First-Line Treatment of Waldenström’s Macroglobulinaemia: Considerations Based on the Dutch National Guideline
, Laurens Nieuwenhuizen 4, Roelandt F. J. Schop 5, Martine E. D. Chamuleau 6, Gerjo A. Velders 7, Monique C. Minnema 8 and Josephine Mathilde Iris Vos 1,2,*
Round 1
Reviewer 1 Report
Dr Amaador and Collaborators provide a significant review article which summarizes first line treatment options available for patients with Waldenström Macroglobulinemia (WM), based on the Dutch National Guideline.
The manuscript is clearly presented, well structured, and of interest for the medical and research Communities.
Minor comments.
1. Authors have properly referred to the fact that CXCR4-mutaed WM patients may present with resistance to Ibrutinib. It would be important to refer to the pre-clinical studies that have described for the first time the role of the CXCR4/C1013G somatic variant in supporting WM pathogenesis and, importantly, ibrutinib resistance. The following studies should be mentioned:
- Treon SP, et al. Blood. 2014;123(18):2791-2796.
- Roccaro AM, et al. Blood. 2014;123(26):4120-4131.
- Hunter ZR, et al. Blood. 2014;123(11):1637-1646.
- Cao Y, et al. Br J Haematol. 2015;168(5):701-707.
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2. Same comment as above, re:MYD88. Important for the Reader to know about the major work on MYD88 and WM:
- Treon SP, et al. N Engl J Med. Aug 6 2015;373(6):584-6.
- Treon SP, et al. N Engl J Med. Aug 30 2012;367(9):826-33.
Author Response
Reviewer #1
Comments and Suggestions for Authors
Dr Amaador and Collaborators provide a significant review article which summarizes first line treatment options available for patients with Waldenström Macroglobulinemia (WM), based on the Dutch National Guideline.
The manuscript is clearly presented, well structured, and of interest for the medical and research Communities.
Response to reviewer #1: We want to thank the reviewer for the positive feedback.
Minor comments.
- Authors have properly referred to the fact that CXCR4-mutaed WM patients may present with resistance to Ibrutinib. It would be important to refer to the pre-clinical studies that have described for the first time the role of the CXCR4/C1013G somatic variant in supporting WM pathogenesis and, importantly, ibrutinib resistance. The following studies should be mentioned:
- Treon SP, et al. Blood. 2014;123(18):2791-2796.
- Roccaro AM, et al. Blood. 2014;123(26):4120-4131.
- Hunter ZR, et al. Blood. 2014;123(11):1637-1646.
- Cao Y, et al. Br J Haematol. 2015;168(5):701-707.
Response to comment 1: We agree with the reviewer and have added “The CXCR4 mutation, which is the second most commonly occurring mutation in up to 40% of WM patients, together with MYD88 mutation determine clinical presentation and have an effect on prognosis in WM.” to the revised manuscript at line 28 and “CXCR4 mutations prevent CXCL12 induced CXCR4 receptor internalization and result in rescue from ibrutinib-triggered apoptosis” at line 196. Also, we have added additional references where this was applicable.
- Same comment as above, re:MYD88. Important for the Reader to know about the major work on MYD88 and WM:
- Treon SP, et al. N Engl J Med. Aug 6 2015;373(6):584-6.
- Treon SP, et al. N Engl J Med. Aug 30 2012;367(9):826-33.
Response to comment 2: This is valid point made by the reviewer and we have therefore added “The genomic understanding of WM vastly improved since the identification of the MYD88L265P mutation in over 90% of patients.” to the revised manuscript at line 27. Also, we have added additional references where this was applicable.
Reviewer 2 Report
The manuscript by K. Amaador et al. reviews the first line treatment options currently available and approved for the treatment of patients with Waldenström’s Macroglobulinaemia (WM).
The review is quite brief but well written and understandable. The authors do a brief introduction to the definition of WM, then they explain when patients should be treated, and then, they describe the first line treatment options approved for this group of patients and other treatments that have not been approved yet.
Some sections could be improved to enhance the quality of the manuscript. Specfically:
Line 92-94: the authors state: “Since there is no consensus about the best first-line treatment, and further reduction of toxicity of conventional chemotherapy is desired, it is recommended that patients are to be treated in a clinical trial whenever possible”.
It is not clear what the authors are trying to say: If responses with current treatments are so good, then, in which cases should patients consider going to a clinical trial?
Table 2: Add ta column with he Toxicity of the treatments mentioned in the Table.
At the end of section 3, do a brief introduction to the next sections saying that the authors will describe more in detail the different treatment options for WM.
Line 127: The information is confusing. Authors mention “Adding vincristine” to which treatment? Rituximab monotherapy, or does it refer to R-CHOP? If the information is related to R-CHOP, R-CHOP is not considered as first line of treatment. Thus, information in this section related to R-CHOP is confusing. Explain better.
Line 166: Authors state: “An alternative in this situation is ibrutinib” It is not clear the message. An alternative to which situation, R-bendamustine or to RBD?
Line 171: change Rituximab-Ixazomib-Dexamethasone for Ixazomib-Rituximab-Dexamethasone (IRD).
Line 171 and line 181: include Rituximab, carfilzomib-dexamethasone, and IRD in Table 2 as treatments with good efficacy but not approved yet as 1st line of treatments.
