Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This case report describes a 36‑year‑old patient with KMT2A‑rearranged AML who relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) and was treated with venetoclax plus azacitidine followed by compassionate‑use revumenib, a menin inhibitor. The objective is to highlight a discordance between systemic and central nervous system (CNS) responses: revumenib induced complete hematologic remission with measurable residual disease (MRD) negativity and resolution of hepatic extramedullary disease (EMD), but an isolated CNS relapse occurred despite systemic disease control and prior intrathecal prophylaxis

In the current study diagnostic work‑up, treatment sequence, and outcomes are clearly described, and relevant literature on KMT2A‑r AML, menin inhibitors, CNS involvement, and EMD is cited. However, key clinical details revumenib dosing schedule, MRD methodology, and CNS prophylaxis regimen—are not fully specified, which limits the ability to generalize or precisely interpret CNS failure. systemic MRD negativity under targeted therapy does not guarantee CNS control, and CNS sanctuary sites may require specific attention in treatment planning.

The current MS required a minor revision. The case report offers valuable real‑world insight into revumenib’s limitations in CNS disease control among patients with KMT2A‑r AML. With added detail on dosing, CNS prophylaxis, MRD methodology, and ethics/consent, the manuscript would be suitable for publication in the journal as a well‑documented hypothesis‑generating case

Major Comments

1. The case report does not specify revumenib dose, administration schedule, number of cycles before achieving CR/MRD negativity, or any dose modifications. Without this information, the relationship between drug exposure and CNS escape cannot be assessed. I would like to suggest the authors to report starting dose, schedule, number of cycles to CR/MRD negativity, dose adjustments, and treatment duration prior to CNS relapse, to contextualize exposure and response
2. The report mentions two intrathecal lumbar punctures prior to revumenib with negative CSF by morphology and multiparameter flow cytometry (MFC), but details about intrathecal agents (e.g., methotrexate, cytarabine), dosing, interval, and whether prophylaxis continued during revumenib are missing. I would like to suggest the author to wok on it and add for further acceptance purpose.
3. The statement that MRD negativity was achieved by MFC lacks detail on the antibody panel, gating strategy, and sensitivity threshold (e.g., 10⁻⁴ or 10⁻⁵), which is critical when using MRD as a bridge‑to‑HSCT decision tool. I would like to suggest the authors kindly specified the MRD methodology and provide details on MFC MRD panel, gating, sensitivity, and criteria for MRD negativity to strengthen the claim of “deep systemic response.
4. Funding and conflict of interest disclosures are present, but there is no explicit statement confirming patient informed consent for publication and ethics committee approval or waiver, which is standard for case reports; kindly provide this. Include a sentence confirming that written informed consent for publication was obtained from the patient (or next of kin) and that institutional ethics approval was obtained or deemed unnecessary per local regulations.
5. In the current MS the discussion suggests that limited activity of menin inhibitors in CNS sanctuary sites may underlie the observed CNS relapse and calls for standardized CNS prophylaxis. While plausible, the report does not provide pharmacokinetic or CSF concentration data on revumenib to support a definitive conclusion about CNS penetration; alternative mechanisms (e.g., pre‑existing CNS‑tropic subclones, timing of prophylaxis) should be more explicitly acknowledged.
6. Please describe intrathecal agents, doses, timing relative to revumenib, and whether prophylaxis was continued during menin inhibitor therapy. And Clarify CNS monitoring schedule (e.g., routine CSF evaluations vs symptom‑triggered) to support conclusions about CNS escape.

Minor comments

1. I would like to suggest to add brief information on revumenib dosing and CNS prophylaxis in the abstract to frame CNS escape more concretely.
2. Remove minor redundancies concerning poor outcomes and EMD propensity to improve readability.
3. Please clarify Figure 1 legend: Ensure the clinical timeline figure legend explicitly annotates key events (diagnosis, HSCT1, relapse, venetoclax/azacitidine, revumenib, CNS relapse, intrathecal therapy, HSCT2, systemic progression and death).
4. As a case report, reproducibility concerns focus on clinical detail rather than experimental methods. Additional information on revumenib dosing, CNS prophylaxis, and MRD assays would enhance transparency and allow clinicians to better contextualize this case relative to their own practice. So a brief data availability statement indicating whether anonymized clinical data can be shared would align with evolving journal policies.
5. The manuscript would benefit from careful proofreading to correct typographical and grammatical errors, along with improvements in figure quality and presentation for better clarity. Minor typographical errors (“heavly”, “trasplant”) should be corrected, and a few long sentences in the discussion can be shortened for clarity

