Myelodysplastic/Myeloproliferative Neoplasms with Features Intermediate between Primary Myelofibrosis and Chronic Myelomonocytic Leukemia: Case Series and Review of the Entity

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

To the authors,

Bonometti and colleagues proposed four new cases of mixed PMF/CMML diseases to be added to previous publications, to highlight the fact that international classifications do not overlap all the potential chronic myeloid diseases. The new cases are well described and seemed more complete than those previously published.

Please find enclosed, my questions and comments.

Title

Should be a question not a simple sentence, as conclusion the authors asked themselves if this new entity exists or not. Authors have the answer or not?

Or explicit MNIPC clearly.

Introduction

Well written, impacting. Questions are posed. Previous cases of MNIPC have been published.

Mat and Met

Case selection is clear. PMF with fibrosis ≥2. But lacking phenotype of monocytes as needed criterion.

Results

Superb images.

Cases seemed very heterogeneous: clinic, mutations, cytogenetic.

Chapman #2 do not have MPN mutation, Chapman #3/Hu#1 and present cases#1and2 have just grade 1 fibrosis: not adapted for PMF! See Mat and Met criteria. Or if considering prefibrotic MF, be more explicit in the title and in the text, as this entity already exists.

Having many (published) cases without bone marrow is a problem to make a single entity.

Discussion

More questions about how to make a clear diagnosis of CMD with monocytosis or how common is monocytosis among MPNs and MDSs.

Table 3 is unclear: Mi/Es/Ma not easy to read…

Tables 3 and 4/figures 5 and 6 are results, should be included in previous section.

The discussion could be drastically reduced with data exposed in the result section: literature vs new cases, step by step. A clear definition of MNIPC is needed by authors to make a new step.

Author Response

Reviewer 1

Bonometti and colleagues proposed four new cases of mixed PMF/CMML diseases to be added to previous publications, to highlight the fact that international classifications do not overlap all the potential chronic myeloid diseases. The new cases are well described and seemed more complete than those previously published.

Please find enclosed my questions and comments.

Title

Should be a question not a simple sentence, as conclusion the authors asked themselves if this new entity exists or not. Authors have the answer or not?

Or explicit MNIPC clearly.

 

AUTHORS: Our and other colleagues’ evidence support MNIPC as a separate entity compared to each MDS or MPN entities included into WHO and ICC classifications. As there is not a specific chapter for MNIPC in ICC/WHO classifications, these cases should be currently included in the basket category of MDS/MPN-U. However, the future recognition of MNIPC as a separate entity may be clinically relevant to both patients’ management and prognostic stratification and a better understanding of myeloid neoplasms biology.

For this reason we would retain our title in the form of a simple sentence. We modified the discussion to better highlight the evidence of MNPIC as a separated and recognizable entity.

 

Introduction

Well written, impacting. Questions are posed. Previous cases of MNIPC have been published.

Mat and Met

Case selection is clear. PMF with fibrosis ≥2. But lacking phenotype of monocytes as needed criterion.

AUTHORS: morphological and clinical stigmata of either CMML or PMF may coexist or not with fibrosis grade >2 in our patients (i.e. also patients meeting WHO/ICC criteria for prefibrotic PMF but having monocytosis are included). 

 

Results

Superb images.

Cases seemed very heterogeneous: clinic, mutations, cytogenetic.

Chapman #2 does not have MPN mutation, Chapman #3/Hu#1 and present cases#1and2 have just grade 1 fibrosis: not adapted for PMF! See Mat and Met criteria. Or if considering prefibrotic MF, be more explicit in the title and in the text, as this entity already exists.

Having many (published) cases without bone marrow is a problem to make a single entity.

 

AUTHORS: MNIPC biological heterogeneity seems in the range of other myeloid neoplasms. More specifically they present with a group of prognostically disadvantageous clinical and pathological features.

Presence of grade >2 fibrosis was not an indispensable criteria for inclusion in the study, as we stated in 2.1 case selection. 

One of the limitations of our study was the lack of certain clinical and histopathological data for some of the patients retrieved from the literature. All patients taken from other articles but Chapman #2 meet the inclusion criteria. We decided to include Chapman #2, as monocytosis was present in association to features that were very suggestive for an overt PMF (fibrosis grade 3, megakaryocyte atypia and cauterization, splenomegaly, leukoerythroblastosis and negativity for MDS-related cytogenetic alteration), even in the absence of molecular data. We included a section disclosing the study limitations.

Discussion

More questions about how to make a clear diagnosis of CMD with monocytosis or how common is monocytosis among MPNs and MDSs.

