Next Generation BTK Inhibitors in CLL: Evolving Challenges and New Opportunities

Round 1

Reviewer 1 Report

In this review, the authors assess the status of covalent and reversible second generation BTKi in CLL.  Ibrutinib revolutionized the treatment paradigm of CLL both in previously treated and TN patients. However adverses effects and resistance to therapy are important limitations for a group of patients. BTKi are an emerging option for patients intolerant to ibrutinib

The authors  analyse in detail the data avalaible concerning the efficacy and tolerability of   second generation BTKi. They discuss data derived from the most important  clinical trials, above all the new data obtained from the head-to-head phase III trials  of ibrutinib versus acalabrutinib and zanubrutinib. Tables thoroughly summarize data from the most important clinical trials.  Additionally they outline recent data from reversible BTKi and its usufelness in mutated BTK patients. The discussion of the data is good and the conclusions  point out the perspectives for these second generation BTKi

It is a clear written review that summarize the current state of the art on this topic. I think it is an important addition to the literature

Minor considerations

L29-51 & L 52-52: Although is not the scope of the review, it would be advisable to add the percentage of AE and  resistance in patients treated with ibrutinib

L63,64,7: Please choose between ACP 5382 and CP5382

L81 The sentence “were not interested by acalabrutinib” should be rephrase.

L102-108. Add reference

L218 AF was not abbreviate before

Author Response

REVIEWER #1

In this review, the authors assess the status of covalent and reversible second generation BTKi in CLL.  Ibrutinib revolutionized the treatment paradigm of CLL both in previously treated and TN patients. However adverses effects and resistance to therapy are important limitations for a group of patients. BTKi are an emerging option for patients intolerant to ibrutinib

The authors  analyse in detail the data avalaible concerning the efficacy and tolerability of   second generation BTKi. They discuss data derived from the most important  clinical trials, above all the new data obtained from the head-to-head phase III trials  of ibrutinib versus acalabrutinib and zanubrutinib. Tables thoroughly summarize data from the most important clinical trials.  Additionally they outline recent data from reversible BTKi and its usufelness in mutated BTK patients. The discussion of the data is good and the conclusions  point out the perspectives for these second generation BTKi

It is a clear written review that summarize the current state of the art on this topic. I think it is an important addition to the literature

We would like to thank the reviewer for his/her comments on this work

Minor considerations

L29-51 & L 52-52: Although is not the scope of the review, it would be advisable to add the percentage of AE and  resistance in patients treated with ibrutinib: added to the text

L63,64,7: Please choose between ACP 5382 and CP5382: Thanks. “CP5382” was replaced with “ACP5382”

L81 The sentence “were not interested by acalabrutinib” should be rephrase:  rephrased

L102-108. Add reference: added

L218 AF was not abbreviate before: thanks, we added the abbreviation

Reviewer 2 Report

This is a typical "data dump" review in which each paragraph describes in excruciating detail the results of a single study.  While this makes it a resource for looking up the various studies, it does not synthesize the material well.  What would be useful would be a critical analysis of the shortcomings of ibrutinib- AE profile, need to dose forever, resistance.  Then a discussion of zanu and acala- not study by study, but thematically with regards to each of the failings of ibrutinib.  It must be made clearer that any suggestion of superiority to ibrutinib is totally inferential, and that the total number of AEs  in comparative trials is similar.  In terms of the non-covalent inhibitors, there is little data available, and the entire field can be synthesized into one or two paragraphs- again, the fussy trial-by-trial details are not interesting to read nor are they helpful.  Finally, I do not think that data presented only in abstract form should be included in a review- they may be proved incorrect by the time the studies are published.

Author Response

REVIEWER #2

This is a typical "data dump" review in which each paragraph describes in excruciating detail the results of a single study.  While this makes it a resource for looking up the various studies, it does not synthesize the material well.  What would be useful would be a critical analysis of the shortcomings of ibrutinib- AE profile, need to dose forever, resistance.  Then a discussion of zanu and acala- not study by study, but thematically with regards to each of the failings of ibrutinib.  It must be made clearer that any suggestion of superiority to ibrutinib is totally inferential, and that the total number of AEs  in comparative trials is similar.  In terms of the non-covalent inhibitors, there is little data available, and the entire field can be synthesized into one or two paragraphs- again, the fussy trial-by-trial details are not interesting to read nor are they helpful.  Finally, I do not think that data presented only in abstract form should be included in a review- they may be proved incorrect by the time the studies are published

We thank Reviewer #2 for his valuable contribution.

We sent our manuscript "Next generation BTK inhibitors in CLL: evolving challenges and new opportunities" with the aim of highlighting in a review the main information gathered from studies with the new BTK inhibitors as requested by the invitation of the publisher. The list of results, sometimes boring to read, is in our opinion essential to understand how we came to postulate a future role of these new drugs in the current CLL armamentarium. A critical analysis of the comparison between the recent past and the possible future would be more in line with reviewer’s comment, but it was not the type of article that we were required to write.

As suggested by Reviewer #2, we have re-written the whole paragraph concerning the AEs in order to inform, in a more critical way, the intentions of the researchers regarding the use of the new inhibitors with respect to the results obtained. We agree with the reviewer that this change greatly improved the readability of this section. Again, on the recommendation Reviewer #2, we have taken steps to contain the part relating to non-covalent inhibitors whose results are still far from being mature but which are a great stimulus for the future of treatment. Many of these data are therefore preliminary and have not yet been published in full. Starting from this consideration, but considering it essential in a review to represent what is moving for the future, we have reduced the number of quoted abstracts, as requested, leaving only those that would have made the new line of research unreportable otherwise. Finally, we have kept a few abstracts referring to updates of already published studies that were presented at the latest editions of the ASH meeting.

Round 2

Reviewer 2 Report

Thank you for a much improved manuscript