 

Author Response

C: The case report does not specify revumenib dose, administration schedule, number of cycles before achieving CR/MRD negativity, or any dose modifications. Without this information, the relationship between drug exposure and CNS escape cannot be assessed. I would like to suggest the authors to report starting dose, schedule, number of cycles to CR/MRD negativity, dose adjustments, and treatment duration prior to CNS relapse, to contextualize exposure and response.

R: Thank you for this valuable comment. We have revised the manuscript accordingly. The patient received oral revumenib at a dose of 160 mg twice daily (160 mg BID), administered continuously on days 1–28 of each 28-day cycle. He completed two treatment cycles without experiencing toxicity, requiring dose reductions, or treatment interruptions. Following two cycles, bone marrow evaluation demonstrated complete remission, with no detectable immunophenotypically abnormal myeloid blast population by multiparameter flow cytometry. Revumenib was subsequently continued as bridge therapy until the occurrence of the isolated CNS relapse, after which the patient proceeded to a second HSCT. These details have now been incorporated into the revised manuscript.

C:

The report mentions two intrathecal lumbar punctures prior to revumenib with negative CSF by morphology and multiparameter flow cytometry (MFC), but details about intrathecal agents (e.g., methotrexate, cytarabine), dosing, interval, and whether prophylaxis continued during revumenib are missing. I would like to suggest the author to work on it and add for further acceptance purpose.

R: We thank the Reviewer for this valuable comment. The intrathecal treatment consisted of cytarabine (40 mg), methotrexate (12.5 mg), and methylprednisolone (40 mg). At the time of relapse, the patient underwent an initial lumbar puncture with routine cerebrospinal fluid (CSF) analysis, followed one month later by a second lumbar puncture including multiparameter flow cytometry (MFC), which did not detect leukemic blast infiltration. For the sake of brevity, these details were summarized in the original manuscript. In response to the Reviewer's suggestion, we have revised the text to provide a more detailed description of the intrathecal treatment, the timing of lumbar punctures, the CSF assessments, and clarified that no scheduled CSF monitoring was performed during revumenib therapy; the subsequent lumbar puncture was prompted by the onset of neurological symptoms.

C: 

The statement that MRD negativity was achieved by MFC lacks detail on the antibody panel, gating strategy, and sensitivity threshold (e.g., 10⁻⁴ or 10⁻⁵), which is critical when using MRD as a bridge-to-HSCT decision tool. I would like to suggest the authors kindly specify the MRD methodology and provide details on the MFC MRD panel, gating strategy, sensitivity, and criteria for MRD negativity to strengthen the claim of “deep systemic response”.

R: Thank you for this valuable comment. We agree that detailed information regarding MRD methodology is essential when MRD status is used to support therapeutic decisions. In our case, however, a standardized MFC-MRD assay was not performed. Rather, bone marrow evaluation included multiparameter flow cytometry with analysis of the total leukocyte population, followed by assessment of the myeloid blast compartment using a myeloid immunophenotypic panel. No immunophenotypically abnormal blast population was detected, with CD34/CD117-positive cells accounting for less than 1% of total bone marrow cells. Because the methodology did not correspond to a validated MRD assay with a defined analytical sensitivity, we revised the manuscript accordingly and replaced the term "MRD negativity" with a more accurate description of the flow cytometry findings, thereby avoiding overinterpretation of the results.

C: 

Funding and conflict of interest disclosures are present, but there is no explicit statement confirming patient informed consent for publication and ethics committee approval or waiver, which is standard for case reports; kindly provide this. Include a sentence confirming that written informed consent for publication was obtained from the patient (or next of kin) and that institutional ethics approval was obtained or deemed unnecessary per local regulations.

R: Thank you for this valuable observation. We have now explicitly included statements regarding written informed consent for publication and institutional ethics approval/waiver, in accordance with local regulations.

