Management of Marginal Zone Lymphoma: A Canadian Perspective

Round 1

Reviewer 1 Report

Comments for author File: Comments.docx

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: The gap in literature of MZL patients being a small portion of published trials is discussed and represented in the provided Tables. There isn’t discussion about why this is relevant (i.e. maybe it isn’t …. are we sure it behaves differently, responds differently, biological differences compared to FL etc). This manuscript does not recognize that identification of this subtype can be difficult due to lack of specific phenotype of biomarkers which influences both trial interpretation and patient management.
  • Whether MZL indeed behaves differently and thus requires different management strategies from FL is unclear, due to the lack of trial data and as you have pointed out, difficulty in distinguishing this subtype, particularly in early trials. We have now clarified this “unknown” in the introduction and why we think it is plausible that MZL should be managed differently. Lines 48-59: “The optimal treatment for MZL is not clear owing to the limited representation of pa-tients with MZL in phase 3 trials for iNHL. In addition phase 2 studies evaluating therapeutic efficacy in MZL generally lack a control arm and pool patients of different subtypes which have heterogeneous clinical behaviour. As MZL lacks specific im-munophenotypic markers, it may also be difficult to distinguish from other lym-phoproliferative disorders with similar morphology and clinical presentation, which can challenge trial interpretation and patient management. Thus, in many cases, treatment strategies for MZL are borrowed from other iNHLs such as follicular lym-phoma (FL). It is plausible however that MZL may respond differently to therapy than other iNHLs given that the clinical presentation, genetics, and natural history of MZL is generally different [8]. Therefore, further study is needed to understand the best treatment for MZL patients.”
  • We have also included a few sentences describing challenges in differential diagnosis in section 2 (lines 73-78): “It should be noted that MZL has historically been difficult to differentiate from other CD5-/CD10- lymphoproliferative disorders, particularly lymphoplasmacytic lymphoma/Waldenstrom Macroglobulinemia which can have similar morphologic findings and disease presentation [10]. Consultation with an experienced hematopathologist and use of MYD88 mutational testing can help distinguish these two entities [11].”
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• Comment 2: R2 is funded for relapse MZL in some provinces and Zanubrutinib while currently available is not funded by provincial health authorities. In the conclusion preference seems to be given to zanubrutinib in relapse over R2 and authors state that for R2 “data supporting efficacy is limited” (line 328). Table 2 illustrates that the amount of data for these 2 agents is comparable as both the Magnolia and Augment trial have ~ 60 pts with R/R MZL and efficacy appears similar though there is no direct comparison or data to inform sequencing or treatment selection.
  • We appreciate your critical review on R2 and agree that through cross-trial comparison the efficacy of R2 and BTK inhibitors in relapsed MZL is similar, therefore we have removed the statement in line 366 that says “data supporting efficacy is limited”. Based on our discussion with colleagues across Canada, we did not find any provinces who had lenalidomide publicly funded specifically for MZL; however, we realize that patients may have private coverage or have access at specific institutions. To account for this we have changed the wording around R2 access to “R2 is not widely available across provinces and may be accessible through private drug coverage” (Line 280-282) and “R2 is not uniformly accessible for the treatment of MZL across all Canadian provinces” (Line 364-365), rather than prior wording that stated it was not accessible in any provinces. We do still feel that because BTK inhibitors are currently easily accessible through compassionate access, which is not the case for R2, BTK inhibitors tend to be prioritized in the relapsed setting; however, the algorithm does not explicitly state that the listed regimens to consider in the relapsed setting are in order of preference.

• Comment 3: Table 2 – Title states first-line whereas this is a Table of treatments for relapse (line 292)
  • Thank you for catching this. The Table 2 title has been adjusted to “Phase 2/3 prospective trials for treatment of relapsed/refractory advanced/symptomatic MZL” (lines 328)
• Comment 4: Ref 8 - ?? incorrect reference – this reference sounds to be for myeloid neoplasm classification (line 396)
  • Thank you for catching this. The reference has been changed to: “Jaffe, E.S.; Harris, N.L.; Stein, H.; Vardiman, J.W. (Eds.) World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon 2001.” (line 447-448)

