Refractory Splenic Marginal Zone Lymphoma Responsive to Combination Venetoclax and Bortezomib (Velcade) (V2) Therapy
and Anita Aggarwal 1,4
Round 1
Reviewer 1 Report
The authors describe an interesting case of multitreated MZL, with a long clinical history. All diagnostic steps are well described. Valuable histological and molecular informations are provided. In my opinion, the greatest interest of the clinical case lies in the precise descriptions of the disease in its different phases. What is proposed as strongly interesting by the authors, namely the effectiveness of the combination treatment venetoclax + bortezomib, perhaps should be better focused. I would therefore invite the authors to support in the conclusions the rationale of this therapeutic association with some pathogenetic considerations.
Author Response
The authors describe an interesting case of multi treated MZL, with a long clinical history. All diagnostic steps are well described. Valuable histological and molecular informations are provided. In my opinion, the greatest interest of the clinical case lies in the precise descriptions of the disease in its different phases. What is proposed as strongly interesting by the authors, namely the effectiveness of the combination treatment venetoclax + bortezomib, perhaps should be better focused. I would therefore invite the authors to support in the conclusions the rationale of this therapeutic association with some pathogenetic considerations.
Response:
We thank the reviewer for their thoughtful response. We have added additional discussion regarding the use of venetoclax and velcade for the treatment of SMZL and expanded upon the pathologic characterizations and implication of the case throughout the patients disease course.
Reviewer 2 Report
In this manuscript, Roche et al. report a case of refractory splenic marginal zone lymphoma (SMZL) with increased large cells in a 71-year-old African American male, responsive to venetoclax and bortezomib combination therapy (V2). The patient was initially treated with other chemo-immunotherapy courses and splenectomy, but, after 18 years, the disease was in progression. V2 therapy was started and the patient showed a 6 month clinical response, until disease progression and transformation to diffuse large B-cell lymphoma (DLBCL) occurred,V2 treatment was stopped and the patient died.
The authors conclude with a review of the current literature on SMZL clinical trials, remarking the absence of standard treatment regimens and suggesting that V2 therapy may represent an effective therapeutic option for refractory SMZL.
MAJOR ISSUES
- In the manuscript, it is stated that SMZL is majorly treated with rituximab and splenectomy, while V2 therapy is being tested in refractory multiple myeloma; what is the rationale for using V2 treatment in refractory SMZL?
- The authors assert that SMZL is a “rare” condition, but a more detailed description would clarify this statement (eg: prevalence and incidence of the disease).
- It is stated that the patient was treated with “several courses of chemotherapy including rituximab, R-CVP, BR, obinutizumab and lenalidomide” (the correct drug name is “obinutuzumab”), with no time reference, while other therapies (e.g. idelalisib treatment) are more detailed. A more consequential and homogeneous report is needed: therapy administrations and subsequent clinical failures/disease remissions should be cited.
- All the blood chemistry test results should be given with their unit of measurement.
- The authors should briefly discuss the many novel drugs under study for B cell lymphoma referring to a recent review on this topic (Patriarca A et al. Investigational drugs for the treatment of diffuse large B-cell lymphoma. Expert Opin Investig Drugs. 2021 Jan;30:25-38). This is important also considering the large cell component of this patient.
MINOR ISSUES
- All abbreviations in the manuscript should be spelled out.
- The text would benefit from further revision, with a particular attention on English language inaccuracies and typing errors.
Author Response
We appreciate the reviewers thoughtful review of our manuscript. Below we have provided answers to outlined concerns:
In this manuscript, Roche et al. report a case of refractory splenic marginal zone lymphoma (SMZL) with increased large cells in a 71-year-old African American male, responsive to venetoclax and bortezomib combination therapy (V2). The patient was initially treated with other chemo-immunotherapy courses and splenectomy, but, after 18 years, the disease was in progression. V2 therapy was started and the patient showed a 6 month clinical response, until disease progression and transformation to diffuse large B-cell lymphoma (DLBCL) occurred,V2 treatment was stopped and the patient died.
The authors conclude with a review of the current literature on SMZL clinical trials, remarking the absence of standard treatment regimens and suggesting that V2 therapy may represent an effective therapeutic option for refractory SMZL.
Major issues
- In the manuscript, it is stated that SMZL is majorly treated with rituximab and splenectomy, while V2 therapy is being tested in refractory multiple myeloma; what is the rationale for using V2 treatment in refractory SMZL?
Response:
Thank you for your thorough review. We have added additional discussion regarding the rationale for use of V2 for the treatment of SMZL. We also have provided more context with respect to other emerging treatment strategies.
- The authors assert that SMZL is a “rare” condition, but a more detailed description would clarify this statement (eg: prevalence and incidence of the disease).
Response:
Thank you for the comment, we have added the incidence of this disease to highlight its rarity.
- It is stated that the patient was treated with “several courses of chemotherapy including rituximab, R-CVP, BR, obinutizumab and lenalidomide” (the correct drug name is “obinutuzumab”), with no time reference, while other therapies (e.g. idelalisib treatment) are more detailed. A more consequential and homogeneous report is needed: therapy administrations and subsequent clinical failures/disease remissions should be cited.
