PONE-D-23-42267Patterns of belatacept use and risk of post-transplant lymphoproliferative disorder in US kidney transplant recipients: an analysis of the Organ Procurement and Transplantation Network databasePLOS ONE

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Additional Editor Comments:

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ACADEMIC EDITOR:Please revise the manuscript according to the Reviewers' comments.

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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: Yes

Reviewer #2: No

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

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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

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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

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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: Thank you for allowing me to review this manuscript for your journal. The authors present a long awaited analysis of the incidence of PTLD in patients receiving belatacept versus those receiving a CNI. The authors did a wonderful job with the statistics and reporting and should be commended. I have a few comments to strengthen the manuscript:

1. The authors need to make it more clear how they "know" patients are on belatacept or CNI throughout the 5 year period. In the methods, it is indicated that the TRR and TRF forms are utilized. These forms are routinely inaccurate. It would be an important addition to the manuscript to describe this in more detail. The results hinge on the confidence level of the data included. I am concerned that some patients started belatacept and stopped early and/or others started and stopped CNI at unknown time periods making the inclusion into different groups problematic.

2. The authors should include how long patients were on each therapy if known.

3. There may be a typo on page 13, "PTLD histopathology was reported in 8.9% of belatacept-treated...". Should this instead be 89%?

4. The paragraph on page 9 describing the baseline characteristics is somewhat clunky and not clearly written. It might be better instead to just refer the reader to table 1 and avoid redundancy.

Reviewer #2: This study attempted to compare the rates of PTLD in adult EBV +ve kidney transplant recipients who have received belatacept vs CNI between Jun 15 2011 to Jun 14 2016 using OPTN database. It's difficult to draw strong conclusions given the confounding variables, the small # of events in both groups and short duration of follow-up.

The following confounders will increase the risk of PTLD and would suggest including some discussions in the limitations:

In the overall cohort,

- The induction agents used were very different between the two groups favoring belatacept: Antithymocyte globulin (ATG) was used in 50.8% vs 22.9% and campath 15.7% vs 9.5% while basiliximab 59.5% vs 18.7% in CNI vs belatacept group, respectively (Table 1)

- Mean/median doses of ATG and Campath used in each group, if available

- rejection rate at 1 year 22.3% vs 9.5% in belatacept vs CNI group - while it's true that maintenance immunosuppressants would usually be intensified, this is rejection rate at 1 year and it's unclear of rejection rates after 1 year. Also, if pts were switched from CNI to belatacept, the risk of rejection would be higher during the switchover period (this may also explain why half of the belatacept pts were also taking CNI at the same time)

- What were the rejection rates during the entire study period? Patients were recruited between 2011 to 2015 and followed until 2019.

- half of the belatacept group was also taking CNI with 3 PTLD cases in this combo group. I assume the combination group was included in the belatacept group to increase its sample size. Were these patients being transitioned off CNI ?

- duration of follow-up in each group was unclear

Table 2 - were all pts followed for 5 years if last patient was enrolled in Jun 2016 and study closed in Apr 2019. What was the mean/median duration of follow-up in each group?

- while most PTLD cases surfaced early post-transplant, the LONG TERM PTLD risk of belatacept is unknown as BENEFIT and BENEFIT-EXT were relatively short duration. It would be more interesting to follow these patients for a longer period of time to realize the true PTLD risk of belatacept

Table 3 PTLD cases - 47.6% of CNI group received other/multiple drugs vs 0% in the belatacept group. What were these agents and could these have influenced the PTLD risks

S1. Why are ATG & 1-yr rejection rates not included in the model? Of the covariates used for matching, these are likely more relevant to the outcome of interest. Please explain 'region observations', 'all observations'

S2 Fig is difficult to understand. Please label the y-axis and legend accordingly. please explain 'region', 'observations', Control=CNI, treated = belatacept

Event rates were low in both overall and PSM cohorts - this could explain why no statistically significant differences were found between belatacept and CNI groups. I'm not sure if we can conclude 'the risk of PTLD is comparable to that observed among pts receiving CNI-based immunosuppression' (p.19)

Discussions - seems biased to me just focusing on confounders that biased against belatacept (p.17-18); underreporting of PTLD in CNI treated patients (p.19). Were all PTLD cases reported in belatacept group and only CNI group was underreported?

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Reviewer #1: No

Reviewer #2: No

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Patterns of belatacept use and risk of post-transplant lymphoproliferative disorder in US kidney transplant recipients: an analysis of the Organ Procurement and Transplantation Network database

PONE-D-23-42267R1

Dear Dr. Gomez-Caminero,

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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Additional Editor Comments (optional):

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 #2: All comments have been addressed

Reviewer #3: 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 #2: Yes

Reviewer #3: Yes

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

Reviewer #2: Yes

Reviewer #3: Yes

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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 #2: Yes

Reviewer #3: Yes

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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 #2: Yes

Reviewer #3: Yes

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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 #2: Thank-you for the revisions and addressing my questions/comments!

I do not any further suggestions.

Reviewer #3: In my opinion, all the reviewers' comments are properly addressed. I only suggest considering in the discussion that low-dose CNI could be combined with belatacept to avoid the risk of acute rejection (and additional multiple treatments) with good outcomes also on the risk of PTLD (10.1371/journal.pone.0240335).

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Reviewer #2: No

Reviewer #3: No

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