Therapeutic Management of Chronic Lymphocytic Leukemia Presenting with Recurrent Massive Ascites

Round 1

Reviewer 1 Report

This is an interesting case of CLL that potentially relapsed with recurrent ascites. That being said, I have significant reservations about the case report, see below Major criticism.

Major:

It’s odd for someone to have no response to ibrutinib + rituximab, then have a response to acalabrutinib + obinutuzumab, as the drugs have the same mechanism of action. This makes me question whether the ascites was truly due to CLL versus an alternative cause. CLL will track anywhere where there is active inflammation, or infection, given it’s a white blood cell. There isn’t much here about what else was occurring with the patient when he developed recurrent ascites. Did he have an alternative cause for the recurrent ascites, explained by his many other comorbidities? He had known heart disease, and ESRD, which both can lead to fluid accumulation. Did he get worked up for liver failure? Similarly, when the patient did finally receive the acalabrutinib and obinutuzumab, he underwent multiple rounds of dialysis, which could be the reason why his ascites improved. He also received high dose steroids as this time, which could have treated another unrelated to CLL problem causing the ascites. The last paragraph showing improvement of ascites accumulation after start of obinutuzumab is reassuring that this was caused by the CLL, but also may just be coincidence and the patient also received high-dose steroids.  Including the workup for alternative explanations for this recurrent ascites would be useful, as it would help show that the ascites was really due to CLL and not an alternative cause.

-In summary. The case would be strengthened by describing what else was occurring around the time of the recurrent ascites to work up, and treat, alternative etiologies for recurrent ascites.

Minor:

First sentence - The diagnosis of SLL does not require the presence of lymphocytosis, would change.

The most common immunophenotypic expression for CLL is CD19, not CD9 (page 2 first sentence), please correct.

Trisomy 12 is not considered low-risk, it is intermediate risk, please correct.

Obinutuzumab is not an anti-cd20 inhibitor, it is an anti-CD20 monoclonal antibody, please correct.

Patient did not have “rediagnosis” he had relapse of his disease (third paragraph of case report)

Discussion - Is CLL the most common hematologic malignancy in older adults now? It’s the most common leukemia in the western world. Please provide citation.

 

Discussion – Would not recommend someone get a laparotomy to perform a biopsy of a peritoneal lymph node in someone with ascites. 

Author Response

Thank you for reviewing the manuscript. We appreciate the time. I have responded to your comments below and I have made changes to the manuscript

 

 

 

Major:

It’s odd for someone to have no response to ibrutinib + rituximab, then have a response to acalabrutinib + obinutuzumab, as the drugs have the same mechanism of action. This makes me question whether the ascites was truly due to CLL versus an alternative cause. CLL will track anywhere where there is active inflammation, or infection, given it’s a white blood cell. There isn’t much here about what else was occurring with the patient when he developed recurrent ascites. Did he have an alternative cause for the recurrent ascites, explained by his many other comorbidities? He had known heart disease, and ESRD, which both can lead to fluid accumulation. Did he get worked up for liver failure? Similarly, when the patient did finally receive the acalabrutinib and obinutuzumab, he underwent multiple rounds of dialysis, which could be the reason why his ascites improved. He also received high dose steroids as this time, which could have treated another unrelated to CLL problem causing the ascites. The last paragraph showing improvement of ascites accumulation after start of obinutuzumab is reassuring that this was caused by the CLL, but also may just be coincidence and the patient also received high-dose steroids.  Including the workup for alternative explanations for this recurrent ascites would be useful, as it would help show that the ascites was due to CLL and not an alternative cause.

-In summary. The case would be strengthened by describing what else was occurring around the time of the recurrent ascites to work up, and treat, alternative etiologies for recurrent ascites.

 

Responses:

Did he have an alternative cause for the recurrent ascites, explained by his many other comorbidities?

• The introduction portion was confusing, and it has been edited. The ESRD/renal disease was diagnosed after he began aca plus obi; renal dysfunction and dialysis occurred after the patient developed ascites from relapsed disease.
• Although the patient had a CABG in the past, he never went into decompensated heart failure; TTE at the time normal left ventricular size. Mild concentric left ventricular hypertrophy. Normal left ventricular systolic function. Left ventricular ejection fraction is 55-59%. CXR also did not show evidence of pulmonary infiltrates or cardiomegaly. Thus, heart failure was ruled out as the cause of the ascites
• Did he get worked up for liver failure?
  • Other explanations of liver failure were worked up.
  • Patient had transudative ascites during relapse: SAAG ~1.8, we ruled out heart failure, and abdominal imaging did not show portal vein thrombosis or liver cirrhosis. Thus, these could not explain the ascites. We had enough evidence that the ascites was due to CLL and not an alternative cause

Minor:

First sentence - The diagnosis of SLL does not require the presence of lymphocytosis, would change.

• This has been fixed

The most common immunophenotypic expression for CLL is CD19, not CD9 (page 2 first sentence), please correct.

• This has been fixed

 

Trisomy 12 is not considered low-risk, it is intermediate risk, please correct.