Response:
Thank you for the opportunity to improve upon the clarity of our report. We provided edits to make this patients extensive treatment course more approachable and uniform in its presentation.
- All the blood chemistry test results should be given with their unit of measurement.
Response:
We have added units of measurement for all blood chemistry results.
- The authors should briefly discuss the many novel drugs under study for B cell lymphoma referring to a recent review on this topic (Patriarca A et al. Investigational drugs for the treatment of diffuse large B-cell lymphoma. Expert Opin Investig Drugs. 2021 Jan;30:25-38). This is important also considering the large cell component of this patient.
Response:
We have incorporated emerging treatment strategies for lymphoma, however, to maintain the focus of our report we predominately discuss combination regimens that include venetoclax. We have also read the recommended paper and have cited the paper in our discussion of BTK inhibitors.
Minor issues
- All abbreviations in the manuscript should be spelled out.
Response:
We have spelled out some of the abbreviations while keeping others that we consider to be commonly used and understood to keep the report succinct.
- The text would benefit from further revision, with a particular attention on English language inaccuracies and typing errors.
Response:
We have further edited the manuscript, correcting punctuality and typing errors.
Reviewer 3 Report
This paper describe a complex case of a patient presenting a multirefractory SMZL achieving a clinical response to a venetoclax and bortezomib combination treatment.
I think it is a quite interesting and original report, worthy of being published. I have several questions/suggestions for the authors:
-I think the authors should give their advice concerning the biologic rational of this combination in this clinical setting, especially for the extremely detailed molecular characterization of the disease.
-the patient received several biological treatments for his SMZL, however he did not receive ibrutinib, which is known to be highly active in this disease. Furthermore, the lymphoma presented a MYD88 mutation, which is a mutation known to be sensitive to BTK inhibitors. Is there a specific reason for that?
-when speaking about CT scan response during treatment, the authors talk about a "reduction in size" for the majority of the adenopathies. It seems like it is a stable disease, according to Cheson criteria. Could you please specify this and express the radiological response according to Cheson criteria?
-when listing the most important clinical trials for MZL treatment i would mention the MAGNIFY trial which reported an interesting PFS/DOR with rituximab and lenalidomide in this disease.
Author Response
We appreciate the reviewers thoughtful review and questions. We hope our answers to their questions/concerns will strengthen the manuscript. Below is a point by point answer for each questions/concern on the list:
This paper describe a complex case of a patient presenting a multirefractory SMZL achieving a clinical response to a venetoclax and bortezomib combination treatment. I think it is a quite interesting and original report, worthy of being published. I have several questions/suggestions for the authors:.
- I think the authors should give their advice concerning the biologic rationale of this combination in this clinical setting, especially for the extremely detailed molecular characterization of the disease.
Response:
As requested, we have added additional discussion regarding the rationale for use of V2 for the treatment of SMZL. We thank the reviewer for their thoughtful response.
- The patient received several biological treatments for his SMZL, however he did not receive ibrutinib, which is known to be highly active in this disease. Furthermore, the lymphoma presented a MYD88 mutation, which is a mutation known to be sensitive to BTK inhibitors. Is there a specific reason for that?
Response:
The patient did in fact receive ibrutinib. We have clarified the language of the report to reflect this aspect of his treatment course.
- When speaking about CT scan response during treatment, the authors talk about a "reduction in size" for the majority of the adenopathies. It seems like it is a stable disease, according to Cheson criteria. Could you please specify this and express the radiological response according to Cheson criteria?
Response:
As requested, we have provided more detail regarding the treatment response observed on CT applying the The Lugano classification as recommended by Cheson et al.
- When listing the most important clinical trials for MZL treatment i would mention the MAGNIFY trial which reported an interesting PFS/DOR with rituximab and lenalidomide in this disease.
Response:
As requested, we have incorporated discussion regarding combination therapy with rituximab and lenalidomide within the report and thank the reviewer for their recommendation.
Reviewer 4 Report
When the SMZL patient received V2 after 20 years of different therapies the histological and biological characteristics of disease were different from classical MZL suggesting progression to/survival of more aggressive clones in a subset of refractory MZL with increased large cells. Thefore, the Authors should present the case report focusing on this different setting which may have influenced the response to V2.
Author Response
Reviewer 4:
When the SMZL patient received V2 after 20 years of different therapies the histological and biological characteristics of disease were different from classical MZL suggesting progression to/survival of more aggressive clones in a subset of refractory MZL with increased large cells. Therefore, the Authors should present the case report focusing on this different setting which may have influenced the response to V2.
Thank you for your comments, we have edited the report with the intention of providing focus on the rationale that drove the decision to use V2 in the context of other emerging therapies for the treatment of lymphomas. This patient had largely exhausted conventional treatment options, prompting a discussion regarding the risks and benefits of V2 therapy. Encouragingly this therapy provided an impressive clinical response for approximately 6 months.
Round 2
Reviewer 2 Report
The authors have addressed the majority of the issues that had been raised. The only issue i would like to underline is the presence of few remaining typing errors (e.g. "mesh works", "(Figure 2", "107 Similar" "increased. Ki67"
Reviewer 4 Report
The manuscript has been sufficiently improved to warrant publication in Current Oncology.
