Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors present interesting case series on particular gene mutation

Abstract:  PPM1D should be written as full gene name with following abbreviations after introduction in   the manuscript text .The main goal of the study needs to be presented in the hypothesis-like manner. Abbreviations are fine. Introduction; For the interested readers the clinical course of MCL should be explained for MCL shares the characteristics of aggressive and indolent lymphoma. Furthemore, with conventional immunochemotherapy , the short summary of the TRIANGLE study should be included Furthermore, SAEs of CART therapy should be shortened due to the fact that ICANS and CIRS are generally known in the interested reading population. The hypothesis about clonal hematopoiesis in patients undergoing CAR-T should be explained more thoroughly especially when authors found their research basis on DLBCL

Material and methods The main outcome of the study should be stated first i.e. being PFS or OS. Due to the fact that the number of participants is low, I would suggest the power analysis.

Results: This section is very well written and I do not have issues with it. 

Discussion This part needs to be shortened with only key points of study, including limitations, stated

Conclusion Conclusion is missing and needs to be introduced.

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

 

The authors have analyzed somatic mutations in 16 cases of relapsed/refractory mantle cell lymphoma treated with CD19-targeted CAR-T cell therapy at their institution, reporting on the frequency and pattern of PPM1D gene mutations, as well as the therapeutic efficacy of CAR-T cell therapy.

 

The differences in treatment outcomes based on the presence or absence of PPM1D gene mutations are striking, making this an impactful and highly interesting report.

 

Below are some points that, if revised, would improve the manuscript:

 

1. Ibrutinib plus Bendamustine and Rituximab therapy for untreated, transplant-ineligible mantle cell lymphoma was reported in the NEJM in 2022, which has brought significant changes to the treatment algorithm. I believe this paper should be cited.
2. You have listed three CD19 CAR-T therapies, but why have you not included lisocabtagene maraleucel?
3. If there are reports on the correlation between BTK inhibitors and PPM1D gene mutations, please include them in the discussion.
4. The content at the beginning of the discussion (LANE 265-276) overlaps with the introduction, so please organize this.
5. In the main text and tables, commas and decimal points are used inconsistently, so please review this.
6. There was a difference in the frequency of CD19 rs29048800. Please add a discussion on this result.

 

 

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

                The authors report their retrospective analysis of the potential impact of PPM1D-variant CH on MCL patients who received brexu-cel CAR T-cell therapy. The report is expertly written and the conclusions appropriately qualified. Still, there is some uncertainty as to whether it is merited to conclude in the Discussion, that “Our data suggest an adverse prognostic and possibly predictive impact of PPM1D mutations in patients with r/r MCL undergoing brexucel CD19-targeted CAR T-cell therapy.” The Discussion goes on to state that “To confirm the impact of low-frequency PPM1D mutations on treatment outcome, a larger study in MCL patients treated with anti-CD19 CAR T-cell therapy is required.”

                The authors should address the following questions:

1) The alternative hypothesis is that the inferior outcome in this study of patients with low-frequency PPM1D mutations is simply a chance phenomenon, due to being confounded with several adverse features of these same patients that the authors have admirably reported. Those features are a worse status of active disease at the time that CAR T-cell therapy was given, and a lower frequency of complete remissions to previous treatments. Why do the authors not think that their results may be a chance association?

2) The authors previously found a similar association between low-frequency PPM1D mutations and worse outcome for CAR T-cell therapy in 85 DLBCL patients (PMID: 38132396). However, PMID: 37799345 reported that for 110 DLBCL patients, in whom PPM1D was the most frequently mutated gene of CH (all VAFs >=1%), there was no association with outcome after CAR T-cell therapy. This study should be cited in the manuscript. What is the authors’ response?

3) Are the variant allele frequencies of PPM1D mutations sufficiently high to be classified as CH? It is generally accepted that mutations of CH are present at a frequency of >=2% (VAF = 0.02); see PMID: 31672865 and PMID: 35788175. Most of the VAFs in Table 1 are below 0.02; however, they are all at least 0.01, and since these 7 mutations are present in 4 patients, it is possible that every patient has a total VAF of PPM1D mutations that exceeds 0.02.

4) Even when summed, is there precedent for CH from such low-frequency VAFs having such a profound systemic effect as is proposed here, i.e., affecting the outcome of anti-CD19 CAR T-cell therapy?

5) Do the authors have a hypothetical mechanism for the proposed effect of PPM1D mutations? Could they be present at high frequency in one subset of PBMCs? PMID: 33020644 reported that high-grade ICANS during CAR T-cell therapy was associated with a rare cell population with monocyte-like transcriptional features.

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The changes made by the authors are appropriate and I recommend the acceptance of the manuscript in the present form.