Myelodysplastic Neoplasms (MDS): The Current and Future Treatment Landscape

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Well written overview on MDS, thank you.

some  major points need to be addressed:

1) I know the wording precision medicine is popular in these times, but your paper demonstrates the opposite of precision medicine in MDS:

- lack of  knowledge on mechanisms of action as well as lack of predictive parameters of HMA

- some kind of precision only in MDS del(5q) with Lena, and SF3B1 with  Luspatercept. 

- no precision medicine but one for all high risk patients with allografting or HMA + Clax

- no ideas about any association of somatic mutations and treatment with the expection of SF3B1

- so the whole story is primarily unprecise, therefore please avoid this term, as it gives the impression that we understood how to treat an individual patient. Please express your critical view on the story.

2) please consider that doctors from ROW (rest of the world) will enjoy reading your paper, therefore you should at least mention and shortly discuss the differential licenced drugs (for example Darbopoietin not licenced in Europe, HMA for lower risk not licenced in Europe, etc)

3) please be more critical when you present compounds: TPO mimetics in higher risk MDS are more or less dead, please shorten. Chemotherapy: there is a consensus not use it in pts with karyotype anomalies (Knipp S et al Cancer, and other manuscripts). Rigosertib and Pevonedistat are dying, Glasdegib not promising, Magrolimab was killed by the pharma company itsself, Sabatolimab results open, Eprenatapopt is on the deathbed.

4) please shortly discuss the way to allografting including upfront allo in MDS IB, please discuss HMA as a bridge to allo (which is not such a good idea)

Author Response

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

This review is clear and exhausitve, with updated informations about targeted treatments in MDS. Only minor few comments:

- at line 267: 2000 should be 2020

- at line 367: “oral hypomethylating agent (CC-486)" can be simply changed in "oral azacitidine".

Author Response

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files.

at line 267: 2000 should be 2020

This change has been incorporated 

at line 367: “oral hypomethylating agent (CC-486)" can be simply changed in "oral azacitidine".

This change has been incorporated 

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

Karel and colleagues provided an effective literature review with up-to-date information documenting MDS classification,  molecular evolution and treatments. Relevant references were properly cited. Authors may wish to address a few specific comments:

1. Provide full name of each gene in Table 1 before the respective abbreviation. It would also help if authors could add one more column to Table 1 pointing to the specific number of the reference(s) that discussed the specific gene in MDS. Currently references 2-7 were cited for the first 9 genes. That is good. Additional references should be provided for the other genes.   

Lines 141 and 152: Refer to Table 2 and point to which of the WHO 2022 and ICC 2022 classification groups are regarded as Lower Risk Disease.

Lines 162-173: If transfusion dependent patients have lower overall survival, then why they are discussed under “lower risk disease” ?

Line 390: Should be “Treatment of High Risk Disease” to be consistent with Line 141.

Lines 391- 396: Very good to describe clearly as which groups are regarded as High risk MDS based on previous classifications. Since authors specifically described the more recent WHO 2022 and ICC 2022 classifications, additional information should be provided in reference to Table 2 to point out which of the WHO 2022 and ICC 2022 groups are regards as High Risk Disease.

Line 507: Reference 64 is an 2021 ASH annual meeting abstract. Reference should be updated if a new report is available about the IDIOME trial.

Lines 612-621: A suggestion: In addition to allo-HSCT, authors could consider highlighting one or a few promising MDS treatment (s), especially new treatments with known molecular insight, that could serve as a take home message for readers and could help to conclude this review in a more positive note.  

Author Response

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files.

Provide full name of each gene in Table 1 before the respective abbreviation. It would also help if authors could add one more column to Table 1 pointing to the specific number of the reference(s) that discussed the specific gene in MDS. Currently references 2-7 were cited for the first 9 genes. That is good. Additional references should be provided for the other genes.   It was from references 2-7 where all of the data in the chart were taken from, the asterisks indicates founding lesions, not the reference. Apologies for the confusion, my wording was quite unclear in the original version. Therefore I changed the wording under the figure to make this more clear. Table 1

Lines 141 and 152: Refer to Table 2 and point to which of the WHO 2022 and ICC 2022 classification groups are regarded as Lower Risk Disease.

Changes have been made to this section. Lines (171-174)

Lines 162-173: If transfusion dependent patients have lower overall survival, then why they are discussed under “lower risk disease” ?

I changed this to say “transfusion dependence is associated with shorter leukemia free survival and overall survival, irrespective of calculated risk score”. I believe this way it fits in better with the flow/formatting of the paper, as transfusion dependent patients still may be low risk per IPSS-R (lines 186-187)

Line 390: Should be “Treatment of High Risk Disease” to be consistent with Line 141.

I renamed them both to “highER risk” and “lowER risk”. This is per newly added reference 79 demonstrating differential outcomes, using IPSS-R Score of 3.5 as the cutoff. I felt that this was reasonable as this is incorporated into the NCCN guidelines as well.

Lines 391- 396: Very good to describe clearly as which groups are regarded as High risk MDS based on previous classifications. Since authors specifically described the more recent WHO 2022 and ICC 2022 classifications, additional information should be provided in reference to Table 2 to point out which of the WHO 2022 and ICC 2022 groups are regards as High Risk Disease.

Changes made, as with the lower risk disease as noted above. Lines 435-440

Line 507: Reference 64 is an 2021 ASH annual meeting abstract. Reference should be updated if a new report is available about the IDIOME trial.

I could not find an update officially published yet?

Lines 612-621: A suggestion: In addition to allo-HSCT, authors could consider highlighting one or a few promising MDS treatment (s), especially new treatments with known molecular insight, that could serve as a take home message for readers and could help to conclude this review in a more positive note.  

I added a final section before the conclusion section “Other potential targets: So many roads” to address this. I added discussion about other antiapoptotic (MCL1), targets in inflammatory pathways, immunotherapy. Is there anything else major in the field that we should make sure we add?

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for addressing the reviewers  points