• This has been fixed

 

Obinutuzumab is not an anti-cd20 inhibitor, it is an anti-CD20 monoclonal antibody, please correct.

• This has been fixed

 

Patient did not have “rediagnosis” he had relapse of his disease (third paragraph of case report)

• This has been fixed

 

Discussion - Is CLL the most common hematologic malignancy in older adults now? It’s the most common leukemia in the western world. Please provide citation.

• This has been fixed

Discussion – Would not recommend someone get a laparotomy to perform a biopsy of a peritoneal lymph node in someone with ascites. 

• removed this statement about “laparotomy….node” from the discussion portion.

 

 

 

Reviewer 2 Report

Were biological risk factors (FISH and p53 mutation) assessed at the relapse?

Author Response

Thank you for reviewing the manuscript. We appreciate the time. I have responded to your comments below and I have made changes to the manuscript

 

 

 

Reviewer 2: Comments and Suggestions for Authors

Were biological risk factors (FISH and p53 mutation) assessed at the relapse?

Yes, these biological risk factors were assessed and changes have been made to the report

• Bone marrow: Deletion of 13q, ATM/11q or TP53 were not detected.
• FISH: positive for Trisomy 12

Round 2

Reviewer 1 Report

The authors attempt to explain all of the reasons why there is not an alternative cause for the ascites other than the CLL. I still have serious concerns with the overall manuscript, and feel it would be improved with further editing from a leukemia expert. For instance, acalabrutinib is a bruton tyrosine kinase inhibitor, and leukemic blasts are not typically seen at diagnosis for CLL. Furthermore, the authors now state the patient has aortic valve stenosis which was treated with CABG. This is not the appropriate treatment for aortic stenosis.

Furthermore, there is no explanation for why the patient developed recurrent soft-tissue skin infections, or renal failure during the course of his recurrent ascites. Once again, ibrutinib and rituximab have the same mechanism of action as obinutuzumab and acalabrutinib. There is no explanation here as to why the authors believe the patient would do better with AO vs. IR. An explanation could be tolerability, and ability to be maintained on therapy, but this is not made clear. All of this continues to complicate the clinical picture, and continues to make me question that the CLL is the root cause of his ascites.

Overall, this is an interesting case report, but should undergo further editing to make sure the clinical details are all accurate. 

Author Response

The authors attempt to explain all the reasons why there is not an alternative cause for the ascites other than the CLL. I still have serious concerns with the overall manuscript and feel it would be improved with further editing from a leukemia expert. For instance, acalabrutinib is a bruton tyrosine kinase inhibitor, and leukemic blasts are not typically seen at diagnosis for CLL. Furthermore, the authors now state the patient has aortic valve stenosis which was treated with CABG. This is not the appropriate treatment for aortic stenosis.

Furthermore, there is no explanation for why the patient developed recurrent soft-tissue skin infections, or renal failure during his recurrent ascites. Once again, ibrutinib and rituximab have the same mechanism of action as obinutuzumab and acalabrutinib. There is no explanation here as to why the authors believe the patient would do better with AO vs. IR. An explanation could be tolerability, and ability to be maintained on therapy, but this is not made clear. All of this continues to complicate the clinical picture and continues to make me question that the CLL is the root cause of his ascites.

Overall, this is an interesting case report, but should undergo further editing to make sure the clinical details are all accurate. 

Responses:

We would like to thank you for taking the time to review the paper.

• Question: The authors attempt to explain all the reasons why there is not alternative cause for the ascites other than the CLL. I still have serious concerns with the overall manuscript and feel it would be improved with further editing by a leukemia expert. For instance, acalabrutinib is a bruton tyrosine kinase inhibitor, and leukemic blasts are not typically seen at diagnosis for CLL
  • Response: Thank you for the comments. We have made all the edits by a leukemia expert.
  • Apologies on not adding Bruton’s before the tyrosine kinase inhibitor. We have made the changes

 

• Question: Furthermore, the authors now state the patient has aortic valve stenosis which was treated with CABG. This is not the appropriate treatment for aortic stenosis.
  • Thank you for the comments. The patient had triple vessel coronary occlusions warranting a CABG. The patient also had asymptomatic aortic stenosis, but CABG is not the treatment for AS. We have made this clearer in the manuscript.

 

Question: Furthermore, there is no explanation for why the patient developed recurrent soft-tissue skin infections or renal failure during his recurrent ascites.

• Renal failure was secondary to recurrent massive ascites (9-11L) and hypoalbuminemia (lack of adequate nutrition from lack of appetite) leading to decrease intravascular volume over a long period of time with massive ascites. --- made clearer in paper

 

 

Question: Once again, ibrutinib and rituximab have the same mechanism of action as obinutuzumab and acalabrutinib. There is no explanation here as to why the authors believe the patient would do better with AO vs. IR. An explanation could be tolerability, and ability to be maintained on therapy, but this is not made clear.

• Response: We have made clearer to the lack of tolerability and response to IB+R hence requiring switching treatment to newer generation. VEN was not an option with renal failure.

 

 

 

Author Response File: Author Response.docx

Round 3

Reviewer 1 Report

Authors addressed all concerns.