Optimizing Access to Unrelated Donors in Canada: Re-Examining the Importance of Donor Factors on Outcomes Following Hematopoietic Cell Transplantation

Round 1

Reviewer 1 Report

This review presents an insightful updated analysis of the Canadian Blood Services Stem Cell Registry along with the array of donor options available within a diverse population base found in Canada. Additionally, the authors provide a comprehensive summary of the evolving landscape of donor selection considerations, particularly pertinent in the modern era where multiple donor options, including haploidentical and mismatched unrelated donors, are increasingly viable with the integration of post-transplant cyclophosphamide and/or ATG for graft-versus-host disease prevention, highlighting the importance of staying updated on donor consideration to optimize transplant success rates.

Author Response

Reviewer 1

This review presents an insightful updated analysis of the Canadian Blood Services Stem Cell Registry along with the array of donor options available within a diverse population base found in Canada. Additionally, the authors provide a comprehensive summary of the evolving landscape of donor selection considerations, particularly pertinent in the modern era where multiple donor options, including haploidentical and mismatched unrelated donors, are increasingly viable with the integration of post-transplant cyclophosphamide and/or ATG for graft-versus-host disease prevention, highlighting the importance of staying updated on donor consideration to optimize transplant success rates.

• We appreciate the reviewer’s comment and support of our manuscript.

Reviewer 2 Report

The authors present a review of donor factors influencing transplantation and how to optimize access to unrelated donors in Canada. I have some comments after reviewing the manuscrip:

- The purpose of the manuscript is good in concept, but poorly implemented. The main text should be better organized. For example, starting with the registry composition is not the best option, and this part should be placed in the end of the main text, to allow the discussion of the different donor variables introduced before. Besides, no conclusion is given. I suggest an alternative structure of the text with a first part reviewing donor factors, and a second part showing how the registry has changed to fit their requests.

- I miss more profound revision of every subheading. Superficial literature revision is given, with little data supporting the statements (e.g: last sentence of first paragraph in page 6: "These factors remain under active research and consideration of these factors would be considered research that should be conducted under approved research protocols"). The reader should read every reference to get knowledge of what is stated in the text. I would appreciate more accurate information on the text if this is suposed to be a review article. For example: explain KIR matching and if any information exist in unrelated donors, better explain what ABO incompatibility means, also during follow up (red cell aplasia, delayed erythroid engraftment...),

- The figure (or table) named Box 1 is not helpful. Sentences are too long. 

- some mistyping errors: 1) "older" is repetated in page 4 , second paragraph, line 9; 2) "areincreasingly" shoud be divided into two words; 3) In page 6 the word "signalling" should be replace by shows or signals...

Author Response

Reviewer 2

- The main text should be better organized. For example, starting with the registry composition is not the best option, and this part should be placed in the end of the main text, to allow the discussion of the different donor variables introduced before. Besides, no conclusion is given. I suggest an alternative structure of the text with a first part reviewing donor factors, and a second part showing how the registry has changed to fit their requests.

• We have moved the section on registry composition to the end (Section 5.0), as suggested by the reviewer.
• We have added a concluding section that summarizes the main points and makes suggestions of how donor factors can be considered in donor selection. The bullet points have been expanded into an expanded paragraph format (Section 6.0)

- I miss more profound revision of every subheading. Superficial literature revision is given, with little data supporting the statements (e.g: last sentence of first paragraph in page 6: "These factors remain under active research and consideration of these factors would be considered research that should be conducted under approved research protocols"). The reader should read every reference to get knowledge of what is stated in the text. I would appreciate more accurate information on the text if this is suposed to be a review article. For example: explain KIR matching and if any information exist in unrelated donors, better explain what ABO incompatibility means, also during follow up (red cell aplasia, delayed erythroid engraftment...),

• Areas that require more research and which remain preliminary are not addressed to the same extent, however, we have added more details on some areas to satisfy reader interest, in accordance with the reviewer’s suggestion.

- The figure (or table) named Box 1 is not helpful. Sentences are too long. 

• The box has been removed and this section is now presented in a paragraph form as the Conclusion (Section 6.0). This also addresses point 1 above.

- some mistyping errors: 1) "older" is repetated in page 4 , second paragraph, line 9; 2) "areincreasingly" shoud be divided into two words; 3) In page 6 the word "signalling" should be replace by shows or signals...

• We appreciate the reviewer highlighting these errors which have been corrected.

