Fitness in CLL

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors present a narrative review of the concept of “fitness” in CLL treatment and how it has changed from the CIT era and should now be assessed in the context of consideration of targeted therapies

 

Major issues:

• The paragraph on “Fitness in AML: transferrable lessons for CLL?” adds no meaningful insights for the reader and should be omitted
• Many of the sections are very “wordy” and repetitive. There could be consolidation / editing to improve succinctness of expression without compromising meaning e.g. section on chronological age
• Table 2 and linked trials discussion has omitted the AMPLIFY study (PMID 39976417) which should be included
• The relevance and impact of sarcopenia is not considered and should be included

Minor comments:

1. In the introduction it states that ECOG score is a “comorbidity scoring system” – this is incorrect – it simply grades functional status, regardless of cause.

Author Response

Reviewer 1

Major issues:

The paragraph on “Fitness in AML: transferrable lessons for CLL?” adds no meaningful insights for the reader and should be omitted

We thank the reviewer for this comment that we have carefully evaluated. The paragraph “Fitness in AML: transferable lessons for CLL?” represents the starting point of our reasoning. In AML, the concept of fitness has evolved significantly and this mindset-change paves the way for developing multidimensional approaches in other settings, such as CLL. Therefore, we have maintained the paragraph, slightly modifying it.

Many of the sections are very “wordy” and repetitive. There could be consolidation / editing to improve succinctness of expression without compromising meaning e.g. section on chronological age.

We have improved the succinctness of the text in all paragraphs. Please refers to the revised version for the modifications.

Table 2 and linked trials discussion has omitted the AMPLIFY study (PMID 39976417) which should be included

We thank the reviewer for this comment; we have added the AMPLIFY study in Table 2.

The relevance and impact of sarcopenia is not considered and should be included

We have included the relevance of sarcopenia in the paragraph: Nutrition and the role of the nutritionist in redefining fitness” -line 564-569.

Minor comments:

In the introduction it states that ECOG score is a “comorbidity scoring system” – this is incorrect – it simply grades functional status, regardless of cause.

We thank the reviewer for this comment; we have corrected the definition of ECOG score -line 63-64.

Reviewer 2 Report

Comments and Suggestions for Authors

Q1.                  Today, fitness also considers biological age, other medical conditions, and overall frailty. What are the other medical conditions?

Q2.                  Chronological age often fails to account for the multidimensional factors that influence treatment outcomes, tolerance, and quality of life. Emerging evidence highlights the relevance of biological age, frailty and comorbidities in providing a more comprehensive assessment. Chronological age often fails to account for the multidimensional factors. Specify multiple factors.

Q3.                  Explain the process of Eastern Cooperative Oncology Group creation.

Q4.                  In hematologic malignancies other than CLL, particularly acute myeloid leukemia (AML), the assessment of patient fitness plays a pivotal role in guiding treatment decisions. Explain the role of fitness.

Q5.                  Different clinical tools are available to evaluate fitness in patients with cancer. What are the clinical tools most suitable?

Q6.                  Patients with high CIRS scores or impaired renal function were treated with less intensive regimens, including chlorambucil-based therapie. References are not sufficient. It needs clarification.

Q7.                  Prospective data on the impact of fitness in targeted therapy settings remain scarce. The meaning is not clear.

Q8.                  A comorbidity score alone may not be sufficient to accurately define the patient's fitness. Defined comorbidity score.

Q9.                  A prospective Mayo Clinic study on 1143 patients with CLL evaluated comorbidities at diagnosis and their relationship to survival and cause of death. It is observed but no conclusions are given.

Q10.                Both CIRS and ECOG-PS are negative prognostic factors for targeted therapies. Authors truly define a patient as ineligible for treatment based solely on these tools. The reason is not specified.

Comments on the Quality of English Language

In each review paper the existing method is defined and then it merits/demerits are specified. It is not written properly in the study.

Author Response

Reviewer 2

Q1.                  Today, fitness also considers biological age, other medical conditions, and overall frailty. What are the other medical conditions?

We thank the reviewer for this comment. In the simple summary, we have revised the sentence to explicitly specify the multidimensional factors that may influence treatment outcomes, tolerance, and quality of life, including functional status, comorbidity burden, cognitive function, nutritional status, polypharmacy, and social support -line 26

Q2.                  Chronological age often fails to account for the multidimensional factors that influence treatment outcomes, tolerance, and quality of life. Emerging evidence highlights the relevance of biological age, frailty and comorbidities in providing a more comprehensive assessment. Chronological age often fails to account for the multidimensional factors. Specify multiple factors.