C: 

In the current manuscript, the Discussion suggests that limited activity of menin inhibitors in CNS sanctuary sites may underlie the observed CNS relapse and calls for standardized CNS prophylaxis. While plausible, the report does not provide pharmacokinetic or CSF concentration data on revumenib to support a definitive conclusion about CNS penetration; alternative mechanisms (e.g., pre-existing CNS-tropic subclones, timing of prophylaxis) should be more explicitly acknowledged.

R: Thank you for this valuable suggestion. We agree with the Reviewer's comment and have expanded this point in the Discussion section, acknowledging that our observation does not allow definitive conclusions regarding the CNS penetration of revumenib. We have revised the manuscript to discuss alternative explanations for the isolated CNS relapse, including the persistence of pre-existing CNS-tropic leukemic subclones, the timing and efficacy of CNS-directed therapy, and other biological mechanisms contributing to CNS sanctuary sites, thereby providing a more balanced interpretation of our findings in the context of the available literature.

C: 

Please describe intrathecal agents, doses, timing relative to revumenib, and whether prophylaxis was continued during menin inhibitor therapy. Also clarify the CNS monitoring schedule (e.g., routine CSF evaluations vs symptom-triggered) to support conclusions about CNS escape.

R: Thank you for this helpful comment. We fully agree with the Reviewer's suggestion and have revised the manuscript accordingly. Specifically, we have expanded the Case Presentation to describe the intrathecal agents, doses, and timing in relation to revumenib treatment. We also clarified that no routine CSF monitoring was performed during revumenib therapy and that cerebrospinal fluid evaluation at CNS relapse was prompted by the onset of neurological symptoms.

C

Minor comment: I would like to suggest adding brief information on revumenib dosing and CNS prophylaxis in the Abstract to frame CNS escape more concretely.

R: Thank you for this valuable observation. We fully agree with the Reviewer's comment and have revised the Abstract accordingly by including brief information on the revumenib dosing schedule and prior CNS-directed therapy to better contextualize the subsequent CNS relapse.

C: 

Remove minor redundancies concerning poor outcomes and EMD propensity to improve readability.

R: Thank you for this helpful suggestion. We appreciate the Reviewer's observation and have revised the manuscript accordingly to improve readability by removing redundant statements regarding the poor prognosis of KMT2A-rearranged AML and its propensity for extramedullary disease.

C

Please clarify Figure 1 legend: Ensure the clinical timeline figure legend explicitly annotates key events (diagnosis, HSCT1, relapse, venetoclax/azacitidine, revumenib, CNS relapse, intrathecal therapy, HSCT2, systemic progression and death).

R: Thank you for this helpful suggestion. We have carefully revised the legend of Figure 1 to explicitly annotate the major clinical milestones, including diagnosis, first HSCT, hematologic relapse, venetoclax plus azacitidine therapy, revumenib treatment, isolated CNS relapse, intrathecal therapy, second HSCT, systemic relapse, and death.

As a case report, reproducibility concerns focus on clinical detail rather than experimental methods. Additional information on revumenib dosing, CNS prophylaxis, and MRD assays would enhance transparency and allow clinicians to better contextualize this case relative to their own practice. A brief Data Availability Statement indicating whether anonymized clinical data can be shared would align with evolving journal policies.

R: Thank you for this thoughtful comment. We agree with the Reviewer's suggestion and have added a Data Availability Statement indicating that anonymized clinical data supporting the findings of this case are available from the corresponding author upon reasonable request, in accordance with institutional policies and patient confidentiality requirements.

C: 

The manuscript would benefit from careful proofreading to correct typographical and grammatical errors, along with improvements in figure quality and presentation for better clarity. Minor typographical errors (“heavly”, “trasplant”) should be corrected, and a few long sentences in the Discussion can be shortened for clarity.

R: Thank you for this helpful comment. We appreciate the Reviewer's careful reading of the manuscript. The manuscript has been thoroughly proofread to correct typographical and grammatical errors, improve language consistency, and enhance the clarity of several long sentences. In addition, Figure 1 has been redesigned to improve its quality, readability, and overall presentation.

 

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript is well focused on a clinical issue, and the observation is clinically significant. 

