitting it (e.g., body composition vs. hematologic/immunologic data) or moving less relevant variables to the supplementary material.

5. Broader Contextualization in the Discussion

In the Discussion section (lines 197–288), the comparison with previous studies is helpful but can be expanded as follows:

How do CLL patients compare with other hematologic cancer populations in terms of physical activity and fitness?
Why do the authors believe that the activity levels in this study are lower than those in similar studies (e.g., Sitlinger et al., MacDonald et al.)?

This manuscript makes an important contribution to the literature on physical activity in patients with CLL. Although it is still in its early phase and based on a limited sample, its exploratory value is significant. I recommend acceptance after revision, especially regarding the clarification of the study’s objectives, a more nuanced interpretation of findings, and an improved data presentation structure.

Comments on the Quality of English Language

Although the manuscript demonstrates a solid grasp of the scientific content and is largely understandable, the quality of English can be improved to enhance clarity, fluency, and overall readability. Several sections would benefit from careful revision of grammar, sentence structure, punctuation, and idiomatic phrasing.

Below are specific observations and examples:

1. Sentence Structure and Grammar

Example (Lines 43–44):
Original: “...interventions that promote physical activity and support the maintenance of independence to perform daily activities.”
Issue: The phrase ‘maintenance of independence to perform’ is awkward and not idiomatic.
Suggested: “...interventions that promote physical activity and help patients maintain independence in their daily activities.”
Example (Lines 217–219):
Original: “...with the best test value in our overall sample of 24.3 ml/kg/min VO2peak, taken by a male patient, nevertheless still below the minimal expected for a healthy female adult...”
Issue: This sentence is too long and lacks clear segmentation. The use of “nevertheless still” is redundant.
Suggested: “The highest VO2peak value recorded was 24.3 ml/kg/min, observed in a male participant—still below the minimum expected for a healthy adult female.”

2. Word Choice and Redundancy

Example (Lines 56–59):
Original: “...improving immune competence acting as a countermeasure against chronic systemic inflammation...”
Issue: “Improving immune competence” and “acting as a countermeasure” overlap in meaning. The sentence has been streamlined.
Suggested: “...enhancing immune function and counteracting chronic systemic inflammation...”
Repetitive phrases such as “this group of patients,” “our data show,” and “participants revealed” appear frequently and could be varied for a better narrative flow.

3. Punctuation and Syntax Errors

Example (Lines 215–216):
Original: “...also in line with available studies with the CLL population...”
Issue: Missing articles and awkward preposition use.
Suggested: “...also consistent with studies on the CLL population.”
Example (Line 264–265):
Original: “...MVPA appears to have no impact on disease parameters. Nevertheless, in our sample...”
Issue: Transition could be smoother; the abrupt “Nevertheless” may not be necessary.
Suggested: “MVPA appeared to have no significant impact on the disease parameters in our sample. However, activity patterns suggest...”

4. Scientific Register

Some expressions are literal translations or lack the appropriate scientific tone expected from high-impact journals.
Example (Lines 218–219):
Original: “...still below the minimal expected...”
Suggested: “...still below the minimum expected value...” – Use “minimum” for scientific precision.
Example (Lines 231–232):
Original: “...where isolated strength training was shown to be the better option...”
Suggested: “...where isolated strength training demonstrated superior benefits...” – Use of “demonstrated” fits better in scientific discourse.

5. Consistency in Terminology

Terms like “physical activity,” “exercise,” “fitness,” and “conditioning” are sometimes used interchangeably. While they are related, each has distinct implications in scientific writing. Ensure consistency and correct usage.
Suggestion: Consider defining key terms early and applying them consistently (e.g., use “moderate-to-vigorous physical activity (MVPA)” after the first mention).

I recommend a full professional language editing and proofreading service before publication. Although the scientific content is sound, enhancing the language will ensure that the findings are communicated with the clarity and precision they deserve.

Author Response

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear researchers, I've attached a Word document with some comments and/or observations.

Congratulations on your manuscript; it's improved considerably since the last time I read it.

