Anti-Thymocyte Globulin (ATG)-Free Nonmyeloablative Haploidentical PBSCT Plus Post-Transplantation Cyclophosphamide Is a Safe and Efficient Treatment Approach for Pediatric Acquired Aplastic Anemia

Round 1

Reviewer 1 Report

The article concerns the well-studied issue of managing severe acquired aplastic anemias (AA) by means of conventional immunosuppression, or hematopoietic stem cell transplantation (HSCT), as a salvage therapeutic option after long-term remission of the disease. The authors describe a sufficient clinical series of 12 patients (children and young qdults) suffering with this rare condition and pathogenic mutations found in some cases. Of interest are shortened telomeres in the patients with SAMD9L
mutation. A part of patients (n=8) received haploidentical HSCT with ATG or post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis. A GVHD-preventing PTCy effect was previously demonstrated in many other hematological conditions treated by HSCT from haploidentical donors. General conclusion on favorable clinical outcomes when using the modified PTCy-based regimen for this group of AA patients is quite adequate, being efficient and safe for salvage treatment.  

Generally, the article confirms  the known efficiency of PTCy regimen post-transplant in this rare group of AA pediatric patients, thus being of sufficient use for HSCT practitioners.  Moreover, the patients underwent whole-genome DNA analysis, a search for risky HLA alleles, and telomere studies, thus expanding the knowledge on molecular basis of the disorder.

There are no sufficient remarks or corrections on the material which is carefully written, designed, and discussed.

The paper may be published without sufficient changes.

Author Response

The article concerns the well-studied issue of managing severe acquired aplastic anemias (AA) by means of conventional immunosuppression, or hematopoietic stem cell transplantation (HSCT), as a salvage therapeutic option after long-term remission of the disease. The authors describe a sufficient clinical series of 12 patients (children and young adults) suffering with this rare condition and pathogenic mutations found in some cases. Of interest are shortened telomeres in the patients with SAMD9L
mutation. A part of patients (n=8) received haploidentical HSCT with ATG or post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis. A GVHD-preventing PTCy effect was previously demonstrated in many other hematological conditions treated by HSCT from haploidentical donors. General conclusion on favorable clinical outcomes when using the modified PTCy-based regimen for this group of AA patients is quite adequate, being efficient and safe for salvage treatment.  

Thank you!

Generally, the article confirms  the known efficiency of PTCy regimen post-transplant in this rare group of AA pediatric patients, thus being of sufficient use for HSCT practitioners.  Moreover, the patients underwent whole-genome DNA analysis, a search for risky HLA alleles, and telomere studies, thus expanding the knowledge on molecular basis of the disorder.

Thank you!

There are no sufficient remarks or corrections on the material which is carefully written, designed, and discussed.

Thank you!

The paper may be published without sufficient changes.

Thank you!

Reviewer 2 Report

The article ”Anti-thymocyte globulin (ATG)-Free Nonmyeloablative Haploidentical PBSCT Plus Post-transplantation Cyclophosphamide is a Safe and Efficient Treatment Approach for Pediatric Acquired Aplastic Anemia” - brings data that sustains the use of the indicated protocol for salvaging refractory pediatric Aplastic Anemia.

The article shows the author's experience and a high level of expertise. The article is addressed mainly to a similar level of readers and gives no chance for non-expertise readers to follow the data. To be able to read, understand and evaluate the article was necessary to look at similar articles to comprehend the content. Fortunately, there are a lot of articles about Acquired aplastic anemia: 751.000 results (0,94 seconds) on google.

It seems necessary for an improved introduction to make possible a large spectrum of readers.

Also necessary is to have a paragraph about study limitations. Why only 12 patients? How we can extend the conclusions? 

Also necessary seems to be a future research directions section in which to detail further steps for the newly proposed protocol.

Author Response

The article ”Anti-thymocyte globulin (ATG)-Free Nonmyeloablative Haploidentical PBSCT Plus Post-transplantation Cyclophosphamide is a Safe and Efficient Treatment Approach for Pediatric Acquired Aplastic Anemia” - brings data that sustains the use of the indicated protocol for salvaging refractory pediatric Aplastic Anemia.

The article shows the author's experience and a high level of expertise. The article is addressed mainly to a similar level of readers and gives no chance for non-expertise readers to follow the data. To be able to read, understand and evaluate the article was necessary to look at similar articles to comprehend the content. Fortunately, there are a lot of articles about Acquired aplastic anemia: 751.000 results (0,94 seconds) on google.

Thank you for the comments! We have tried to better explain the background more clearly about how we assigned different approaches including HSCT and non-HSCT measures to treat the various adverse events of the transferred pediatric patients with aplastic anemia in the introduction (Page 1 Line 44 – Page 2 Line 8) and results (Page 2 Line 37 - 39). We have added and rearranged references relevant to the new revised version. We have tried to provide more comprehensive contents for a broader spectrum of readers.

It seems necessary for an improved introduction to make possible a large spectrum of readers.

We have added contents in the “introduction” to explain the evolution of treatments for pediatric aplastic anemia and to help readers understand why we applied the haploidentical measures. (Page 1 Line 44 – Page 2 Line 8).

Also necessary is to have a paragraph about study limitations. Why only 12 patients? How we can extend the conclusions? 

We have added statements about the study limitations followed by the statements about the preliminary success to explain our conclusions. (Page 11 Line 32-34).

Also necessary seems to be a future research directions section in which to detail further steps for the newly proposed protocol.

We have added statements about the future research directions (Page 11 Line 40-42).

Round 2

Reviewer 2 Report

Regarding the article: ”Anti-thymocyte globulin (ATG)-Free Nonmyeloablative Haploidentical PBSCT Plus Post-transplantation Cyclophosphamide is a Safe and Efficient Treatment Approach for Pediatric Acquired Aplastic Anemia”, the authors sufficiently improved the manuscript in order to be published in IJMS.

After the changes made in the introduction, study limitations, and future research directions, and after rereading the manuscript, I consider that the revised version is properly improved and all my concerns and comments were adequately addressed, so I do not have further comments and conclude for acceptance for publication in the present form.