Outcomes of decitabine treatment for newly diagnosed acute myeloid leukemia in older adults​

Kwai Han Yoo; Jinhyun Cho; Boram Han; Se Hyung Kim; Dong-Yeop Shin; Junshik Hong; Hawk Kim; Hyo Jung Kim; Dae young Zang; Sung-Soo Yoon; Jong-Youl Jin; Jae Hoon Lee; Dae-Sik Hong; Seong Kyu Park

doi:10.1371/journal.pone.0235503

Peer Review History

Original SubmissionJanuary 8, 2020
12 Feb 2020 Decision Letter - Francesco Bertolini, Editor PONE-D-20-00626 Outcomes of decitabine treatment for newly diagnosed acute myeloid leukemia in older adults and the role of a mini nutritional assessment short form PLOS ONE Dear Dr. Hong, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process by both Reviewers, experts in the field. We would appreciate receiving your revised manuscript by Mar 28 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. 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We will update your Data Availability statement on your behalf to reflect the information you provide. 4. Please include your tables as part of your main manuscript and remove the individual files. Please note that supplementary tables should remain as separate "supporting information" files. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: No ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Thank you for the opportunity to review this article. This article is well written and deals with an interesting topic on real-life assessment and treatment with decitabine. Subsequently, the authors tried to evaluate prognostic factors. The major problem is the construction of the article, which oscillates between real-life study and the identification of prognostic factors. This can be seen from the title to the discussion. The prognostic factor MNA-SF that is put forward is too unreliable in its mode of evaluation. I will focus more on real-life data and secondly on prognostic factors in the minor axis. TITLE : The major point of the publication is the evaluation of the survival of patients on decitabine in real world and it should be highlighted in the title and not the identification of prognostic factors The title should not include prognostic factors. Introduction Indications of decitabine for older adults with AML are still controversial. You must insist on this point the United States Food and Drug Administration did not approve decitabine for the treatment of newly diagnosed AML based on the results of a clinical trial reported by Kantarjian, et al the European Medicines Agency Committee for Medicinal Products for Human Use approved decitabine as a first-line treatment for older adults with AML as the Korean Food and Drug Administration (KFDA). Your objectif was to analyse outcomes in real world of decitabine treatment in older patients with newly diagnosed. It shoul be clearly define. Do not put a reference (13) in your objective. The notion of nutritional status should not to be introduced int this part because it is not your main objective. Patients and Methods How were you able to do the MNA-SF retrospectively ? how do you find the data of "Acute illness or psychological stress in the last 3 months" or "Has the patient eaten less in the last 3 months due to lack of appetite, digestive problems, chewing or swallowing difficulties? " Give more tell about the factors that we included in multivariate analysis. Please detail the multivariate statistical analyses and explain cut-off of MNA-SF. Most of time : Baseline bone marrow blast, Baseline platelets and / WBC were included in multivariate analysis Resutls I don’t understand this sentence : “Forty-five patients (45/90, 50.0%) showed HI in absolute neutrophil count (29/78, 37.2%)” because you describe 18 patients with HI. I think you should rephrase or add punctuation. Explain in materiel and methods your definition of “infectious complications” . It included bacterial infections and fungal infection complications? Discussion The most limiting point is the identification of the MNA-SF, which is unreliable. Its identification as a prognostic factor must be taken with caution. You do not enough compare your results (cut-offs, results) with other existing publications (10-12) and I added news references : “Decitabine as a First-Line Treatment for Older Adults Newly Diagnosed with Acute Myeloid Leukemia” Hyunsung Park et al. “Decitabine improves outcomes in older patients with acute myeloid leukemia and higher blast counts“. Kadia et al. “Multivariate and subgroup analyses of a randomized, multinational, phase 3 trial of decitabine vs treatment choice of supportive care or cytarabine in older patients with newly diagnosed acute myeloid leukemia and poor- or intermediate-risk cytogenetics.” Mayer J et al. Figures Poor quality figures due to a pixel problem, impossible to read Reviewer #2: 1. The authors stated in the “treatment and evalution paragraph” that “considering the palliative nature of the HMA treatment, disease evalutation was often not performed unless clear signes of disease progression”. I think that treatment with HMA is not a palliative treatment but an active therapy for elderly AML that can