Reviewer 3 Report

In this review, the authors describe an access to unrelated donors in Canada. Authors present the importance of donor factors on outcomes following hematopoietic cell transplantation. The article is well written and quite interesting, although not innovative. I suggest checking references.

The topic is not innovative, but Authors present and summarize it in a quite interesting way.

I think that this review focuses on donor factors on outcomes following HCT. This analysis is added to the subject area compared with other published material.

Methodology is well written and clear.

The conclusions should be added by authors.

The tables are well and clear.

English is well.

Author Response

Reviewer 3

The topic is not innovative, but Authors present and summarize it in a quite interesting way.

• We feel the topic was worth revisiting with improved approaches for the prevention of GVHD (use of ATG and use of post-transplant cyclophosphamide) which introduce a timely need for a re-evaluation of how donor factors impact transplant outcomes.

The conclusions should be added by authors.

• Please see our revised final section (Section 6.0) which provides conclusions for the reader.

Reviewer 4 Report

The authors presented a review of non-HLA factors and recommendations on the selection of optimal non-related donors for HCT. The subject is interesting and worth to be reviewed; however, the suggested recommendations/considerations (Box 1) are not proven by adequate articles / studies. The recommendations must be made according to well-known standards. 

For example: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 Mar 29;372:n71. doi: 10.1136/bmj.n71. PMID: 33782057; PMCID: PMC8005924.

There are neither the Method, the Discussion, nor the Conclusions sections in the manuscript, which are both necessary to summarise presented publications and conclude on the present state of the art in this field. If the authors want to present only Canadian experience based on CBS SCR, it should be also stated, and the paper should be rewritten - the discussion and conclusion is the must. 

Minor comments:

There are many minor errors in the text, such as interpunctions, doublets of words, etc. The article form used does not include numbered lines, so it is hard to show exactly where the error is.  

Some articles by authors are cited in an inappropriate way. 

Author Response

Reviewer 4

The authors presented a review of non-HLA factors and recommendations on the selection of optimal non-related donors for HCT. The subject is interesting and worth to be reviewed; however, the suggested recommendations/considerations (Box 1) are not proven by adequate articles / studies. The recommendations must be made according to well-known standards. 

• Our recommendations are now prefaced by a statement that they are not graded in accordance with specific guidelines due to the limited available data from the era of improved prevention of GVHD, and we now offer that this may be warranted for more precise evaluation of donor factors in subsequent systematic reviews. [see Section 6.0, first sentence]. Also, the abstract now refers to these “suggestions for consideration” rather than formal recommendations or guideline.

There are neither the Method, the Discussion, nor the Conclusions sections in the manuscript, which are both necessary to summarise presented publications and conclude on the present state of the art in this field. If the authors want to present only Canadian experience based on CBS SCR, it should be also stated, and the paper should be rewritten - the discussion and conclusion is the must. 

We have structured this review article in accordance with the Instructions to authors [https://www.mdpi.com/journal/curroncol/instructions] which suggests that Reviews offer a comprehensive analysis of the existing literature within a field of study, identifying current gaps or problems. … The structure can include an Abstract, Keywords, Introduction, Relevant Sections, Discussion, Conclusions, and Future Directions, with a suggested minimum word count of 4000 words. We have changed Section 5.0 to Discussion: How can registries reflect the changing needs? A closer look at the CBS Stem Cell Registry. Section 6 is now Conclusions and Future Directions: Considerations for Unrelated Donor Selection. The manuscript is now approximately 4000 words.

Minor comments:

There are many minor errors in the text, such as interpunctions, doublets of words, etc. The article form used does not include numbered lines, so it is hard to show exactly where the error is.  

• Line numbers are now provided. We have carefully reviewed the manuscript for errors and have edited it accordingly. Thanks for this comment.

Some articles by authors are cited in an inappropriate way. 

• We have reviewed all references and have removed several, and replaced several with more appropriate references. Due to reorganization of the manuscript, many references were renumbered.

Round 2

Reviewer 2 Report

The manuscript has notably improved with the revision of the authors. Only one minor comment:

- In section 4.5, please address that this kind of studies are applied to related donors.

Author Response

We have added a comment in 2 places in section 4.5 that indicates these factors may be implicated in either related or unrelated allogeneic donor HCT.

Reviewer 4 Report

No further remarks.

Author Response

We are grateful for the reviewers perspective. No specific changes made.