However, some parameters need to be improved:

1. In the case presentation, the therapeutic regimen needs to be described more clearly and elaborately.
2. The therapeutic outcomes or results need more visual representation to understand the effects of the drug, such as the flow cytometry data and imaging of the hepatic lesions before and after treatment. 

 

Author Response

C: 

The manuscript is well focused on a clinical issue, and the observation is clinically significant. However, some parameters need to be improved. In the Case Presentation, the therapeutic regimen needs to be described more clearly and elaborately.

R: Thank you for this valuable comment. We fully agree with the Reviewer's observation and have revised the Case Presentation accordingly. Specifically, we have expanded the description of the therapeutic timeline by including the doses and schedules of induction chemotherapy, venetoclax plus azacitidine, revumenib, intrathecal therapy, and both HSCT procedures, together with the corresponding response assessments. These additions improve the clarity and completeness of the patient's clinical course.

C: 

The therapeutic outcomes or results need more visual representation to understand the effects of the drug, such as the flow cytometry data and imaging of the hepatic lesions before and after treatment.

R: Thank you for this valuable suggestion. We agree with the Reviewer's observation regarding the importance of clearly illustrating the therapeutic response. Accordingly, we have redesigned Figure 1 to provide a more comprehensive and visually informative representation of the patient's clinical course, including the major treatment milestones and response assessments. In addition, we have expanded the description of the bone marrow multiparameter flow cytometry findings and the radiological evaluation documenting complete resolution of the hepatic lesions after revumenib treatment.

Reviewer 3 Report

Comments and Suggestions for Authors

This is a valuable case that astutely identifies a potentially underestimated clinical issue in trial settings, though its presentation could be further refined.

1. The following clinical details should be supplemented:

（1）The specific KMT2A fusion partner subtype at initial diagnosis, along with any concurrent            gene mutations.

（2）A detailed treatment timeline, including specific drugs, doses, and cycles for each              induction/consolidation chemotherapy, as well as the results of each efficacy assessment (e.g., bone marrow blast percentage, MRD level).

（3）Comprehensive information on both HSCTs: specific drug dosages of conditioning regimens, stem cell source (peripheral blood/bone marrow), donor type (matched sibling/unrelated/haploidentical), and CD34+ cell dose infused.

（4）Standardized data on CNS diagnosis and monitoring: although "prior intrathecal prophylaxis" was mentioned, the specific number of injections, drug combinations, and timing of the last intrathecal administration were not provided. At the time of CNS relapse, detailed CSF findings (cytology, flow cytometry MRD, biochemical parameters) should be reported.

2. Both the abstract and discussion refer to "hepatic involvement" with "complete resolution of  hepatic lesions" after revumenib therapy. However, no imaging (e.g., PET/CT, contrast-enhanced CT, or MRI) or histopathological evidence (liver biopsy) is presented to substantiate this diagnosis or the therapeutic response. This raises uncertainty regarding the diagnosis of hepatic extramedullary disease.

3. As the sole figure, Figure 1 bears the critical task of illustrating the entire clinical course. Its current design is overly simplistic and fails to clearly convey the chronological sequence and key therapeutic milestones. It is recommended that the figure be redesigned to distinctly present treatment events (chemotherapy, HSCT, revumenib), efficacy assessments (bone marrow findings, MRD status), adverse events/complications, and clinical outcomes (CNS relapse), accompanied by a standardized legend.

4. Several typos and formatting issues were noted (e.g., "althought" on line 97 should read "although"). Authors should carefully revise the manuscript for language consistency.

5. Recent pivotal studies on menin inhibitors in KMT2A-r AML should be added. Reference 4 concerns KMT2A-PTD rather than KMT2A-r，these are distinct biological entities，and should be replaced with literature specifically addressing KMT2A-r prognosis or therapy.

Author Response

（1）The specific KMT2A fusion partner subtype at initial diagnosis, along with any concurrent            gene mutations.

R: Thank you for this helpful comment. However, at diagnosis, the patient was investigated by fluorescence in situ hybridization (FISH) using a KMT2A break-apart probe, which confirmed the presence of a KMT2A rearrangement and conventional cytogenetic which revealed translocation t (11;17). No additional molecular studies aimed at identifying the specific KMT2A fusion partner were performed. 

