Post-Transplant Cyclophosphamide versus Anti-Thymocyte Globulin in Patients with Hematological Malignancies Treated with Allogeneic Hematopoietic Stem Cell Transplantation from Haploidentical and Matched Unrelated Donors: A Real-Life Experience

Round 1

Reviewer 1 Report

The authors present a retrospective study comparing cyclophosphamide with ATG in allo recipients with haploidentical donors.  The paper is well written, nevertheless there are some concerns and improvement suggestions I would like to address:

1)      The groups are unbalanced with respect to Stem cell source, which could explain differences in engraftment times. Could you present a multivariable analysis regarding this endpoint?

2)      Conditioning regimens were unbalanced between groups. What is the explanation for that? Could that explain differences found in both groups? This should be addressed in the discussion.

3)      Remission status before therapy could also influence the relapse curves. Can you present any information on that?

4)      Patients received prophylaxis with Letermovir. How was CMV statuts between donor and recipient?

5)      I would be very careful stating that GvHD rates between both groups are similar, as both groups are quite small. In addition, the groups are quite unbalanced, as mentioned above, thus the sample size may have been insufficient to detect differences between groups.

6)      One important endpoint in this comparison would be the NRM, as it helps to illustrate all-cause mortality in both groups. More specifically, as both groups are small, it would be interesting to describe cause of death (Infections, GvHD and Relapse), as they are also influenced by degree of immunosuppression. In addition, NRM could work as a confounder, as early death for other reasons may happen before progress. Would it be possible to present curves of NRM and Relapse mortality?

7)       In line 140, authors justify the protective effect of PTCY with the argument that it would cause a prompter immunological reconstitution. Nevertheless, engraftment was slower in these groups… I assume the T-cell-compartment is referred. Could you elaborate more on these possible differences? What are other possible causes of these differences in relapse?

8)      There were only 2 patients with MM in the PTCY groups. Please be careful drawing any conclusions based on this fact (line 155)

9)      No mentions to study limitations. Please add this to your manuscript based on these suggestions.

Author Response

Please see attached file

Author Response File: Author Response.pdf

Reviewer 2 Report

The authors present their studies on the use of cyclophosphamide in GvHD prophylaxis based on a retrospective study. The study is very interesting, I only have a few remarks: 

1) The main issue I see with this study is that there are diverse drugs used in the two treatment arms. Therefore, the findings could be - at least partially - explained by these (MMF vs. MTX and tacrolimus). The authors should discuss this in more detail. Further, is it possible to access the potential contribution of these drugs?

2) Introduction, line 40: The authors claim that immunosuppressors are used in GvHD prophylaxis. More examples should be given for this. Please add. 

3) The authors should include more details on potential side effects of cyclophosphamide in the therapy regimen into the discussion. 

4) Is the tumor entity important for the cyclophosphamide treatment outcome?

Author Response

Please see attached file

Author Response File: Author Response.pdf

Reviewer 3 Report

The authors conducted a retrospective data analysis of patients who underwent allogeneic stem cell transplantation from haploidentical and matched unrelated donor. They compared the outcome and the analyzed the AEs of patients who received for GVHD prophylaxis ATG and those who received post-transplant cyclophosphamide in a comparative manner.

The authors did not find significant difference between the two cohorts (Cycloph. Versus ATG). However, the number of pts included in both arms is small. The authors are encouraged to discuss limitation of their study such as the previously mentioned small number of included patients, the strong heterogeneity between both groups (disease type, source of stem cells, type of donors and conditioning regimens received). Al of these, but not limited to, can certainly influence the results. This has to be acknowledged and discussed.

Author Response

The authors conducted a retrospective data analysis of patients who underwent allogeneic stem cell transplantation from haploidentical and matched unrelated donor. They compared the outcome and the analyzed the AEs of patients who received for GVHD prophylaxis ATG and those who received post-transplant cyclophosphamide in a comparative manner.

Response to General Comments. We thank the Reviewer for this positive feedback on our work and we hope we have addressed all concerns.

The authors did not find significant difference between the two cohorts (Cycloph. Versus ATG). However, the number of pts included in both arms is small. The authors are encouraged to discuss limitation of their study such as the previously mentioned small number of included patients, the strong heterogeneity between both groups (disease type, source of stem cells, type of donors and conditioning regimens received). Al of these, but not limited to, can certainly influence the results. This has to be acknowledged and discussed.

Response to Comment 1. We apologize for this missing part, and we have added the following paragraph in the discussion section.

On lines 181-188, the following text was added “Our study has some limitations: (i) the retrospective nature of this work; (ii) a small sample size with some population heterogeneity, such as hematological disease type, stem cell source, donor type, conditioning regimen, and GvHD prophylaxis. Of note, GvHD prophylaxis regimens are frequently heterogeneous, especially outside clinical trials and in real-life retrospective observational studies [32-34], and conditioning regimens are chosen based on international guidelines, disease type, clinical decisions, and local Institution guidelines. However, logistic regression analysis did not show a significant impact of these variables on GvHD incidence or disease relapse.”

Round 2

Reviewer 1 Report

The authors have answered my questions sufficiently and carefully.