Debulking Therapy with Obinutuzumab Is Helpful and Safe in Chronic Lymphocytic Leukemia with Extreme Hyperleukocytosis: A Case Report

Round 1

Reviewer 1 Report (New Reviewer)

Comments and Suggestions for Authors

The authors  present the case of obinutuzumab debulking in the patient with extreme lymphocytosis.following venetoclax initiation. The abstract part is appropriate. In the introduction part the authors should clearly state wihic TLS criteria was used. Case is not  clearly written because  splenomegaly and lymphadenopathy are not described, CLL IPI should be calculated. The part obinutuzumab  velocity may help the other hematologists facing the same dilemma. The authors state that CAR was achieved by the EOT but do not provide the evidence of CR. Table 1. should use SI units. Discussion part is appropriate although  the experimental clinical trials should be cited.I propose minor review.

Author Response

Reviewer 1
Dear Reviewer, thank you for your kind and concise revision. We improved the whole manuscript following
your suggestions.

You can find here our point-to-point reply.

- We properly specified the TLS criteria used.
- We added information regarding splenomegaly, lymphadenopathy and CLL IPI.
- We added the WBC count and outcome of splenomegaly and lymphadenopathy after completing
obinutuzumab-venetoclax therapy.
- We updated table 1 with SI units and normal range values.
- We properly cited the clinical trials.

Thank you for your valuable time and thoughtful feedback, which have greatly contributed to improving the
quality of our manuscript. We look forward to your final evaluation.
Sincerely,

Dr. Dario Leotta, Dr. Andrea Duminuco

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

The Authors presented a case report involving Debulking therapy with obinutuzumab. The manuscript addresses a critical clinical challenge in chronic lymphocytic leukemia (CLL) management, specifically in patients with extreme hyperleukocytosis and tumor lysis syndrome (TLS) risk. The use of debulking therapy with obinutuzumab followed by venetoclax is described in a case report, providing valuable insights into the therapeutic approach, efficacy, and safety. The case presentation is wide, and the outcomes are well-documented with supportive data. However, the manuscript could benefit from improved clarity in certain areas, additional context in the discussion, and more focus on clinical implications.

Remarks to the paper:

Introduction The introduction provides a good overview of CLL and its challenges. However, it lacks sufficient context regarding why extreme hyperleukocytosis in CLL is rare and its unique clinical considerations. I recommend adding a brief review of existing therapeutic options for similar cases would strengthen the background.

Case Presentation: The patient’s clinical presentation and laboratory findings are detailed, but there is no clear timeline for disease progression before hospitalization. Including more specific data on previous interventions, if any, would help contextualize the severity of the case.

The rationale for choosing venetoclax-obinutuzumab over other options (e.g., BTK inhibitors) could be expanded to emphasize clinical decision-making. For example, a comparison with alternative treatments would provide a stronger justification for the chosen regimen.

The description of infusion-related reactions and their management is reletively good, but should include a more detailed explanation of why such reactions are common with obinutuzumab in this context and how they were mitigated effectively.

Discussing the risks of TLS with specific reference to venetoclax’s mechanism of action and its relevance to the presented case would enhance understanding.

Figures and Tables: The trend of WBC count during therapy (Figure 1) is helpful. However, it could be improved by annotating key interventions (e.g., start of therapy, dose adjustments) to link clinical events with laboratory changes. Table 1 is informative but could be expanded to include reference ranges for laboratory parameters for better interpretation of results.

Discussion section The discussion mentions leukapheresis as an option but does not delve into why it was ultimately not used beyond the patient’s poor condition. A more detailed analysis of the risks and benefits of leukapheresis versus debulking therapy would add depth. The authors should consider exploring the broader implications of their findings. For example, how does this case inform the treatment of similar patients, and what gaps in the current guidelines does it highlight?

Citing more recent studies (2022–2024) on venetoclax-obinutuzumab regimens, particularly in high-risk populations, would enhance the manuscript's relevance.

The conclusion is concise but could include specific recommendations for managing similar cases in clinical practice, focusing on decision-making frameworks for choosing therapies and mitigating TLS risks.

Additional Suggestions - Consider including a brief section on future directions, such as the potential role of emerging therapies or biomarkers in predicting TLS risk.

It should be also mentioned that results were presented here https://library.ehaweb.org/eha/2024/eha2024-congress/421334/dario.leotta.obinutuzumab.as.debulking.therapy.for.a.successful.delivered.of.html

 

 

in general, the manuscript addresses an important clinical issue and presents a compelling case. With revisions to enhance clarity, expand the discussion, and emphasize clinical relevance, it could significantly contribute to the field of hematology and oncology.

Comments on the Quality of English Language

As was mentioned above, "The English could be improved to more clearly express the research".

Author Response

Dear reviewer 2, thank you for your thoughtful revision. We improved the text according to your suggestions.

1) We added a brief review of hyperleukocytosis adding a brief review of existing therapeutic options for
similar cases would strengthen the background.
2) We addressed the timeline of disease progression as requested.
3) We deepened rationale, features and future outcomes for obinutuzumab-venetoclax.
4) We adjusted Figure 1 and Table 1 with your advice.
5) We expanded on Leucoapheresis and its outcomes.

Thank you for your valuable time and thoughtful feedback, which have greatly contributed to
improving the quality of our manuscript. We look forward to your final evaluation.

Sincerely,

Dr. Dario Leotta, Dr. Andrea Duminuco

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors Title: Debulking therapy with obinutuzumab is helpful and safe in CLL with extreme hyperleukocytosis: a case report Authors: Dario Leotta *   This brief report describes initial treatment of a patient with CLL with a very high WCC with single agent obinutuzumab, with a slow rate of infusion.   These data are really of little interest and do not in my view merit publication. It is well known that obinutuzumab can induce tumor lysis under these conditions an in my view, the authors were fortunate to avoid this complication. Moreover, the MS is poorly written with key details missing including:- a) levels of surface CD20 expression b) molecular characterization of the CLL subtype c) what are the units on the abscissa of Figure 1? d) CD20 antibody was given in the face of previous HepB infection?  What was the patient's viral status please? e) what is pulmonary sub edema? (Line 107)    

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors, an interesting case report on the venetoclax-obinutuzumab regimen for a CLL patient with extreme hyperleukocytosis. I believe minor revisions are required before the submission can proceed further. Thus, please answer or consider the following:

(1) Please standardize the unit for WBC count – currently, there is either mm3 (in Simple Summary) or mmc (probably the rest of the paper).

(2) Section 2, case presentation: Please combine separated sentences (in lines 79-82) with other paragraphs – currently they constitute their own paragraphs while they could be, e.g., put at the end of the first paragraph of section 2.

(3) Section 2, line 129: What did you mean by the “Day Unit regimen”?

(4) Figure 1: Are there months on the X-axis? Please annotate the axis. Moreover, is there a measurement available after 29,000 (currently the last one)?

(5) Based on your experience, what kind of alternative regimen would be suitable for CLL patients with extreme hyperleukocytosis, given that there are various BCL-2 inhibitors (e.g., navitoclax, obatoclax, BCL201, lisaftoclax) and CD20 antibodies (e.g., rituximab, ublituximab, ocrelizumab, ofatumumab) instead of venetoclax-obinutuzumab combination? Please elaborate in a sentence or two in your Discussion.

(6) Publisher’s note/Disclaimer is missing after References.

(7) Include a CARE checklist to formally acknowledge that your study was performed according to relevant guidelines. Approval by the Ethics Committee and Signed Consent are also welcomed.