 

（2）A detailed treatment timeline, including specific drugs, doses, and cycles for each              induction/consolidation chemotherapy, as well as the results of each efficacy assessment (e.g., bone marrow blast percentage, MRD level).

R: Thank you for this valuable comment. We agree with the reviewer's suggestion and have revised the manuscript accordingly. 

（3）Comprehensive information on both HSCTs: specific drug dosages of conditioning regimens, stem cell source (peripheral blood/bone marrow), donor type (matched sibling/unrelated/haploidentical), and CD34+ cell dose infused.

R: Thank you for this helpful suggestion. In accordance with the reviewer's recommendation, we have revised the manuscript to include additional details regarding the allogeneic hematopoietic stem cell transplantation, thereby providing a more comprehensive description of the patient's treatment course.

（4）Standardized data on CNS diagnosis and monitoring: although "prior intrathecal prophylaxis" was mentioned, the specific number of injections, drug combinations, and timing of the last intrathecal administration were not provided. At the time of CNS relapse, detailed CSF findings (cytology, flow cytometry MRD, biochemical parameters) should be reported.

R: Thank you for this valuable comment. We agree with the reviewer's suggestion and have revised the manuscript accordingly.

2. Both the abstract and discussion refer to "hepatic involvement" with "complete resolution of  hepatic lesions" after revumenib therapy. However, no imaging (e.g., PET/CT, contrast-enhanced CT, or MRI) or histopathological evidence (liver biopsy) is presented to substantiate this diagnosis or the therapeutic response. This raises uncertainty regarding the diagnosis of hepatic extramedullary disease.

R: We have clarified the diagnosis of hepatic involvement and the assessment of response to revumenib therapy in the main text, providing additional details to better support our statements.

3. As the sole figure, Figure 1 bears the critical task of illustrating the entire clinical course. Its current design is overly simplistic and fails to clearly convey the chronological sequence and key therapeutic milestones. It is recommended that the figure be redesigned to distinctly present treatment events (chemotherapy, HSCT, revumenib), efficacy assessments (bone marrow findings, MRD status), adverse events/complications, and clinical outcomes (CNS relapse), accompanied by a standardized legend.

R: Thank you for this valuable suggestion. We fully agree with the reviewer’s observation regarding the importance of Figure 1 in summarizing the entire clinical course. Accordingly, we have redesigned the figure to provide a clearer and more comprehensive chronological overview of the patient’s history. The revised version now includes the main therapeutic milestones (chemotherapy, HSCT, and revumenib treatment), efficacy assessments ), relevant adverse events/complications, and clinical outcomes, including CNS relapse. We have also revised and standardized the figure legend to improve clarity and readability.

4. Several typos and formatting issues were noted (e.g., "althought" on line 97 should read "although"). Authors should carefully revise the manuscript for language consistency.

R: Thank you for this helpful comment. We appreciate the reviewer’s careful reading of the manuscript. We have thoroughly revised the text to correct the reported typographical errors and other formatting issues, and we have performed an overall language revision to ensure consistency, clarity, and accuracy throughout the manuscript.

5. Recent pivotal studies on menin inhibitors in KMT2A-r AML should be added. Reference 4 concerns KMT2A-PTD rather than KMT2A-r，these are distinct biological entities，and should be replaced with literature specifically addressing KMT2A-r prognosis or therapy.

R: Thank you for this valuable comment. We agree with the reviewer’s observation and have revised the manuscript accordingly. Specifically, we have replaced the inappropriate reference concerning KMT2A-PTD with literature specifically addressing KMT2A-rearranged (KMT2A-r) AML 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have provided a comprehensive, rigorous, and point-by-point response to all comments raised during the initial reviewing. The revised manuscript significantly improves upon the original submission in terms of scientific transparency, clinical utility, ethical compliance, and overall presentation.  Though some qestions couldn't be answerded or done  the modification but robust explanation has been provided by the Authors. As my point of view the revised MS could be accepted for publication.

Comments on the Quality of English Language

While the overall readability and narrative flow of the revised manuscript have significantly improved, the English language could still be polished further prior to publication. The prose is generally clear and understandable, but a final stylistic and grammatical edit would enhance precision and professional polish.  

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for your responses. The revised treatment plan is more detailed and answers the question. The revised figure is clinically cleared. So, it's satisfactory to me.