AUTHORS: According to WHO and ICC classification the presence at diagnosis of > 0.5x 109/L monocytes, being > 10% of the WBC, rule out any subtype of MDS and MPN. Rare cases of PMF may present during the follow-up (not at the time of diagnosis) with an absolute and/or relative monocytosis (according to WHO 2022). 

Table 3 is unclear: Mi/Es/Ma not easy to read…

AUTHORS: we modified it to let the Table be more easy to read.

Tables 3 and 4/figures 5 and 6 are results, should be included in the previous section.

AUTHORS: we moved tables 3 and 4 and figures 5 and 6 in the results section as suggested.

The discussion could be drastically reduced with data exposed in the result section: literature vs new cases, step by step. A clear definition of MNIPC is needed by authors to make a new step.

AUTHORS: we shortened the discussion and tried to make it more clear. We provided a definition for MNIPC.

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

The manuscript by Bonometti et al highlights the challenges in applying diagnostic criteria to two diseases – primary myelofibrosis and chronic myelomonocytic leukemia (CMML) using a retrospective case series of 13 cases.  They add an additional 4 cases to the 9 in the literature for the total 13 cases and argue for a provisional entity - myeloid neoplasms with features intermediate between PMF and CMML (MNIPC).  While this manuscript is well written and has merit for providing an additional 4 cases, it lacks the data and strength to truly provide an argument for this additional entity (please see major concern below).

 

Major comments/suggestions:

1. The major concern with this manuscript that that it lacks control groups either from the investigators’ institutional cohort or cohorts in their literature search.  It is not immediately clear how their small cohort of 13 (4 in their institutional and 9 in the literature) cases compares to a confirmed cohort of PMF and a confirmed cohort of CMML in their institution or other groups.  It may be that these confirmed cohorts also suffer from these specific challenges in diagnostic ambiguity that the authors are trying to distinguish from.  An independent reviewer and adjudication of those cases need to be performed to assign each of the cases to their proper groups and should be documented.  The paper requires a thorough review of these additional cohorts and provide a table that compares the 13 selected patients as the “new entity” with the patients in each of the confirmed PMF & CMML cohorts.  I.e. modifying their Table 3 for these other cohorts to compare with the 13 selected patients.

 

2. All sentences that document data that the authors have not proven in their own work in the manuscript requires a reference.  Eg. Add references to the first 2 sentences.  It is not immediately obvious that those data come from the references 1-4 ascribed to sentence 3.  That is the same with sentence 4 and throughout the paper.   Do the same in the sentences and paragraphs in the discussion.

 

3. In Case selection, it is not clear what the denominator data is in the 5 years that were reviewed.  How many MDS, MPN, MDS/MPN overlap cases in total, how many were PMF or CMML, how many were excluded.  Consider a flow diagram if it cannot be explained easily. 

 

4. In Methods or Case selection, what is the inclusion/exclusion criteria.  Specifically, what level of monocytosis was used? Monocytes > 0.5 or 1.0 x 10^9/L?  Monocyte count at time of presentation, at bone marrow biopsy stage or at time during assessment?  The monocyte count cut off for CMML should be discussed as well given the change from 1.0 to 0.5 in the WHO 2022 and ICC 2022.

 

5.  In Results, was monocytosis sustained in the patients selected or was it based on 1 reading?

 

6.  The histopathological features of each of the 4 cases are good quality but is not necessary for the main text and can be added as supplemental figures.

 

7. Please include a Limitations section or discussion in the Discussion section.

 

Minor comments/suggestions:

1. In Case selection, please specify the exact dates of study rather than generic “last 5 years”.

 

2. In Case selection, please also specify if other laboratory data were collected – such as CBC and differential.

3. Should spell out all acronyms if used for the first time even if obvious: WHO, ICC and even in the abstracts.  Eg. Line 26 for WHO & ICC.  Eg. Line 27 CMML – should add that acronym to line 18 when first used then line 27 you don’t have to spell it out.

Comments on the Quality of English Language

The manuscript is well-written with minimal issues with spelling or grammer.

Author Response

Reviewer 2

The manuscript by Bonometti et al highlights the challenges in applying diagnostic criteria to two diseases – primary myelofibrosis and chronic myelomonocytic leukemia (CMML) using a retrospective case series of 13 cases.  They add an additional 4 cases to the 9 in the literature for the total 13 cases and argue for a provisional entity - myeloid neoplasms with features intermediate between PMF and CMML (MNIPC).  While this manuscript is well written and has merit for providing an additional 4 cases, it lacks the data and strength to truly provide an argument for this additional entity (please see major concern below).

