Fasting and Diet: Overview in Chronic Lymphocytic Leukemia

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors review literature on diet and fasting specifically in chronic lymphocytic leukemia.

Author Response

Comments: The authors review literature on diet and fasting specifically in chronic lymphocytic leukemia.

Response: We have reviewed the literature on diet and fasting in CLL and added the following references: 52, 57, 58, and 66.

Please see the attachment. We have highlighted the changes made to the paper in red in response to your comments.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

In their review, "Fasting and Diet," Trojani et al. provide an overview of the relationships between fasting and diet and disease progression or treatment success in the context of chronic lymphocytic leukemia (CLL) treatment. Trojani et al. review a substantial number of existing studies on the subject, yet the topic is frequently addressed in a cursory and superficial manner. It is imperative that improvements be made in both the content and the manner of its presentation.
1. The authors dedicate a significant amount of effort to identifying and delineating the key factors associated with CLL, with a particular focus on genetic markers that influence the disease's progression. However, the summary is largely inconsequential for further understanding, as no implications emerge from it when fasting and dieting are considered in the context of the discussion of Nevertheless, an analysis of case reports is not a suitable approach for a review, given that the scientific findings have not been obtained on the basis of controlled studies. It is also noteworthy that case number three was authored by the same individuals.
3. The role of vitamin D in other forms of lymphatic diseases has been the subject of more extensive investigation than its impact on CLL. It would be beneficial to include the findings of other studies, such as those on DLBCL, to provide a more comprehensive review. For instance, Nakamura et al. (2024) investigated the effect of vitamin D and skeletal muscle mass on the prognosis of patients with diffuse large B-cell lymphoma. Their findings could be included in this discussion.
4. In recent years, a substantial body of literature has emerged examining the relationship between fasting and dietary patterns and the development of solid tumor diseases, particularly breast cancer and colorectal cancer. While these findings may not be directly applicable to CLL, they offer insights that could inform future research directions.

Comments on the Quality of English Language

Minor adjustement needs to be applied

Author Response

Comments 1: The authors dedicate a significant amount of effort to identifying and delineating the key factors associated with CLL, with a particular focus on genetic markers that influence the disease's progression. However, the summary is largely inconsequential for further understanding, as no implications emerge from it when fasting and dieting are considered in the context of the discussion of Nevertheless, an analysis of case reports is not a suitable approach for a review, given that the scientific findings have not been obtained on the basis of controlled studies. It is also noteworthy that case number three was authored by the same individuals.

Response 1: Thank you for pointing this out, and we agree with your observations. We have accordingly revised the discussion to emphasize the role of fasting and dieting in cancer, particularly in CLL. Page number: 14, Paragraph: Conclusions, Line: 546-558 and 560-572.

We also agree with your comment that analysing case reports is not the most suitable approach for a review, as the findings are not based on controlled studies but in addition to the studies presented, we explored the literature to identify patients with CLL who followed a specific diet or fasting regimen. To the best of our knowledge, there are only three such cases. We are particularly interested in the association between fasting/diet and CLL. One of these cases was studied at our hospital, where the patient exhibited a unique pattern of lymphocytosis associated with prolonged fasting. We believe presenting these three cases in our review would be valuable, as the association between cancer and fasting/diet is an increasingly interesting topic.

Comments 2: The role of vitamin D in other forms of lymphatic diseases has been the subject of more extensive investigation than its impact on CLL. It would be beneficial to include the findings of other studies, such as those on DLBCL, to provide a more comprehensive review. For instance, Nakamura et al. (2024) investigated the effect of vitamin D and skeletal muscle mass on the prognosis of patients with diffuse large B-cell lymphoma. Their findings could be included in this discussion.

Response 2: Thank you for your observations regarding the role of vitamin D in diseases beyond CLL. As you suggested, we have included the findings on vitamin D in DLBCL from the study by Nakamura et al. (Reference 57). These findings have also been incorporated into the discussion, in line with your recommendation Page number: 10, Paragraph: Diet and fasting in CLL, Line: 379-387. Page number: 14, Paragraph: Conclusions, Lines: 546-553.

