Fatal Progression of Mutated TP53-Associated Clonal Hematopoiesis following Anti-CD19 CAR-T Cell Therapy

Round 1

Reviewer 1 Report

The clinical case is interesting and concerns a field of strong interest: clonal hematopoiesis and its relation to innovative CAR-T therapy. However, I have to make some questions and considerations:

 

lines 12-13, in abstract

 

“Next Generation Sequencing analysis was initiated”

 

Please change the world “initiated” with Performed

 

Lines 40-42

 

 “However, 15 months after initial diagnosis the lymphoma recurred, and 40 was histologically confirmed to be a relapse of the known LBCL and synchronously a  classical Hodgkin lymphoma”

 

Unclear. Please better explain what kind of recurrence the patient had: where it was located (same site as diagnosis? another site?).

 

Line 42

 

 “classical Hodgkin lymphoma”

 

this is crucial: please explain in great detail why anti-CD 19 CAR-T cell product was chosen despite the clone of Hodgkin lymphoma that usually does not express CD 19 antigen

 

 

Line 44

When did cytopenia appear? since diagnosis? after transplantation? before CAR-T infusion?

Specify other features, including mean cell volume (MCV).

 

lines 47-49

 

Bone marrow or peripheral blood NGS? Were other alterations present?

 

lines 45-47; 53-54

 

Has a bone marrow biopsy ever been performed or are they just bone marrow aspirates?

 

 

Line 55

Has the diagnosis of hypoplastic myelodysplastic syndrome been considered? Why was only allogeneic transplantation and not hypomethylating agent therapy discussed?

 

Line 64

Specify whether the diagnosis of myelodysplastic syndrome was confirmed and the IPSS-R score

Please, explain whether G-CSF and erythropoietin  were not  used (and why) or were ineffective

 

Please specify why the patient was considered ineligible to hypomethylating agent treatment

Author Response

Dear editor, dear reviewers,

thank you very much for your recommendations. We changed revised our manuscript and want to respond to your comments. Please see the attachtment.

Kind regards,

Lea Naomi Eder

Author Response File: Author Response.docx

Reviewer 2 Report

Dear colleagues, I was very glad to read your manuscript.

I have several recommendations:

1. I recommend to describe in more detail the possible gene toxicity of IFNg and TNFa cytokines, which are very important for tumor killing during CAR-T therapy.

2. I recommend clarifying which NGS was made, if it is a panel of genes, then what kind of panel it is and whether there are mutations in other genes or not.

3. There is no strong evidence to me that MDS did not develop independently of CAR-T therapy, as well as due to lymphodiplecia. How can you strengthen the conclusion or discussion and suggest other possible reasons for the events you describe?

4. What other mutations can you recommend for early screening other than in the TP53 gene and why?

5. TET2 and KMT2A were not included in NGS sequencing? Can you recommend these genes also for early diagnosis before CAR-T therapy?

6. Have you tested for cytokines and CAR-T persistence? Please indicate CRS and ICANS grade. Could clonal evolution and secondary MDS be related to side effects in the cases you describe in your discussion?

Author Response

Dear editor, dear reviewers,

thank you very much for your recommendations. We changed revised our manuscript and want to respond to your comments. Please see the attachtment.

Kind regards,

Lea Naomi Eder

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Thank you for the revisions. 

Reviewer 2 Report

Thank you for significant improvement of the manuscript.