A Canadian Perspective on the Treatment of Waldenström Macroglobulinemia
Round 1
Reviewer 1 Report
The manuscript entitled: “A Canadian Perspective on the Treatment of Waldenström Macroglobulinemia” by Kaedbey et al. summarizes intensively the efficacy and safety of WM therapies and discuss special considerations for the therapy from a Canadian perspective.
Albeit the paper is well written, prepared and of special interest, some comments should be addressed.
Comments:
1. The authors should highlight in more detail what is the exact different in Canada compared to other countries e.g. Europe concerning therapy.
2. Abstract: The sentence: “….no standard of care exists.” is not quite right and should be corrected. Additionally, please provide of definition BTK where appropriate.
3. Table 4. Please highlight and provide a definition of frail or unfit where appropriate.
4. Figure 1. Should be enlarged.
Author Response
Reviewer 1
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: The authors should highlight in more detail what is the exact different in Canada compared to other countries e.g. Europe concerning therapy. The above-mentioned sentence has been removed.
- As the group of authors all reside in Canada, we do not feel we can adequately comment on treatment access outside of Canada; however, we have included some detail on potential differences in use of bortezomib in Canada versus Europe and the United States, as well as details on the difference in CXCR4 testing in Canada versus the United States. See section 4.1, paragraph 1, sentence 2 and 3: “American and European practice guidelines recommend BR, BTK inhibitors, and BDR as preferred first-line treatment for WM [18, 20]. Canadian practice is generally aligned with these recommendations as BR and BTK inhibitors are considered standard of care for first-line therapy; however, bortezomib is generally reserved for the relapsed setting due in part to the incidence of neuropathy, as well to restricted access in some provinces, given the lack of Health Canada indication in WM.” See section 4.2, last sentence: “The National Comprehensive Cancer Network guidelines for WM recommend all patients who are being considered for BTK inhibitor therapy be tested for CXCR4 mutations as certain mutations have been associated with ibrutinib resistance [18].”
- As the group of authors all reside in Canada, we do not feel we can adequately comment on treatment access outside of Canada; however, we have included some detail on potential differences in use of bortezomib in Canada versus Europe and the United States, as well as details on the difference in CXCR4 testing in Canada versus the United States. See section 4.1, paragraph 1, sentence 2 and 3: “American and European practice guidelines recommend BR, BTK inhibitors, and BDR as preferred first-line treatment for WM [18, 20]. Canadian practice is generally aligned with these recommendations as BR and BTK inhibitors are considered standard of care for first-line therapy; however, bortezomib is generally reserved for the relapsed setting due in part to the incidence of neuropathy, as well to restricted access in some provinces, given the lack of Health Canada indication in WM.” See section 4.2, last sentence: “The National Comprehensive Cancer Network guidelines for WM recommend all patients who are being considered for BTK inhibitor therapy be tested for CXCR4 mutations as certain mutations have been associated with ibrutinib resistance [18].”
- Comment 2: Abstract: The sentence: “….no standard of care exists.” is not quite right and should be corrected. Additionally, please provide of definition BTK where appropriate.
- The abstract has been adjusted to say there is “no definitive standard of care” for WM, similar to how it is worded in the introduction. We agree it is not accurate to say there is no standard of care, as several regimens are considered standard of care; however, the optimal selection is unclear given the lack of phase III randomized trials. As suggested, BTK has been defined as “Bruton’s tyrosine kinase” in the abstract.
- The abstract has been adjusted to say there is “no definitive standard of care” for WM, similar to how it is worded in the introduction. We agree it is not accurate to say there is no standard of care, as several regimens are considered standard of care; however, the optimal selection is unclear given the lack of phase III randomized trials. As suggested, BTK has been defined as “Bruton’s tyrosine kinase” in the abstract.
- Comment 3: Table 4. Please highlight and provide a definition of frail or unfit where appropriate.