Comments 3: In recent years, a substantial body of literature has emerged examining the relationship between fasting and dietary patterns and the development of solid tumour diseases, particularly breast cancer and colorectal cancer. While these findings may not be directly applicable to CLL, they offer insights that could inform future research directions.

Response 3: Thank you for pointing this out. We agree with your comments regarding the association between fasting, dietary patterns, and specific solid tumours. In response, we have included three studies focusing on breast cancer and colorectal cancer (References: 18,19, and 20). Page number: 3, Paragraph: Fasting, diet and metabolism in cancer Line: 112-134.

Please see the attachment. We have highlighted the changes made to the paper in red in response to your comments.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Line 148-154	Please, reformulate the definition of CLL Indeed, the diagnosis of CLL requires the presence of ≥5 × 109/L B lymphocytes in the peripheral blood for at least 3 months. CLL cells are characteristically mature lymphocytes.
Line 162-163	The Authors should reformulate the definition of CLL progression and active disease.
Figure 1	Please, correct “7p-“
Line 241	Ref. 37 The authors should be more explicit about the fact that the study in question is a preclinical study.
The Authors are strongly encouraged to summarize the therapeutic paradigm of CLL based on novel target agents and to report prognostic factors in early stage CLL. In addition, the Authors should also indicate the possible role of fasting in TLS and gastrointestinal bleeding in patients treated with novel agents, as reported by Benkhadra et al. [ref. 52].

Author Response

Comments 1: Line 148-154. Please, reformulate the definition of CLL Indeed, the diagnosis of CLL requires the presence of ≥5 × 10⁹/L B lymphocytes in the peripheral blood for at least 3 months. CLL cells are characteristically mature lymphocytes.

Response 1: Thank you for your suggestions. We have revised the definition of CLL diagnosis as you kindly recommended. Page number: 5, Paragraph: CLL, Line: 178-180.

Comments 2: Line 162-163. The Authors should reformulate the definition of CLL progression and active disease.

Response 2: Thank you for pointing this out. We agree with your suggestions and have accordingly revised the definitions of disease progression and the active form of CLL. Page number: 5, Paragraph: CLL, Line: 193-204.

Comments 3: Figure 1. Please correct 7p-

Response 3: Sorry for our mistake. We have corrected "7p-" to del(17p13) in Figure 1. Page number: 7.

Comments 4: Line 241. Ref. 37. The authors should be more explicit about the fact that the study in question is a preclinical study.

Response 4: We agree with your comment. We have added further explanations about the study by Darwiche et al., emphasizing the preclinical findings of their research. Page number: 9, Paragraph: Diet and fasting in CLL, Line: 347-355.

Comments 5: The Authors are strongly encouraged to summarize the therapeutic paradigm of CLL based on novel target agents and to report prognostic factors in early stage CLL.

Response 5: Thank you for your suggestions. We have accordingly emphasized the therapeutic paradigm of CLL based on novel targeted agents and added information on prognostic factors in early-stage CLL. Page number: 8, Paragraph: CLL, Line: 327-339. Page number: 5, Paragraph: CLL, Line 201-204. Page number 6, Paragraph: CLL, line: 205-243.

Comments 6: In addition, the Authors should also indicate the possible role of fasting in TLS and gastrointestinal bleeding in patients treated with novel agents, as reported by Benkhadra et al. [ref. 52].

Response 6: We agree with this comment. We have reported the findings by Benkhadra et al., who highlighted the potential role of fasting in tumour lysis syndrome (TLS) and gastrointestinal bleeding in CLL patients treated with novel drugs. Page number: 14, Paragraph: Conclusions, Line: 560-572. 

Please see the attachment. We have highlighted the changes made to the paper in red in response to your comments.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Adjustments have been implemented, remarks and concerns by the reviewer have been adressed