 

Major comments/suggestions:

1. The major concern with this manuscript is that it lacks control groups either from the investigators’ institutional cohort or cohorts in their literature search.  It is not immediately clear how their small cohort of 13 (4 in their institutional and 9 in the literature) cases compares to a confirmed cohort of PMF and a confirmed cohort of CMML in their institution or other groups.  It may be that these confirmed cohorts also suffer from these specific challenges in diagnostic ambiguity that the authors are trying to distinguish from.  An independent reviewer and adjudication of those cases need to be performed to assign each of the cases to their proper groups and should be documented.  The paper requires a thorough review of these additional cohorts and provide a table that compares the 13 selected patients as the “new entity” with the patients in each of the confirmed PMF & CMML cohorts.  I.e. modifying their Table 3 for these other cohorts to compare with the 13 selected patients.

AUTHORS: We based our diagnoses on objective and reproducible criteria including clinical findings, CBC, genetic data and well-defined morphological features. Formally, all our patients were classified as MDS/MPN-U based on WHO and ICC criteria, and specifically, none of them could be formally classified as PMF or CMML, as we describe in the manuscript.

In our article we do not compare MNIPC with PMF and CMML cases for several reasons: at first because of the very low number of patients and the very large overlap between MNIPC and PMF or CMML we could not provide clinically or statistically significant data. 

Furthermore, the goal of our study is to describe in detail the global features of a very rare but already characterized entity, to discuss its differential diagnosis and to highlight the fact that “atypical” cases of PMF or CMML should be reviewed in light of our and previous work. 

Our article is a necessary first step to the characterization of a myeloid neoplasm with specific features. Future studies (and collaborations) are needed in order to gather a larger case series and obtain statistically significant data on prognosis and especially on treatment response (i.e. if these cases respond better to PMF or CMML-oriented regimens).

2. All sentences that document data that the authors have not proven in their own work in the manuscript requires a reference.  Eg. Add references to the first 2 sentences.  It is not immediately obvious that those data come from the references 1-4 ascribed to sentence 3.  That is the same with sentence 4 and throughout the paper.   Do the same in the sentences and paragraphs in the discussion.

AUTHORS: We changed the references citation as required.

 

3. In Case selection, it is not clear what the denominator data is in the 5 years that were reviewed.  How many MDS, MPN, MDS/MPN overlap cases in total, how many were PMF or CMML, how many were excluded.  Consider a flow diagram if it cannot be explained easily. 

AUTHORS: We added in the result section a paragraph with the required information.(line 141)

 

4. In Methods or Case selection, what is the inclusion/exclusion criteria.  Specifically, what level of monocytosis was used? Monocytes > 0.5 or 1.0 x 10^9/L?  Monocyte count at time of presentation, at bone marrow biopsy stage or at time during assessment?  The monocyte count cut off for CMML should be discussed as well given the change from 1.0 to 0.5 in the WHO 2022 and ICC 2022.

AUTHORS: we specified the inclusion criteria for our patients in section 2.1 of materials and methods (from line 89 on). As we didn’t specify which cut-off we employed for (persistent) monocytosis, we included in the materials and in the discussion the cut-off of > 0.5 x 10^9/L, even though all but one patients displayed a monocytosis of >1.0 x 10^9/L at presentation. (line 90) We also discuss the change of the required value for monocytosis in the WHO and ICC classifications. (line 295 and following)

 

5. In Results, was monocytosis sustained in the patients selected or was it based on 1 reading?

AUTHORS: Monocytosis was present for at least six months and in each patient was present at the time of the diagnosis. We specified more in detail this important point in either the materials, results and discussion sections. (line 90, and 295 and following)

 

6. The histopathological features of each of the 4 cases are good quality but are not necessary for the main text and can be added as supplemental figures.

AUTHORS: if possible, we would like to maintain the 4 panels to fully depict the histopathological spectrum of the patients. As these are rare cases, we believe that it may be useful for pathologists and researchers to have the chance to critically analyze the histological features of our patients from the main part of the article.

 

7. Please include a Limitations section or discussion in the Discussion section.

AUTHORS: we included the limitation section as suggested

 

Minor comments/suggestions:

1. In Case selection, please specify the exact dates of study rather than generic “last 5 years”.

AUTHORS: we modified the text as suggested (lines 92-93)

2. In Case selection, please also specify if other laboratory data were collected – such as CBC and differential.

AUTHORS: we better specified the retrieved data as suggested.

3. Should spell out all acronyms if used for the first time even if obvious: WHO, ICC and even in the abstracts.  Eg. Line 26 for WHO & ICC.  Eg. Line 27 CMML – should add that acronym to line 18 when first used then line 27 you don’t have to spell it out.

AUTHORS: we corrected the text accordingly. (lines 21-22)

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

No other recommendations