We have revised the manuscript to explicitly specify the multidimensional factors that may influence treatment outcomes, tolerance, and quality of life, including functional status, comorbidity burden, cognitive and nutritional status, polypharmacy, and social support – line 52-55

Q3.                  Explain the process of Eastern Cooperative Oncology Group creation.

We thank the reviewer for this comment. We have clarified in the manuscript that ECOG performance status is a clinician-assessed measure based on the evaluation of patients’ functional capacity and daily activity level, and we have added an appropriate reference -line 63-64

Q4.                  In hematologic malignancies other than CLL, particularly acute myeloid leukemia (AML), the assessment of patient fitness plays a pivotal role in guiding treatment decisions. Explain the role of fitness.

We have revised the introductory sentence to more explicitly highlight the role of fitness in guiding treatment selection, tailoring therapy, and minimizing treatment-related toxicity. We also note that the subsequent sentences in the paragraph further elaborate on this role, including how fitness informs treatment intensity, predicts treatment-related outcomes, and supports individualized patient care in AML -line 91-95.

Q5.                  Different clinical tools are available to evaluate fitness in patients with cancer. What are the clinical tools most suitable?

We would like to clarify that, at present, no single clinical tool can be considered the most suitable for fitness assessment in patients with cancer. Available instruments evaluate different and often complementary dimensions of fitness, each with intrinsic limitations. For this reason, current clinical practice relies on a combination of performance status, comorbidity indexes, and geriatric assessment tools rather than on a single optimal score. We have revised the manuscript accordingly to better reflect this concept -line 191-211.

Q6.                  Patients with high CIRS scores or impaired renal function were treated with less intensive regimens, including chlorambucil-based therapies. References are not sufficient. It needs clarification.

We thank the reviewer for this comment. We have clarified the clinical rationale underlying this treatment approach, specifying that high comorbidity burden and impaired renal function historically represented contraindications to intensive fludarabine-based chemoimmunotherapy due to increased toxicity. We also strengthened the reference list to better support the use of chlorambucil-based regimens in this patient population -line 225-230

Q7.                  Prospective data on the impact of fitness in targeted therapy settings remain scarce. The meaning is not clear.

We clarified the specific outcomes to which the statement refers -line 265-267

 

Q8.                  A comorbidity score alone may not be sufficient to accurately define the patient's fitness. Defined comorbidity score.

We thank the reviewer for this comment. We have clarified the statement by explicitly specifying commonly used comorbidity scores, such as the Cumulative Illness Rating Scale and the CLL- comorbidity index , and by highlighting their limitations when used as standalone measures of fitness -line 306-308

Q9.                  A prospective Mayo Clinic study on 1143 patients with CLL evaluated comorbidities at diagnosis and their relationship to survival and cause of death. It is observed but no conclusions are given.

We have revised the manuscript to clarify the implications of the study’s findings -line337- 344

Q10.                Both CIRS and ECOG-PS are negative prognostic factors for targeted therapies. Authors truly define a patient as ineligible for treatment based solely on these tools. The reason is not specified.

We thank the reviewer for this comment. We would like to clarify that the sentence in question is posed as a rhetorical question to highlight the limitations of using CIRS and ECOG-PS alone for determining treatment eligibility. It is not intended to imply that patients should be deemed ineligible solely based on these scores. The manuscript maintains this question to emphasize the need for a more comprehensive assessment in the era of targeted therapies. To avoid confusion, we have decided to remove the question.

In each review paper the existing method is defined and then it merits/demerits are specified. It is not written properly in the study. We thank the Reviewer for this important methodological observation.

We agree that a systematic evaluation of each tool's strengths and weaknesses is essential for a high-quality review. Accordingly, we have extensively revised the section "Limits of comorbidities score systems: how to cross them to redefine fitness". For each clinical tool discussed (CIRS, CLL-CI, ECOG PS, CCI and CGA), we have now provided:

1. A clear definition of the method.
2. An explicit description of its clinical merits (e.g., predictive value, ease of use).
3. A critical discussion of its demerits or limitations (e.g., time consumption, lack of multidimensionality).

We believe that this structured approach provides the "critical balance" requested and offers the reader a clearer guide for choosing the most appropriate tool in clinical practice -Line 191-211

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Q1.                  Chronic lymphocytic leukemia (CLL) predominantly affects older adults, and for decades, chronological age has been the principal criterion used to define patient fitness and guide treatment decisions. Reference is still not given.

Q2.                  Chronological age often fails to capture the multidimensional factors. Explain Chronological age and why it is used before age?

Q3.                  Traditional fitness scores appear increasingly outdated and insufficient to identify the most appropriate treatment strategy. Reason is not specified.

Q4.                  Fitness assessment should go beyond age. Clarify it.

Q5.                  In AML, several clinical scores have been developed. Explain the clinical scores with example. It is not answered though indirectly it was asked to explain.