Include a brief introduction at the beginning, saying that treatments that have been used in different studies as first line of treatments but have not been approved yet will be also presented here.
Line 201-204. Reading that information it looks that R-ibrutinib is better than ibrutinib. However, authors state that there is insufficient evidence for R-ibrutinib to be recommended as first line. Please explain better why if R-ibrutinib is better than ibrutinib there is not enough evidence to be approved as 1st line of treatment.
Minor changes:
Along the manuscript: In all the sentences, the dots appear after and not before the references.
Line 118: DRC is already abbreviated earlier in the manuscript.
Line 246: “these data could be a biased”. Remove the "a".
Author Response
Reviewer #2
Comments and Suggestions for Authors
The manuscript by K. Amaador et al. reviews the first line treatment options currently available and approved for the treatment of patients with Waldenström’s Macroglobulinaemia (WM).
The review is quite brief but well written and understandable. The authors do a brief introduction to the definition of WM, then they explain when patients should be treated, and then, they describe the first line treatment options approved for this group of patients and other treatments that have not been approved yet.
Some sections could be improved to enhance the quality of the manuscript. Specfically:
Line 92-94: the authors state: “Since there is no consensus about the best first-line treatment, and further reduction of toxicity of conventional chemotherapy is desired, it is recommended that patients are to be treated in a clinical trial whenever possible”.
It is not clear what the authors are trying to say: If responses with current treatments are so good, then, in which cases should patients consider going to a clinical trial?
Response to comment: Although the treatment options for WM have increased and do result in good responses, they are still accompanied by serious drug-specific toxicities. Taken into consideration that WM remains incurable and that patient preferences play an increasingly important role in the development of new drugs, the need for novel less toxic regimens is high and thus whenever possible patients should be included in these clinical trials. We have adjusted the text as follows:
“Since WM is still incurable, there is no consensus about the best first-line treatment, and further reduction of (late) toxicity of conventional chemotherapy is desired, it is recommended that patients be treated in a clinical trial whenever possible to allow for development of novel treatment modalities.”
Table 2: Add ta column with the Toxicity of the treatments mentioned in the Table.
Response to comment: A column with the main toxicities of the treatments has been added to table 2 in the revised manuscript.
At the end of section 3, do a brief introduction to the next sections saying that the authors will describe more in detail the different treatment options for WM.
Response to comment: We agree and we have added “In the following section the various first-line treatment options for WM will be discussed in more detail.” To the revised manuscript at line 118.
Line 127: The information is confusing. Authors mention “Adding vincristine” to which treatment? Rituximab monotherapy, or does it refer to R-CHOP? If the information is related to R-CHOP, R-CHOP is not considered as first line of treatment. Thus, information in this section related to R-CHOP is confusing. Explain better.
Response to comment: We agree that this information can be confusing. We meant to say ‘Adding vincristine’ to the DRC regimen. We have reworded this as “Adding vincristine to cyclophosphamide/prednisone/rituximab (R-CP)” at line 133 in the revised manuscript.
Line 166: Authors state: “An alternative in this situation is ibrutinib” It is not clear the message. An alternative to which situation, R-bendamustine or to RBD?
Response to comment: We agree. We meant an alternative for BDR. We have replaced ‘in this situation’ with ‘for BDR’ in the revised manuscript at line 174. .
Line 171: change Rituximab-Ixazomib-Dexamethasone for Ixazomib-Rituximab-Dexamethasone (IRD).
Response to comment: We thank the reviewer for this suggestion and have adjusted this in the revised manuscript.
Line 171 and line 181: include Rituximab, carfilzomib-dexamethasone, and IRD in Table 2 as treatments with good efficacy but not approved yet as 1st line of treatments.
Response to comment: we have added these to table 2 in the revised manuscript
Include a brief introduction at the beginning, saying that treatments that have been used in different studies as first line of treatments but have not been approved yet will be also presented here.
Response to comment: We have added “Agents that were assessed in first-line but not yet approved as first-line treatment options will also be discussed.” At line 119 in the revised manuscript.
Line 201-204. Reading that information it looks that R-ibrutinib is better than ibrutinib. However, authors state that there is insufficient evidence for R-ibrutinib to be recommended as first line. Please explain better why if R-ibrutinib is better than ibrutinib there is not enough evidence to be approved as 1st line of treatment.
Response to comment: Apparently our wording was confusing. The Innovate trial compared rituximab to R-ibrutinib. We meant to emphasize that indeed data on ibrutinib versus R-ibrutinib are lacking which makes it problematic to recommended adding R to ibrutinib. We have reworded this somehat for clarification.
This section now reads: “Unfortunately, this trial does not provide data on how useful it is to add rituximab to ibrutinib therapy, since ibrutinib monotherapy was not an experimental arm. We conclude there is insufficient evidence that R-ibrutinib should be recommended in first line treat-ment, especially since the added value and toxicity of adding rituximab to ibrutinib (which is already known to be highly efficacious as monotherapy) is currently unknown. “
Minor changes:
Along the manuscript: In all the sentences, the dots appear after and not before the references.
Response to comment: This has been fixed in the revised manuscript.
Line 118: DRC is already abbreviated earlier in the manuscript.
Response to comment: This has been adjusted in the revised manuscript.
Line 246: “these data could be a biased”. Remove the "a".
Response to comment: Thank you for pointing this out, we have removed this in the revised manuscript.
