Comparison of dose-adjusted EPOCH-R and R-CHOP in diffuse large B-cell lymphoma with high Ki67 expression: Results from a prospective observational study

Wenxin Jiang; Peng Liu

doi:10.1371/journal.pone.0350024

Peer Review History

Original SubmissionMarch 14, 2026
8 Apr 2026 Decision Letter - Francesco Bertolini, Editor -->PONE-D-26-12059-->-->Comparison of dose-adjusted EPOCH-R and R-CHOP in diffuse large B-cell lymphoma with high Ki67 expression: results from a prospective observational study-->-->PLOS One Dear Dr. Liu, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.-->-->Please re-submit only if you can fully answer criticism from both Reviewers, and in particular those from Reviewer #1. Please submit your revised manuscript by May 23 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. 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Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. --> Reviewer #1: No Reviewer #2: Yes ******** -->2. Has the statistical analysis been performed appropriately and rigorously? --> Reviewer #1: No Reviewer #2: Yes ****** -->3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.--> Reviewer #1: Yes Reviewer #2: No ****** -->4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.--> Reviewer #1: Yes Reviewer #2: Yes ****** -->5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)--> Reviewer #1: Jiang and colleagues reported the results of both retrospective and prospective studies comparing the therapeutic efficacy of DA-EPOCH-R and R-CHOP in patients with high Ki-67 DLBCL. This manuscript contains some interesting information; however, there are some severe problems in this manuscript. Major comments: 1) The rationale for selecting DA-EPOCH-R for patients with Ki-67-high DLBCL is not entirely clear. Although a high Ki-67 index may reflect a highly aggressive proliferative phenotype, it remains unclear whether this alone justifies the use of DA-EPOCH-R. The authors should provide a clearer explanation of the biological and/or clinical rationale for this treatment strategy and present evidence to support it. 2) The manuscript lacks essential information regarding the study design. Specifically, the phase of the clinical trial is not specified, and key statistical parameters such as the alpha level and statistical power are not described. Without these details, it is difficult to interpret the validity of the study as a prospective clinical trial. The authors should clearly define the trial phase and provide a detailed statistical design, including assumptions for sample size calculation. 3) The prior retrospective analysis reported a 2-year PFS of approximately 75% in the patients with high KI-67 DLBCL received DA-EPOCH-R. In this context, the assumption of a 2-year PFS of 90% with DA-EPOCH-R appears overly optimistic and lacks sufficient justification. This substantial discrepancy is not addressed in the manuscript. The authors should clarify the rationale for this assumption or provide supporting evidence. 4) The proportion of GCB-type DLBCL in this cohort is relatively high (69%). Although the authors state that HGBCL cases were excluded, it is unclear whether MYC and BCL2 rearrangements were systematically assessed by FISH. Without such evaluation, the possibility that HGBCL cases were inadvertently included cannot be excluded. Reviewer #2: This is prospective cohort study using a retrospective propensity score matched population to compare DA-EPOCH-R with R-CHOP in pts with KI67> 80%. No differences are seen in PFS / OS. The study design is solid, the manuscript well written and results are resented in a clear way. I only have a few minor suggestions for improvement: Minor comments: line 126: "treatment regimens were chosen by patients". Surely the patients did not choose the treatment regiments. Please adjust the wording for clarity. line 194: Instead of "elderly" please state the exact age cut off you used, because for me it was not clear. line 278: "high-risk" can be misinterpreted, as risk is usually defined per IPI. I Would suggest to write instead "with high Ki67 expression" ****** -->6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.--> Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. https://doi.org/10.1371/journal.pone.0350024.r001
Revision 1
17 Apr 2026 Author Response Dear editors and reviewers: We greatly appreciate your efforts during the review process and the opportunity to make corrections and supplements, which have significantly improved the quality of our manuscript. We have revised the content according to the reviewers’ comments, with the changes clearly marked (in red font, excluding changes in reference numbers due to added citations), and have provided point-by-point explanations for the revisions. We would like to express our sincere gratitude for your valuable time and constructive feedback. Should there be any further concerns or additional modifications required, we are more than willing to make any necessary revisions promptly. Point-by-point response Reviewer #1: Jiang and colleagues reported the results of both retrospective and prospective studies comparing the therapeutic efficacy of DA-EPOCH-R and R-CHOP in patients with high Ki-67 DLBCL. This manuscript contains some interesting information; however, there are some severe problems in this manuscript. Major comments: 1)The rationale for selecting DA-EPOCH-R for patients with Ki-67-high DLBCL is not entirely clear. Although a high Ki-67 index may reflect a highly aggressive proliferative phenotype, it remains unclear whether this alone justifies the use of DA-EPOCH-R. The authors should provide a clearer explanation of the biological and/or clinical rationale for this treatment strategy and present evidence to support it. Response: We fully agree with your reasonable concern. We agree that a high Ki-67 index alone, as a measure of proliferation, is insufficient to justify the selection of a specific chemotherapy regimen. In the revised manuscript, we have provided a clearer biological and clinical rationale for choosing DA-EPOCH-R in this setting (line 82-87), which we summarize as follows: 1.Biological Rationale: A previous study indicated that unlike traditional chemotherapy (e.g., CHOP), DA-EPOCH utilizes a 96-hour continuous infusion, which may be more effective against rapidly dividing tumors and are consistent with in vitro models that showed an increased sensitivity of dividing cells to DNA-damaging agents [Blood. 2002 Apr 15;99(8):2685-93. doi: 10.1182/blood.v99.8.2685.]. Therefore, we hypothesized that DLBCL with high Ki67 expression might benefit from DA-EPOCH-R. 2.Clinical Evidence: The R-EPOCH regimen achieved superior PFS and OS compared to the R-CHOP regimen in DLBCL patients with high Ki67 expression in a previous study [Oncotarget. 