How We Manage Patients with Indolent B-Cell Malignancies on Bruton’s Tyrosine Kinase Inhibitors: Practical Considerations for Nurses and Pharmacists

Round 1

Reviewer 1 Report

 

Nixon et al aim to provide a comprehensive and practical view on how to manage patients with indolent B-cell malignancies on BTK inhibitors. It is well structured, clearly written and easy to read. Overall, I enjoyed reading the manuscript and I consider it suitable for publication.

 

However, there are some minor comments/questions I would like to make

 

-       In real life, in which patients are these BTK inhibitors used? Age? Comorbidities? Outcome? I think that the manuscript would benefit from the inclusion of a couple of sentences explaining this.

-       As stated by the authors (Table 3 & pages 6-7), one of the considerations to be taken into account when treating with ibrutinib, acalabrutinib and zanubrutinib is the coadministration of CYP3A inhibitors/inducers. Is the genotype of CYP3A analyzed in the clinical practice? Do the authors consider that the result of this analysis could modify the dosage?

Author Response

Thank you for reviewing our manuscript and for your thoughtful suggestions. A description of how we have addressed your comments in the revised manuscript are listed below:

• Comment 1: In real life, in which patients are these BTK inhibitors used? Age? Comorbidities? Outcome? I think that the manuscript would benefit from the inclusion of a couple of sentences explaining this.
  • We have included a paragraph in the introduction to address where BTK inhibitors may best fit in the management of patients with CLL and indolent NHLs (Lines 66-78): “Bruton’s tyrosine kinase inhibitors may be used in the first-line (CLL and WM) or relapsed setting (CLL and iNHL), depending on access within jurisdictions. Phase 3 trials in first-line CLL have demonstrated improved progression-free survival with BTK inhibitors over standards of care at the time of study initiation [13-17]; however, they have not yet been directly compared to fixed-duration venetoclax-based regimens which have also demonstrated improved efficacy over standards of care in CLL [18, 19]. As BTK inhibitors are given orally, they may be a suitable option for patients who have difficulty travelling to cancer centres for treatment or who may wish to reduce public exposure to prevent infections. They also have a favourable toxicity profile compared to chemoimmunotherapy, with lower rates of hematological toxicity and infection, making them an attractive option for patients who are older or with multiple comorbidities. This represents a significant proportion of patients with NHL and CLL, as the median age of diagnosis is 67-70 years [6-20].”

 

 

• Comment 2: As stated by the authors (Table 3 & pages 6-7), one of the considerations to be taken into account when treating with ibrutinib, acalabrutinib and zanubrutinib is the coadministration of CYP3A inhibitors/inducers. Is the genotype of CYP3A analyzed in the clinical practice? Do the authors consider that the result of this analysis could modify the dosage?
  • The following sentences have been included to address the potential effect of CYP3A genotype on BTK inhibitor metabolism (lines 174-178): “Variations in CYP3A genotype have been associated with altered metabolism for several non-cancer drugs and could alter BTK inhibitor metabolism [33]. However, testing for CYP3A genotype is not routinely performed for patients with lymphoma, and clinical studies are needed to understand the potential value of CYP3A genotyping in this setting.”

 

Reviewer 2 Report

Very good summary of BTK inhibitors, help for clinical practise.

Author Response

Thank you for reviewing our manuscript. We acknowledge there are no comments to address.

Reviewer 3 Report

This review provides a comprehensive overview of the current knowledge and side effects of BTK inhibitors in non-Hodgkin's lymphoma and chronic lymphocytic leukemia. The paper is overall well written with some complex periods and some omitted references. The authors summarized the various side effects and how to handle them. However, there are many reviews in the literature describing BTK inhibitors, and I do not think the contribution of this paper is particularly innovative or important. The overall discussion is similar to the previous reviews and does not propose a new perspective.

Author Response

We thank you for reviewing our manuscript and appreciate your input on the novelty of this manuscript. We agree that some of the content in this review paper has been described in other review papers; however, many of the review papers referenced have been authored by physicians only and are targeted for a physician audience. The novelty of this manuscript lies in the discussion of both pharmacology and adverse event management in a single reference document which is intended specifically for nurses and pharmacists. Although we have found some papers that are targeted towards nurses and pharmacists separately (e.g. DOI: 10.1016/j.soncn.2021.151177 and DOI: 10.6004/jadpro.2021.12.4.8, respectively), we feel our manuscript is more extensive in the adverse events covered and pharmacy discussion.

We would also like to highlight the inclusion of updated data and discussion on some potentially late-presenting adverse events, such as second primary malignancies, hypertension (with new data reported for zanubrutinib), and sudden deaths (additional case reports reporting sudden deaths with all BTK inhibitors and a new black box warning label for sudden death with ibrutinib).