Comments for author File: Comments.pdf

Author Response

1. Summary

Thank you very much for taking the time to review this REV 1 manuscript. And thank you for your encouraging words regarding first revision. In fact, only possible due to reviewers’ professionalism and pedagogic approach with their comments. Please find the detailed responses below and the corresponding revisions/corrections highlighted in blue color

2. Point-by-point response to Comments and Suggestions for Authors

Introduction

Adding levels of physical activity to the statement "that activity levels in all studied groups" sounds strange; just "activity". (line 48-49)

R.: Corrected. Changed “activity levels” for “physical activity” in lines 48-49. Hope this clarifies.

In this paragraph you could specify that you are talking about cancer patients, it adds much more interest to the writing.

R.: Added your suggestion in lines 52-53, emphasizing that CLL is a hematologic cancer.

Several controlled trials indicate significant improvements on cardiovascular fitness with aerobic exercise [17-19], on muscle fitness with resistance exercise [20], with impact on immunological response [20-22] and cancer related fatigue [17, 18].

specify “levels of physical activity” (This objective data on patients' activity levels).

R.: Corrected that paragraph, incorporating your suggestion. Please report to page 2, between lines 72-77.

Materials and Methods

My main concern here is the design they've described in relation to their objective... I have the feeling it's a cross-sectional correlational study (It's not an intervention that lasts for weeks; for example, in the end they seek a characterization or to describe a profile.)

They mention it's a randomized controlled trial, but it isn't... there are no details about the randomization process or what the control group would do (plus they mention it's blinded, but there's no proof of that).

I have the feeling this study is a derivative of a randomized controlled trial, and that's where the confusion lies.

R.: Totally agree with you. I explain in text that the present manuscript only addresses baseline data (without intervention, without group allocation), but as I sometimes “connect” this study to the main study (the randomized clinical trial), the confusion may appear. So, in line with your comments, I have corrected the first paragraph of Materials and Methods (between line 113-117). Hope this clarifies your doubts.

This section has improved considerably, but after reading through everything, I think it's missing details about the participants and the percentage of men and women. Some information can be gleaned from Figure 1, but it would be better to include this population detail.

R.: I have this stated in the first paragraph of results but added also this information in line 153-154.

I also believe it's a convenience sample because there's no sample size calculation.

R.: It this regard, the sample size calculation was made, but not achieved (during recruiting period). So, we’ve opted to include also a post hoc power analysis to verify the statistical power. But to cope with your comment, and keep it clearer, I have included the “convenience sample” nomenclature in lines 153-154 and 269-270.

After warmup, the incremental exercise phase is initiated, with each step increasing 15 watts per minute until 85% heart rate is achieved or other standardized criteria for stopping occurs.

In this they must add that it is 85% of the maximum heart rate...

R.: Corrected in line 183.

But we return to the details: you're using a tool to evaluate cross-sectional studies, therefore, you yourself say it's cross-sectional.

That's the point to correct.

R.: Already corrected in the first paragraph of Materials and Methods (between line 113-117). Hope this clarifies your doubts.

Results

Good results section.

Table 1 needs to be updated to indicate that the symbol means significant difference.

R.: Regarding table 1, the symbol does not mean significant difference. It means that the evaluated value is out of international guidelines for “healthy values”. That’s why I have made the statement: “Bold values are out of the normative reference intervals”. I have made this highlight to catch attention about the base values for this sample of CLL patients, showing their differences against sedentary people, age matched. I may take off this highlight if your considerer that it induces in error.

Discussion

Could the high percentage of body fat also be due to the low muscle mass in your sample?

Perhaps this could be helpful in your discussion (lines 392-393).

R.: It is a very well pointed comment! Didn’t occurred to me to discuss according to that point of view, and it is very pertinent. I have updated the paragraph in page 13, lines 398-410 to encompass this thought. Thank you!

I would like you to add subheadings for the paragraphs about limitations, practical implications, and future studies.

R.: Added the 3 subheadings at the end of Discussion: Limitations (line 535), Practical Implications (line 545), Future Research (line 553).

Can failing to achieve the required sample size, as calculated in your sample calculation, be considered a limitation? This is more of a question than a suggestion, because your justification has made me doubt myself. I leave it to your discretion.

R.: Since this is a baseline assessment, I believe that a small sample can be both. In one side, correlation may not imply causality because of sample power, but one the other hand, this is an exploratory study with data unexplored in present literature, so, a moment to analyze CLL untreated patients. In my humble opinion, I believe that small sample should remain as a limitation to alert readers and future researcher to account for the difficulties on recruiting sample.