- There are no assessment tools specific to Waldenstrom Macroglobulinemia and a physician may use any available tools to assess frailty as well as their own clinical judgement. We have included the following footnote in Table 4 to address this:
a There is no standard frailty or fitness assessment tool used in clinical practice in Canada for WM. Physician’s determine whether a patient is likely to tolerate therapy based on their own judgment and may include general geriatric assessment tools that take into consideration the comorbidities and functional status of a patient.
- There are no assessment tools specific to Waldenstrom Macroglobulinemia and a physician may use any available tools to assess frailty as well as their own clinical judgement. We have included the following footnote in Table 4 to address this:
- Comment 4: Figure 1. Should be enlarged.
- Figure 4 has been enlarged, as suggested.
Reviewer 2 Report
The paper presents a rich literature review on Waldenstrom's therapeutic options that are well presented and the rationale for each choice is well argued. The tables are very well done and well summarize the therapeutic options
However, even if the focus of the paper is on therapies, I believe it is necessary to better structure a brief initial paragraph, separate from the introduction, on the criteria of diagnosis, prognosis and initiation of therapy. To this, it would be necessary to add an equally short paragraph on the clinical presentation of the disease, which are instead only stated, in a heterogeneous way during the treatment of therapies, without having previously explained their origin or effects. As example, the Bing-Neel syndrome, a very rare presentation in the CNS, has had about 10 lines of presentation, while more frequent and important situations such as amyloidosis, cold agglutinin haemolytic anemia, cryoglobulinemia, have only been stated in paragraph 3.4.
In my opinion, the paragraph on clinical presentation must be inserted first, in order to better explain after, the rationale of the therapeutic choices that are suggested.
- In paragraph 3.1 the sentence: "potential constraints on stem cell collection that are associated with BR, particularly in very young patients and if subsequent ASCT is being considered" I believe is questionable and not supported by sufficient evidence.
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: It was suggested that a paragraph separate from the introduction be created to explain the criteria of diagnosis, prognosis, and initiation of therapy for Waldenstrom Macroglobulinemia (WM) as these were felt as necessary background for the understanding of the paper. It was also suggested that a paragraph on clinical presentation also be included.
- To address this comment, the introduction has been reorganized, with parts discussing genetic testing useful for diagnosis (MYD88 and CXCR4) as well as initiation of treatment moved to a new section directly following the introduction called “Clinical Presentation, Diagnosis, and Initiation of Treatment”. Also included in this section are a more detailed description of diagnosis (paragraph 1) and a more detailed description on clinical presentation of IgM-mediated complications (last paragraph).
- To address this comment, the introduction has been reorganized, with parts discussing genetic testing useful for diagnosis (MYD88 and CXCR4) as well as initiation of treatment moved to a new section directly following the introduction called “Clinical Presentation, Diagnosis, and Initiation of Treatment”. Also included in this section are a more detailed description of diagnosis (paragraph 1) and a more detailed description on clinical presentation of IgM-mediated complications (last paragraph).
- Comment 2: In paragraph 3.1 the sentence: "potential constraints on stem cell collection that are associated with BR, particularly in very young patients and if subsequent ASCT is being considered" I believe is questionable and not supported by sufficient evidence
- Although there is some evidence that suggests prior bendamustine may negatively impact stem cell collection [1,2], this evidence comes from retrospective data and other studies report conflicting results [3,4]. For this reason, we have removed the flagged sentence.
References
- Alahwal, H.; Chapani, P.; Villa, D.; Abou Mourad, Y.; Power, M.; Nantel, S. H.; Sanford, D.; Sreenivasan, G.; Sutherland, H. J.; Sehn, L. H.; et al. Bendamustine Adversely Affects Stem Cell Mobilization Among Patients with Mantle Cell Lymphoma (MCL): A Comparison of the BR Vs RCHOP Eras in British Columbia (BC), Canada. Blood. 2018;132:4556.