Q6.                  Consideration of table 2 where trial is mentioned. It is to be justified its requirement.

Q7.                  The presence of comorbidities often requires the administration of concomitant therapies that may interfere with CLL treatments. It is not explained.

Comments on the Quality of English Language

In each review paper the existing method is defined and then it merits/demerits are specified. It is not written properly in the study.

Author Response

Comments and Suggestions for Authors

Q1.                  Chronic lymphocytic leukemia (CLL) predominantly affects older adults, and for decades, chronological age has been the principal criterion used to define patient fitness and guide treatment decisions. Reference is still not given.

We thank the reviewer for this comment. We have revised the manuscript by adding three appropriate references to support the statement that CLL predominantly affects older adults and that chronological age has historically been used to guide treatment decisions.

Q2.                  Chronological age often fails to capture the multidimensional factors. Explain Chronological age and why it is used before age?

We thank the reviewer for this comment. We used the term chronological age in contrast to biological age, to emphasize that chronological age refers solely to the number of years lived, whereas biological age better reflects an individual’s overall health status and the heterogeneity of aging. This distinction was intentionally adopted to highlight the limitations of chronological age as a surrogate for patient fitness and to introduce the concept of more comprehensive fitness assessment. Aging by itself is not a disease but leads to diminished physical function and quality of life in older individuals, of course. Biological age is not necessarily the same for every patient because it reflects the heterogeneity of the aging pathological process of everyone. Specialists talk about the difference between biological and chronological aging about how some people age more or less than others. In summary, chronological age measures the linear passage of time from birth until old age while biological age reflects the pathophysiological changes that occur over time. Even if older patients have goals of care and quality of life, age should not be a conditioning factor for effective therapy.

Q3.                  Traditional fitness scores appear increasingly outdated and insufficient to identify the most appropriate treatment strategy. Reason is not specified.

We thank the reviewer for this comment. We would like to clarify that this statement is intentionally placed in the introductory section to provide a general conceptual framework. The reasons underlying the limitations of traditional fitness scores are subsequently detailed in the following paragraph and supported by real-world evidence, as illustrated by the cited studies [9]. For this reason, we believe that further elaboration at this point would be redundant and disrupt the flow of the introduction.

Q4.                  Fitness assessment should go beyond age. Clarify it.

We thank the reviewer for this comment. In the manuscript, we clarify this statement by specifying that fitness assessment should extend beyond chronological age and comorbidities to include additional patient-centered factors such as polypharmacy, physical and cognitive function, nutritional status, ability to perform daily activities, and social support. These elements are explicitly listed to illustrate the multidimensional nature of fitness.

 

Q5.                  In AML, several clinical scores have been developed. Explain the clinical scores with example. It is not answered though indirectly it was asked to explain.

Acute myeloid leukemia was used only as an example to demonstrate the difficulty of assessing fitness, even in diseases that have been extensively studied. A thorough discussion of fitness scores in AML is beyond the scope of this review and would only make an already long paper even longer.

Q6.                  Consideration of table 2 where trial is mentioned. It is to be justified its requirement.

We thank the reviewer for this comment. Table 2 is included to explicitly document the eligibility criteria of pivotal clinical trials, particularly performance status requirements, and to illustrate the inherent selectivity of trial populations. While this concept is introduced in the text, the table provides a clear and immediate comparison across studies, showing that patients with ECOG performance status >2 were systematically excluded. This supports the statement that evidence from pivotal trials is largely derived from younger and fitter patients and highlights the gap between clinical trial populations and real-world patients.

Q7.                  The presence of comorbidities often requires the administration of concomitant therapies that may interfere with CLL treatments. It is not explained.

The opening sentence is intentionally introductory, and its rationale is directly explained in the subsequent sentences of the paragraph. Specifically, we detail how comorbidities frequently necessitate concomitant medications that interact with targeted CLL therapies through shared metabolic pathways, particularly the CYP3A-mediated system. We further discuss the clinical consequences of these interactions, including the need for dose adjustments, increased toxicity, or reduced treatment efficacy. We believe the paragraph as structured provides a logical progression from the general concept to its mechanistic and clinical implications.

Comments on the Quality of English Language

In each review paper the existing method is defined and then it merits/demerits are specified. It is not written properly in the study.

We thank the reviewer for this comment. We have extensively revised the section "Limits of comorbidities score systems: how to cross them to redefine fitness". At the end of the Introduction we have specified that this is a narrative review and, methodologically, does not required a predetermined protocol of research.

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

Authors changed the manuscript based on Reviewer comments. Now it is better than previous one.

Comments on the Quality of English Language

In each review paper the existing method is defined and then it merits/demerits are specified. It is not written properly in the study.