2016 May 10;7(27):41242-41250. doi: 10.18632/oncotarget.9271], we hypothesized that the DA-EPOCH-R regimen might offer greater benefits for this patient population. We have added the following references and corresponding text to the manuscript to support this rationale. 2) The manuscript lacks essential information regarding the study design. Specifically, the phase of the clinical trial is not specified, and key statistical parameters such as the alpha level and statistical power are not described. Without these details, it is difficult to interpret the validity of the study as a prospective clinical trial. The authors should clearly define the trial phase and provide a detailed statistical design, including assumptions for sample size calculation. Response: We fully agree with your valuable comment. The design of this trial followed standard sample size and statistical analysis procedures. However, we inappropriately omitted certain methodological details during writing. We have now re-added the alpha level and statistical power used in the study design to the Statistical Analysis section (line 164-165, “Using a one-sided significance level of α=0.05 and a power (1-β) of 80%”). Since this is an observational study, the concept of clinical trial phases does not apply. 3) The prior retrospective analysis reported a 2-year PFS of approximately 75% in the patients with high KI-67 DLBCL received DA-EPOCH-R. In this context, the assumption of a 2-year PFS of 90% with DA-EPOCH-R appears overly optimistic and lacks sufficient justification. This substantial discrepancy is not addressed in the manuscript. The authors should clarify the rationale for this assumption or provide supporting evidence. Response: We fully agree with and understand your considerate comments. We also took into account the current state of research at the time when designing the study, but we did not clearly mention this in the manuscript. In a previous study, the R-EPOCH regimen (not DA-EPOCH-R) achieved a 2-year PFS rate more than 85% in DLBCL patients with high Ki67 expression [Oncotarget. 2016 May 10;7(27):41242-41250. doi: 10.18632/oncotarget.9271], thus we anticipate that DA-EPOCH-R could further improve this outcome based on the biological rationale. The relevant statements have now been re-added to the manuscript (line 161-164, “Given the R-EPOCH regimen achieved a 2-year PFS rate more than 85% in DLBCL patients with high Ki67 expression , we anticipate that DA-EPOCH-R could further improve this outcome based on the biological rationale”). 4) The proportion of GCB-type DLBCL in this cohort is relatively high (69%). Although the authors state that HGBCL cases were excluded, it is unclear whether MYC and BCL2 rearrangements were systematically assessed by FISH. Without such evaluation, the possibility that HGBCL cases were inadvertently included cannot be excluded. Response: We fully understand this reasonable concern. All patients in the cohort underwent FISH testing to rule out HGBCL. However, patients with a single MYC or BCL2 rearrangement were not excluded, as they accounted for a relatively small proportion of the cohort. We have added this information back into the baseline characteristics (Table 1). Reviewer #2: This is prospective cohort study using a retrospective propensity score matched population to compare DA-EPOCH-R with R-CHOP in pts with KI67> 80%. No differences are seen in PFS / OS. The study design is solid, the manuscript well written and results are resented in a clear way. I only have a few minor suggestions for improvement: Minor comments: line 126: "treatment regimens were chosen by patients". Surely the patients did not choose the treatment regiments. Please adjust the wording for clarity. Response: We apologize for any ambiguity caused by unclear expressions in the manuscript. We agree that the original wording “chosen by patients based on physician recommendations” was imprecise and could be misinterpreted as patients independently selecting specific treatment regimens. In fact, as a prospective observational study, the decision-making process was as follows: physicians first provided recommended treatment options based on clinical guidelines and their judgment; patients then made the final choice after being fully informed, in consultation with their physicians, the choice was strongly guided by physician recommendations. We have revises the sentence as “the treatment regimens were not randomized but were chosen by patients in consultation with their physicians, who provided treatment recommendations.” (line 131-132) line 194: Instead of "elderly" please state the exact age cut off you used, because for me it was not clear. Response: Thank you for your correction. This was indeed an inaccuracy in our writing. We have now added an explanation of the age cutoff value (age≥60 years old) to the manuscript (line 201). line 278: "high-risk" can be misinterpreted, as risk is usually defined per IPI. I Would suggest to write instead "with high Ki67 expression" Response: Thank you for your correction. We have revised the ambiguous term 'high risk,' which will undoubtedly enhance the scientific rigor of the manuscript (line 284-285). Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0350024.r002
7 May 2026 Decision Letter - Francesco Bertolini, Editor Comparison of dose-adjusted EPOCH-R and R-CHOP in diffuse large B-cell lymphoma with high Ki67 expression: results from a prospective observational study PONE-D-26-12059R1 Dear Dr. Liu, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. 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Has the statistical analysis been performed appropriately and rigorously? --> Reviewer #1: Yes Reviewer #2: Yes ****** -->4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.--> Reviewer #1: Yes Reviewer #2: No ****** -->5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.--> Reviewer #1: Yes Reviewer #2: Yes ****** -->6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)--> Reviewer #1: The manuscript has been revised appropriately in response to the reviewers’ comments, and the overall quality of the manuscript has been substantially improved.　Therefore, in its current form, this manuscript is considered acceptable for publication. Reviewer #2: No more comments, I appriociate you for taking my suggestions into consoderation. The manuscript remains of limited clinical significance, however is suitable for publication. ****** -->7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.--> Reviewer #1: No Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0350024.r003
Formally Accepted
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