Primary Myelofibrosis Occurring during Targeted Therapy for Chronic Lymphocytic Leukemia: A Report of Two Cases

Round 1

Reviewer 1 Report

Dear Authors,

congratulations for your valuable paper. Here are my comments:

Line 13: along with

Line 18 & 21 & title: targeted agents or therapies instead of target agents

Line 20: the need to for; pls omit "to"

Line 100: in July

Line 108: normal-looking pls change to "seemingly normal" or else

Line 120: the role of t(1;6) has been discussed by Darawshy et al. but there is no mention in text

Line 115: pls replace casual

According to citation No6 the median time between CLL and MPN diagnosis has been calculated at 72 months. Please comment the findings of this paper.

Please provide a more solid theory on specifically how these two targeted therapies might link with myelofibrosis (and not with previously used targeted therapies like obinotuzumab; doi: 10.1155/2019/1486476).

The opposite effect has been already reported (doi: 10.1097/HS9.0000000000000356). Please comment on that too.

Possible pathogenetic mechanisms for the concurrent manifestation of CLL and myelofibrosis include: a bilineage manifestation of a pluripotent stem cell proliferation, independent proliferations of two distinct cell lines under a common leukemogenic stimulus or an accidental association (doi: 10.1007/s12288-010-0020-8). Please discuss on the role of JAK-2 V617F mutation and why it is not the only determinant (doi: 10.3109/10428194.2015.1092527).

Thank you in advance for your time and cooperation.

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

In the current manuscript, the authors preset two cases with chronic lymphocytic leukemia who developed primary myelofibrosis (PMF) during target therapy. The clinical course of those two cases is interesting, and the manuscript is almost well written.

1. It is unclear how the authors found no JAK2 and MPL mutations in both CLL cells.
2. It needs to describe the difference between PMF and secondary fibrosis based on the current cases (e.g. Clonal expansion of the cells is never observed in the secondary cases.) so that the readers clearly understand the significance of these cases.

Author Response

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Author Response File: Author Response.docx

Reviewer 3 Report

In the present case report, the authors presented two cases of CLL with occurrence of PMF post therapy with ibrutinib and venetoclax. The reported findings are interesting, but the results are not enough to complement the study conclusions. The reviewer has following concerns over the care report findings:

1) As there are several reports that indicated existence of CLL and PMF (simultaneous or CLL precede PMF), the necessity for the current case report is not justified. Moreover, the stated conclusions that co-occurrence of CLL and PMF during targeted therapy has not been verified. In most of the cases >70% of 41 cases reported CLL precedes PMF as the current case report. So, this is the clinico-biological characteristics of of CLL that results in PMF. Either you treat or not with targeted therapy results in PMF post therapy of CLL. So, the role of targeted therapies in the PMF occurrence was not justified in this report. 

2) Authors made TWO contradictory statements: 1) in the introduction (line33-35) that no association existed between CLL and PMF occurrence, while 2) stated in line117-120 that PMF is frequently diagnosed after CLL. So, please make adjustments to the statements made in the introduction as the current literature supports second statements. 

3) In line 32, authors stated that 27 cases reported. But, in the recent review by Darawshy (ref.7) provided a summary of 41 cases of CLL and PMF. So, please make corrections to the statements.

4) Correct "1.2 x10⁹/L" in line 60 to "1.2 x 10¹²/L".

5) Figure-1 would look good if authors provide the BM biopsy results for second case before the start of therapy (similar to first case). 

6) As there is NO association of 'therapy type' in CLL with PMF occurrence was existed in the current literature, the current conclusions stating targeted therapies role in PMF post CLL therapy needs further analysis of previously reported cases or more of new cases in the future may support the findings. 

Author Response

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Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Dear authors,

thank you for your latest contribution.

Reviewer 3 Report

Dear authors,

Thanks for providing the revised version of case report which is in good shape.  Please correct 'neative' to 'negative' in line 71 in the final version.

Best wishes,