Review Reports
- Shintaro Izumi1,2,
- Yosuke Minami3,* and
- Shinichi Masuda1
- et al.
Reviewer 1: Anonymous Reviewer 2: Anonymous
Round 1
Reviewer 1 Report
Authors have made some effort to improve the paper , however, there asre still major concerns about it:
- The assessment of a causal relationship between gilteritinib and NK-LGL are still too strong, staring from the title that sould be modified (such as…Emergence of Large granular lymphocytes during gilteritinib treatment in acute myeloid leukemia with FLT3-ITD mutation)
- The attemp to correlate the emrgence of NK-LGL in other leukemia patients treatted with TK-inhibitors should be taken with caution as it has been hypothesized based on similarities between gilteritinib and others TK-inhibitors but there is no evidence that gilteritinib works in the same way as dasatinib or sorafenib. So, this part of the discussion should be straightforward.
English needs to be improved throughout the manuscript
Author Response
To Reviewer 1
Thank you very much for giving me good advice. I agree with all advices and incorporated them to R2 version (red color).
(1) The assessment of a causal relationship between gilteritinib and NK-LGL are still too strong, staring from the title that should be modified (such as…Emergence of Large granular lymphocytes during gilteritinib treatment in acute myeloid leukemia with FLT3-ITD mutation).
→Thank you for your suggestion. I've modified it as follows.
[Emergence of natural killer cell large granular lymphocytes during gilteritinib treatment in acute myeloid leukemia with FLT3-ITD mutation]
(2) The attempt to correlate the emergence of NK-LGL in other leukemia patients treated with TK-inhibitors should be taken with caution as it has been hypothesized based on similarities between gilteritinib and others TK-inhibitors but there is no evidence that gilteritinib works in the same way as dasatinib or sorafenib. So, this part of the discussion should be straightforward.
→Thank you for your suggestion. I've deleted some sentences and 2 references as shown below.
[Line 117-123 of the original version: Because dasatinib and gilteritinib have a common point of action in the tyrosine kinase cascade, RAS and STAT5, CMV reactivation may be related to gilteritinib-related LGL lymphocytosis. In the case presented here, the patient’s CMV seroprevalence was not examined, but it is assumed to be positive based on previous studies reporting that CMV seroprevalence rates in older adults are over 90 percent[11]. However, the clinical course differed from that of the past report[12]. LGL developed soon after the start of the gilteritinib administration and did not persist during gilteritinib treatment.]
[Line 135-136 of the original version: The possible one hypothesis is that gilteritinib also enhanced NK-LGL activation through increasing IL-15 production in leukemia cells.]
[Line 177-182 of the original version:
- Staras, S.A.; Dollard, S.C.; Radford, K.W.; Flanders, W.D.; Pass, R.F.; Cannon, M.J. Seroprevalence of cytomegalovirus infection in the United States, 1988-1994. Clin Infect Dis 2006, 43, 1143-1151, doi:10.1086/508173.
- Kreutzman, A.; Juvonen, V.; Kairisto, V.; Ekblom, M.; Stenke, L.; Seggewiss, R.; Porkka, K.; Mustjoki, S. Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy. Blood 2010, 116, 772-782, doi:10.1182/blood-2009-12-256800.
(3) English needs to be improved throughout the manuscript.
→ Thank you for this precious suggestion. We’ve fixed it.
We believe that incorporating your advice into R2 version has made the manuscript better. Thank you once again.
Reviewer 2 Report
The manuscript is now suitable for the publication.
Author Response
Thank you very much for reviewing my manuscript and giving me favorable comments.
Round 2
Reviewer 1 Report
none
This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.
Round 1
Reviewer 1 Report
In my opinion, this study is interesting and get further insights in the use of kinase inhibitors for different pathologies.
I think that the article can be accepted for the publication in Reports after the following minor revisions:
- Line 35: Mutations in FLT3 internal tandem duplications (FLT3-ITD): a short explanation on ITD should be added
- Line 39: percentages of patients with remission than was observed with… This sentence must be reformulated. It is awkward.
- The authors should explain the reason why they are sure that the detection of NK-LGL in the patients is due to the treatment with gilteritinib.
- Lines 103-122: these paragraphs should be improved. It is not clear if the presence of NK-LGL has been reported in the literature also with other kinase inhibitors. Moreover, the link among CMV, kinase inhibitors and NK-LGL is not well explained.
- English must be revised, there are some typos.
- The references must be reported in the style indicated by the journal
Reviewer 2 Report
Authors report the case of a 79-year old patient with a FLT3-ITD positive AML, who developed an NK-LGL during treatment with gilterinib. Authors concluded that gilterinib induced the transient NK-LGL espansion. As this assessement has not been supported by any functional/experimental data, authors’ conclusion is hard to be accepted. The fact that NK-LGL develops during treatment with gilteritinib is not per se enough to demonstrate a cause-effect relationship. The action of gilteritinib on NK-LGL should have been assessed in more than one patient and/or in preclinical studies. Moreover, it would be necessary to understand why the expansion of NK-LGL was observed only during the firt cycle of treatment. Therefore, although it is an interesting observation, further cases and an experimental approach are necessary to correctly understand it.