Reviewer 2 Report

This is a well-written, comprehensive report of the current state of treatment possibilities in marginal zone lymphomas, with special attention to the Canadian practice. The manuscript does not describe patophysiology, molecular genetics or diagnostic challenges, as this was not authors´ intention. After brief review of clinical characterictics and epidemiology, authors describe the indications for treatment in these indolent malignancies and then go directly to the treatment of newly diagnosed and relapsed/refractory patients. Due to lack of randomized studies, the treatment choices in marginal zone lymphoma are significantly influenced by the different centers´ expirience (and maybe tradition), however, the important point of view is also reimbursement possibilities in the particular country. The Canadian perspective, as the authors describe it, is not significantly different from, say, European perspective, though it slightly differ from practice in United States. This makes this comprehensive review of interest and potential guidance to hematology/oncology proffesionals worldwide.

Major comment: From the article, I understood that Health Canada (a governmental agency?) has an important word in reimbursement policy in this country, but the provinces have certain possibilities to go beyond the Health Canada opinion. For non-Canadian readers, it would be useful to add a short paragraph at the beginning of the article to explain the particularities of the Canadian health system and reimbursement policy. 

Minor comments: 

1. Wrong description in Figure 1 (e and f comments are switched)

2. Second line in the first paragraph of Summary and Canadian perspective: subtypes instead of subtype. 

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: From the article, I understood that Health Canada (a governmental agency?) has an important word in reimbursement policy in this country, but the provinces have certain possibilities to go beyond the Health Canada opinion. For non-Canadian readers, it would be useful to add a short paragraph at the beginning of the article to explain the particularities of the Canadian health system and reimbursement policy. 
  • Thank you for this suggestion. We have briefly described the pathway to drug approval and access in Canada that may help international readers who are unfamiliar with it. This can be found in the introduction, lines 60-68: “Treatment decisions in MZL are also largely driven by drug access. New drugs must first be authorized for sale by Health Canada, a governing body which reviews the evidence submitted by the manufacturer on the safety, efficacy, and quality of a drug. Once Health Canada has issued a notice of compliance, the drug may be accessible through private insurance plans or manufacturer-led compassionate access programs. Public funding decisions for drugs are made at the provincial level and aided by recommendations from health technology assessment bodies and price negotiations from the pan-Canadian Pharmaceutical Alliance. However, this does not guarantee access uniformity across the country.”
• Comment 2: Wrong description in Figure 1 (e and f comments are switched)
  • Upon review of the footnotes for ‘e’ and ‘f’’ in figure 1 (page 12), we noticed that they were the correct description; however, the placement of the footnotes was confusing. We have now moved ‘e’ following the text “EMZL stage I/II” with the description: “Testing for C. psittaci in ocular adnexal MALT lymphoma is not routinely performed in Canada but may be considered. In patients who are C. psittaci-positive and do not require immediate disease control, treatment with doxycycline may be considered.”. We have also moved ‘f’ following the text “NMZL stage I” with the description: Stage I NMZL is extremely rare, but ISRT may be considered in these patients based on extrapolation from studies in follicular lymphoma suggesting a chance for a functional cure [102, 103].
• Comment 3: Second line in the first paragraph of Summary and Canadian perspective: subtypesinstead of subtype. 
  • Thank you for catching this, we have adjusted the text as per your recommendation (line 338)

Reviewer 3 Report

An interesting review of the Canadian treatment approach on the various types of marginal lymphoma. The work is really well written, clear, understandable and summarizing.

Congratulations

Just a few minor clarifications:

- In the caption of Table 2, correct first line with refractory/relapsed MZL

- line 186: specify whether it includes all NHLs or only indolent ones

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 the caption of Table 2, correct first line with refractory/relapsed MZL
  • Thank you for catching this. The Table 2 title has been adjusted to “Phase 2/3 prospective trials for treatment of relapsed/refractory advanced/symptomatic MZL” (line 328)
• Comment 2: line 186: specify whether it includes all NHLs or only indolent ones
  • We have adjusted the text in line 219 to say the BRIGHT and StiL NHL1 studies include both indolent NHLs as well as mantle cell lymphoma (which may be indolent or aggressive).