Reviewer 4 Report

This is a very detailed and excellent overview on the management of patient with B-cell malignancies who are treated with Bruton`s tyrosine kinase inhibitors. Above the title is written „Article“, but it is rather a „Review Article“ in the sense that there are no original new data, but it is a summary of existing data and knowledge.

Specific Points of Criticism and Suggestions for Alterations:

(1)  Lines 38-39:  This statement is correct. According to the most recent 5th Edition of the WHO Classification of Hematolymphoid Tumours CLL belongs to the "mature B-Cell Neoplasms" (see: Alaggio et al., Leukemia 36: 1720-1748, 2022 - there Table 1). It might be worthwhile to cite this reference.

(2)  Line 74:  This paper could serve as a reference not only for medical staff in Canada but also elsewhere. Hence, why the emphasis on "Canadian nurses and pharmacists"? (The title is deservedly more general).

(3)  Line 289:  The acronym "ASL" should be defined.

(4)  Paragraph 6.2.8:   A single sentence might be added: "It is, however, not clear/known whether the SPM are treatment-related or patient-related (or genetic predisposition-related)". (or similar).

(5)  Table 6:  This large table might be better readable in the horizontal format than in the present vertical format.

(6)  It is interesting to note that the authors aka the writing assistance uses American English for "standardize, optimize, recognize, localize, randomize" etc. (instead of British English with the ending "...ise"), the British English is used for "tumour, favourable" (instead of "tumor, favorable"). Just an observation.

Author Response

Thank you for reviewing our manuscript and for your thoughtful suggestions. A description of how we have addressed your comments in the revised manuscript are listed below:

• Comment 1: Lines 38-39:  This statement is correct. According to the most recent 5th Edition of the WHO Classification of Hematolymphoid Tumours CLL belongs to the "mature B-Cell Neoplasms" (see: Alaggio et al., Leukemia 36: 1720-1748, 2022 - there Table 1). It might be worthwhile to cite this reference.
  • This reference had been cited in the preceding sentence describing the number of subtypes of NHL and has now also been cited following the above suggested sentence (now found on lines 39-41).

 

• Comment 2: Line 74:  This paper could serve as a reference not only for medical staff in Canada but also elsewhere. Hence, why the emphasis on "Canadian nurses and pharmacists"? (The title is deservedly more general).
  • Since there is Canadian specific-content referenced throughout the paper (e.g. Canadian drug indications, references to Canadian monographs, lack of current access to different acalabrutinib formulations), we feel it is important to specify that this content comes from a Canadian perspective, but acknowledge that much of the content can be applied beyond these borders. To reflect this we have changed the last two sentences of the introduction to the following (lines 88-91): “This paper discusses the dosing, co-administration considerations, and AE management strategies for BTK inhibitors from a Canadian perspective. It intends to serve as a reference for nurses and pharmacists, involved in the care of patients with indolent B-cell NHL or CLL who are being treated with BTK inhibitors.”
    
    
• Comment 3: Line 289:  The acronym "ASL" should be defined.
  • The acronym “ASL” was intended to be “ADL”, meaning activities of daily living. The acronym was replaced with the intended definition (now on line 309 in the tracked changes version)
    
    
• Comment 4: Paragraph 6.2.8:   A single sentence might be added: "It is, however, not clear/known whether the SPM are treatment-related or patient-related (or genetic predisposition-related)". (or similar).
  • At the end of the first paragraph in section 6.2.8 on second primary malignancies, we have added the following statement (lines 590-591): “It remains unclear whether this increase in SPM is treatment-related or is linked to a disease-related genetic predisposition.”
    
    
• Comment 5: Table 6:  This large table might be better readable in the horizontal format than in the present vertical format.
  • We have followed up with Current Oncology to see if the table can be published in landscape format.
    
    
• Comment 6: It is interesting to note that the authors aka the writing assistance uses American English for "standardize, optimize, recognize, localize, randomize" etc. (instead of British English with the ending "...ise"), the British English is used for "tumour, favourable" (instead of "tumor, favorable"). Just an observation.
  • Although “Canadian English” is not formally recognized, both “ise/ize” spellings are acceptable in Canada, and often the American spelling for these words are favoured. This appears to be in line with other recently published articles in Current Oncology (e.g. https://0-www-mdpi-com.brum.beds.ac.uk/1718-7729/30/1/34). We will follow-up with the journal on their preference for spelling of “ise/ize” words.

Round 2

Reviewer 3 Report

Thank you for your answers!