- Bastos-Oreiro, M.; Anguita, J.; Fernández, J.; Gonzalez, A. P.; Córdoba, R.; Jiminez Ubieto, A. I.; Garcia, D.; Martínez-Laperche, C.; Delgado, V.; Garcia-Arroba, J.; et al. Impact of the Use of Bendamustine Immediately before the Collection of Hematopoietic Stem Cells in Lymphoma. a Study By the Geltamo Group. Blood. 2021;138:1771.
- Iliff, A.; Divine, C.; Diaz, F.; Aljitawi, O.; Abhayankar, S.; McGuirk, J.; Ganguly, S. Adequacy of peripheral blood stem cell mobilization in patients with relapsed B-cell non-Hodgkin lymphoma treated with bendamustine. Lymphoma. 2016;57:1189-90.
- Martin, P.; Chen, Z.; Cheson, B. D.; Robinson, K. S.; Williams, M.; Rajguru, S. A.; Friedberg, J. W.; Van Der Jagt, R. H.; Lacasce, A. S.; Joyce, R.; et al. Long-term outcomes, secondary malignancies and stem cell collection following bendamustine in patients with previously treated non-Hodgkin lymphoma. J. Haematol. 2017;178:250-6.
Reviewer 3 Report
The Authors described the Canadian perspective about Waldenstrom disease treatment. All the currently available strategies have been clearly presented and discussed. Tables have been used to simplify and summarize their findings and recommendations (based on Candian experiences).
Overall very nicely writeen and complete
Author Response
Thank you for reviewing our manuscript. We do not feel there are any actionable suggestions based on your comments; however, we appreciate this feedback!
Reviewer 4 Report
Excellent review article.
Specific comments:
Page 4 second paragraph: consider replacing reference 35 with one related to lymphoma patients rather than patients receiving rituximab for autoimmune disease.
Page 4 paragraph 3: would be good to comment whether proteosome inhibitors are generally available Canada.
Page 4 Table 2: please include neuropathy with all regimens that include bortezomib. Also which regimen has neutropenia as a notable AE for bortezomib-RCD vs R-CD (or both)?
Page 5 1st paragraph last sentence: change "however" to "and".
Page 6 2nd paragraph: change "indicated" to "approved"
Page 8 1st paragraph and Figure 1: It would be good to mention whether or not any provinces have frontline access.
Page 9 2nd paragraph: The second sentence (re carfilzomib) does not add any value. Consider deleting.
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: Page 4 second paragraph: consider replacing reference 35 with one related to lymphoma patients rather than patients receiving rituximab for autoimmune disease.
- The following reference (now reference 43) which focusses on the impact of COVID-19 on patients with B-cell lymphomas has been included in place of the previous reference 35. In addition, the language surrounding this statement has been adjusted to indicate a potential for severe outcomes with COVID-19 in rituximab-treated patients rather than stating an “increased risk” as more data is needed to confirm this observation. Gaitzsch, E.; Passerini, V.; Khatamzas, E.; Strobl, C. D.; Muenchhoff, M.; Scherer, C.; Osterman, A.; Heide, M.; Reischer, A.; Subklewe, M.; et al. COVID-19 in Patients Receiving CD20-depleting Immunochemotherapy for B-cell Lymphoma. Hemasphere. 2021;5:e603.
- The following reference (now reference 43) which focusses on the impact of COVID-19 on patients with B-cell lymphomas has been included in place of the previous reference 35. In addition, the language surrounding this statement has been adjusted to indicate a potential for severe outcomes with COVID-19 in rituximab-treated patients rather than stating an “increased risk” as more data is needed to confirm this observation. Gaitzsch, E.; Passerini, V.; Khatamzas, E.; Strobl, C. D.; Muenchhoff, M.; Scherer, C.; Osterman, A.; Heide, M.; Reischer, A.; Subklewe, M.; et al. COVID-19 in Patients Receiving CD20-depleting Immunochemotherapy for B-cell Lymphoma. Hemasphere. 2021;5:e603.
