PONE-D-24-36417Potential Impact of Opioid Use in the Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation: Increased Incidence of Relapse and Worse Survival Among Intense Opioid UsersPLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. 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: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: No

Reviewer #2: Yes

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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: - The manuscript was submitted with tracked changes and comments, making it very difficult and unpleasant to read. This feels more like a draft version than a completed manuscript.

- All predictors in Cox, Kaplan-Meier and Grey's analysis must either be known at time 0 (transplant in this case), or be treated as time dependent covariates (which is only available for Cox).

- The authors observe a correlation and not causation, but make claims toward the latter. The use of opioids may have actually followed a significant medical problem (for example, a relapse) and not the other way around. Therefore, the conclusions are unfounded.

Reviewer #2: I congratulate the authors for this rare mentioned title on opiate use in alloHCT. I appreciate the methodology and idea behind it, but strong conclusive remarks and correlating opiate use with relapse and dismal outcome needs more clarification. My comments are shared below;

Major:

1- Title: Too strong, did we have any clue or proıf how to explain this phenomenon beyond immunosupressive effect of opiates.

2- Aim: Since 30 years I am a clinical transplanter I hardly remember any patient of mine, except autologous myeloma patients , and patients with avascular necrosis or severe osteoporosis needs opiate prescriptions. I am not convinvrd why these patients are on opiates.

3- Study population: Do patients started opiate use or the physcisians , it is not clear in the paper. The paper exludes before hand patients started opiates after 1 year post allo, and underlines the bias for relapse vulnerable period. How do they know that opiates will have impact on relapse beforehand? This is a hypothesis and should be performed in all opiate users, and selective analyses can be performed on selected populations.

4- Definition: According which reference or infobase you established the definition of IOU. Why you did not include the non malignant diseases? They suffer for certain degree transplant complications. The exclusion of benign disorders means that your intent is not only alloHCT base but malignant hematology based.

5- Methodology for relapse: For RFS we use 2 years threshold but you did not consider patients starting to use opiates after 1 year, this approach is erratic.

6- How do you biologically prove without knowing any exact dose, rason for prescription etc. that intense use is correlated with poor outcome. This is an observation of a retrospective single center cohort which has to be taken very cautiously.

7- L409 "Given the widespread use of opioids in the alloHCT setting", is this correct, do we have any clear data or publication so far since 60 years of alloHCT history.

Minor:

1- T1 please define Molecular and cytogenetics more clearly as caption,

2- T2 please revise as 2a UVA and 2b MVA, in current form not legible, and difficult to evaluate.

3- L380 "Several in vitro studies have shown that opioids can be immunosuppressive", very speculative either share details on pathophysiology or revise.

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Reviewer #1: No

Reviewer #2: Yes:  mutlu arat

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Exploring the impact of opioid use on outcomes in allogeneic hematopoietic stem cell transplantation

PONE-D-24-36417R1

Dear Dr. Mattsson,

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.

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Kind regards,

Monia Marchetti

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

the authors fulfilled the reviewers request and the manuscript can be published in its present format

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. 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: Yes

Reviewer #2: (No Response)

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: (No Response)

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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 Response)

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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: (No Response)

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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: (No Response)

Reviewer #2: (No Response)

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Reviewer #1: No

Reviewer #2: No

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