Treatment Strategies Used in Treating Myelofibrosis: State of the Art

Round 1

Reviewer 1 Report

This review nicely summarizes the current state of myelofibrosis therapy focusing on the approved JAK inhibitors. While this topic has been published many times, it doesn't hurt to have another refresher

Few recommendations to make the manuscript stronger

-For section 2 would recommend making a table of diagnostic criteria instead of writing it in the text

It seems odd that pacritinib is not mentioned as first line therapy as it can be used first line in patients with low platelets

Momelotinib - MOMENTUM study should be mentioned and discussed

 

 

 

Figure 4 is confusing and needs more work: 

-It is possible to go directly to transplant without any therapies. There should be an indication for direct route, esp in cytopenic patients

-Iron chelation is not standard and might confuse readers that it is required to go to transplant

-ruxolitinib (vaccination)-it is not clear what that means. One could read it as ruxolitnib is a vaccination (perhaps should say consider vaccinations for VZV prior to starting?)

-tapering (4-7 days) is also confusing. perhaps a longer explanation of what the authors mean-like taper right before conditioning regimen starts?

 

It seems odd that pacritinib is not mentioned as first line therapy as it can be used first line in patients with low platelets

Momelotinib - MOMENTUM study should be mentioned and discussed

Navitoclax development in MF is currently stopped. Should either say that or not talk about it, May want to mention imetelstat or navtemadlin for example if want to discuss another novel drug

LIne 216- selinexor is being investigated in MF but is an FDA approved for Multiple myeloma so not an investigational drug completely

Author Response

The diagnostic criteria are summarized in the table 2.

We mentioned pacritinib as first line therapy and that the drug can be used first line in patients with low platelets (chapter 3).

We mentioned and discussed MOMENTUM study (chapter 3).

The figure summarizing the proposals for patients to be sent for transplantation has been changed. It is now Figure 3.

We emphasized in the text that the development of Navitoclax had been suspended. The text read as follows (expert opinion chapter) “In TRANSFORM-1, adding navitoclax to ruxolitinib significantly improved the SV reduction rate. However, Navitoclax development in MF is currently stopped”.

 We have removed the indication that Selinexor is not an investigational drug.

Reviewer 2 Report

The writing of this manuscript is very clear and provides a description of first line JAK inhibitor therapies and combination therapies. However, the review should be a lot broader in its scope. Instead of focusing only on JAK inhibitors and new combination therapies that include JAK inhibitors, a review with this title should encompass more broadly the novel strategies and drugs being developed for MF beyond those 2 categories. A more broad current pipeline of novel drugs for myelofibrosis should be included both into the text, and to the figures and table of the review manuscript. For example, no other strategies and drugs in development were mentioned. Molecular strategies other than direct JAK inhibition, to name but a few, would include: BET inhibitors, telomerease inhibitors, AURKA inhibitor, TGF-beta or serum amyloid P targeting the bone marrow environment etc. etc.. Also some discussion into how this is clinically relevant given patients who are refractory to JAK inhibition have very poor survival and novel strategies for this patient group would be highly beneficial to the MF patient population. 

The text very clearly describes the clinical trials behind first line JAK inhibitors and JAK inhibitor combination therapies (lines 99-232). However a table to summarize such text would be very helpful to visulize and review this information. A table showing current/newly approved drugs and drug combinations with columns such as: year licensed, patient group in which it was tested, # of patients in the major clinical trial(s) leading to their approval, # relapsed, # intolerant, the molecular mechanism/target of the drug, etc. would be a central table/figure for such aa review and help to understand the development and evidence behind the newer JAK inhibitor therapies. In my mind such a table would be more important in this review about novel therapies than, for example, Figure 1 which shows the differential diagnosis characteristics among chronic myeloproliferative neoplasms. I can see the title of supplementary table 2. is "Novel Therapies for Disease Progression or Intolerance to Initial Therapy" - this would be more main table or main figure material than many of the current figures (although i am unable to see it) 

Of the current 5 figures of the main manuscript (for which figure legend is not provided) there is not a single figure describing the novel therapies for MF. They are also too small (both in print, and on a digital screen) for easy viewing. The figures, both in content and presentation, could be heavily improved. One could show a molecular schema of novel therapeutic strategies for AML that is included in the text (e.g. JAK inhibition, anti-apoptotic B cell lymphoma to protein inhibition NAVI, bromodomain and extra terminal domain inhibitors PELA etc.). Alternatively, one could include a figure showing the currently evolving preclinical studies, phase 1, and phase 2-3 studies and summarize new approaches in that way. One could also show how Allo-SCT approaches have been continuously researched and improved to optimize safety and survival for MF patients. 

 

Here are some of my further comments on the supplementary file.    The text is repetitive within the table. For example in table 2 for MOMENTUM trial, the results column has repetitive information that is already partly present in the design column. The results column starts with  "195 patients were randomly assigned to..." this information should be included in the design column. The results column could just read: "50% reduction in TSS in momelotinib group vs. danazol group".  The design column should include details such as: random assignment (2:1), duration of follow up: 24-weeks    The column of the tables can be re-organized and the text re-written for better readability. Adding more columns would help to break down the information in more visible chunks. e.g.  add separate columns for "study drugs",  "follow-up duration"   "cohort size" etc. to break up the information in a more visible way   For those study designs in which new combinations are tested against BAT, should describe what the BAT regimen was.    The tables are also missing some data. For example in table 1 for the REALISE trial, there is no endpoint marked on the table. Also, despite there being safety data available for the trials in table 1, they are not filled out (e.g. COMFORT I trial).

 

1. Line 99 suggested comment - explicitly introduce RUXO, when it was approved, since when it was used, how it forms the mainstay of JAK inhibition therapy etc. 

2. Figure 1-5 necessary comment - please increase the size/font of the figures

3. Figures necessary comment - please provide figure legends 

4. Unable to see supplementary tables 

Author Response

The commentary helped us to improve the quality of the paper. We changed the title and added Chapter 8, where we commented on possible developments of non-JAK therapies in MF.

We have included Tables 5 and 6 (not as supplementary files), which summaries the main studies and, where appropriate, the results related to the topic of the article.

We have eliminated some of the figures and improved the quality of them

We have detailed as follow in the text: “The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib (RUXO) was initially approved by the US Food and Drug Administration in 2011 for the treatment of patients with intermediate or high-risk MF, including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF, based on efficacy and safety findings from the randomized, controlled, phase 3 COMFORT trials [23,24]. Over a decade later, RUXO continues to be the standard of care in higher-risk MF, and dose optimization and management remain crucial for safely maximizing clinical benefits.

I hope that the changes made to our work will make it suitable for publication.

Round 2

Reviewer 2 Report

Compared to the prior draft, the authors have changed the title so as to more accurately reflect the focus/scope of the manuscript. The tables and figures have been improved to present prior trial data more clearly, and to also present current treatment flows more clearly (which reflects well on their title change to encompass "state of the art" for current treatment strategies). The text has also been broadened to include some short commentary on investigational non-JAK inhibitors for MF. Thank you for your revising the manuscript. 

I have just a few minor comments to add. 

- For Table 4 and 5. Specify somewhere what the BAT actually was in that trial.

- For example, in table 4 for the comfort II trial you can specify somewhere "BAT was investigator-determined and included any commercially available therapy (single or combination) or observation only".

- Similar explanation is required for BAT in the PERSIST-2 trial in table 5. 

- Table 2: make first column narrower as to give second column more space. 

Author Response

Dear Reviewer,
We have updated Tables 4, 5, and 2 as directed. Thank you for reviewing!