- Comment 2: Page 4 paragraph 3: would be good to comment whether proteosome inhibitors are generally available Canada.
- Instead of including this at the suggested location, we have included a sentence about proteasome inhibitor availability in the Canadian perspective section where access to other therapies is also discussed. See section 4.1, first paragraph, third sentence: “Canadian practice is generally aligned with these recommendations as BR and BTK inhibitors are considered standard of care for first-line therapy; however, bortezomib is generally reserved for the relapsed setting due in part to the incidence of neuropathy, as well to restricted access in some provinces, given the lack of Health Canada indication in WM.”
- Instead of including this at the suggested location, we have included a sentence about proteasome inhibitor availability in the Canadian perspective section where access to other therapies is also discussed. See section 4.1, first paragraph, third sentence: “Canadian practice is generally aligned with these recommendations as BR and BTK inhibitors are considered standard of care for first-line therapy; however, bortezomib is generally reserved for the relapsed setting due in part to the incidence of neuropathy, as well to restricted access in some provinces, given the lack of Health Canada indication in WM.”
- Comment 3: Page 4 Table 2: please include neuropathy with all regimens that include bortezomib. Also which regimen has neutropenia as a notable AE for bortezomib-RCD vs R-CD (or both)?
- Neuropathy has been added as a notable AE for all trials investigating bortezomib containing regimens; however, for rows 3-5, a footnote “j” was included to indicate that grade 3/4 peripheral neuropathy occurred in ≤5% of patients (which can be attributed to the subcutaneous or weekly delivery of bortezomib).
- Neuropathy has been added as a notable AE for all trials investigating bortezomib containing regimens; however, for rows 3-5, a footnote “j” was included to indicate that grade 3/4 peripheral neuropathy occurred in ≤5% of patients (which can be attributed to the subcutaneous or weekly delivery of bortezomib).
- Comment 4: Page 5 1st paragraph last sentence: change "however" to "and"
- This change has been made. See section 3.2, paragraph 2, last sentence: “Bortezomib, cyclophosphamide, and rituximab (BCR) has also demonstrated similar overall and major response rates to FCR in a phase 2 in treatment-naïve WM and BCR resulted in less hematological toxicities [56].”
- This change has been made. See section 3.2, paragraph 2, last sentence: “Bortezomib, cyclophosphamide, and rituximab (BCR) has also demonstrated similar overall and major response rates to FCR in a phase 2 in treatment-naïve WM and BCR resulted in less hematological toxicities [56].”
- Comment 5: Page 6 2nd paragraph: change "indicated" to "approved"
- This change has been made. See section 3.3, paragraph 3, first sentence: “Zanubrutinib monotherapy is indicated by Health Canada for the treatment of WM at a recommended total daily dose of 320 mg given either once- or twice-daily.”
- This change has been made. See section 3.3, paragraph 3, first sentence: “Zanubrutinib monotherapy is indicated by Health Canada for the treatment of WM at a recommended total daily dose of 320 mg given either once- or twice-daily.”
- Comment 6: Page 8 1st paragraph and Figure 1: It would be good to mention whether or not any provinces have frontline access (to BTK inhibitors).
- The following has been included in Section 4.1, paragraph 2, fourth sentence: “As of September 2022, ibrutinib is accessible through public reimbursement for the first-line treatment of WM in some provinces, while zanubrutinib is not yet reimbursed in the first-line but is accessible by compassionate access across Canada.”
- The following has been included in Section 4.1, paragraph 2, fourth sentence: “As of September 2022, ibrutinib is accessible through public reimbursement for the first-line treatment of WM in some provinces, while zanubrutinib is not yet reimbursed in the first-line but is accessible by compassionate access across Canada.”
- Comment 7: Page 9 2nd paragraph: The second sentence (re carfilzomib) does not add any value. Consider deleting.
- The above-mentioned sentence has been removed.
Round 2
Reviewer 2 Report
No other comments