be berfomed when the patient is considered unfit for aggressive therapy; Unfit patient must be defined based on a multidimentional geriatric assesment that ditiguish them clearly from a frail patient for which best supportive care is suggested. In absence of a systematic disease evaluation for all patient population with bone marrow aspirate/biopsy how could you determine properly disease response ( es CR/CRi)? In Table 1 which describes the patients characteristics their multidimentional geriatric assesment is missing. Thus how did you decided that patients were unfit for aggressive chemotherapy or frail? I do not think that ECOG performance status assesment in sufficient for a correct fitness evaluation 2. The highlight and the novelty of the study is that MNA-SF assessment ≥8 predicts improved survival in decitabine treated AML patients. I think that it should be specified when MNA-SF score was performed. If was performed at diagnosis and /or every how many months durnig decitabine treatment. Infact a dynamic assesment is more significative because the score value can chage a lot along tratment and on the base of disease response to therapy ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. 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Revision 1
6 Apr 2020 Author Response Reviewer #1: Thank you for the opportunity to review this article. This article is well written and deals with an interesting topic on real-life assessment and treatment with decitabine. Subsequently, the authors tried to evaluate prognostic factors. The major problem is the construction of the article, which oscillates between real-life study and the identification of prognostic factors. This can be seen from the title to the discussion. The prognostic factor MNA-SF that is put forward is too unreliable in its mode of evaluation. I will focus more on real-life data and secondly on prognostic factors in the minor axis. TITLE : The major point of the publication is the evaluation of the survival of patients on decitabine in real world and it should be highlighted in the title and not the identification of prognostic factors. The title should not include prognostic factors. --> We changed the title to “Real-world outcomes of decitabine treatment for newly diagnosed acute myeloid leukemia in older adults”. Introduction Indications of decitabine for older adults with AML are still controversial. You must insist on this point the United States Food and Drug Administration did not approve decitabine for the treatment of newly diagnosed AML based on the results of a clinical trial reported by Kantarjian, et al. The European Medicines Agency Committee for Medicinal Products for Human Use approved decitabine as a first-line treatment for older adults with AML as the Korean Food and Drug Administration (KFDA). Your objective was to analyze outcomes in real world of decitabine treatment in older patients with newly diagnosed. It should be clearly defined. Do not put a reference (13) in your objective. The notion of nutritional status should not to be introduced int this part because it is not your main objective. --> We added controversies about the use of decitabine for the first-line treatment of AML. A sentence and a reference about MNA-SF in the part of introduction were removed following the reviewers’ recommendations. Patients and Methods How were you able to do the MNA-SF retrospectively? how do you find the data of "Acute illness or psychological stress in the last 3 months" or "Has the patient eaten less in the last 3 months due to lack of appetite, digestive problems, chewing or swallowing difficulties?" --> All institutions participating in this study had acquired all MNA-SF-related indicators at the time of diagnosis of AML, through hospitalization records, baseline nursing records, and nutritional records by on-site nutritionists. We could access the data about "Acute illness and psychological stress in the last 3 months" in hospitalization records and baseline nursing records, and the data about "Has the patient eaten less in the last 3 months due to lack of appetite, digestive problems, chewing or swallowing difficulties?" in baseline nursing records, and nutritional records. Give more tell about the factors that we included in multivariate analysis. Please detail the multivariate statistical analyses and explain cut-off of MNA-SF. Most of time : Baseline bone marrow blast, Baseline platelets and / WBC were included in multivariate analysis --> In multivariate analysis by Cox regression model, we used 5 covariates (age, ECOG PS, MNA-SF score, the absence of PB blasts, and cytogenetic risk). Four of them (Age, ECOG PS, MNA-SF score, and the absence of PB blasts) showed significance in univariate analyses of both PFS and OS. Cytogenetic risk (favorable or intermediate risks vs. poor risk) which was statistically associated with improved PFS (P = .007), but not OS (P = .096), was also added in the model. Baseline bone marrow blasts percentage and platelet count were not associated with survivals in our study population. Therefore, we did not use those factors in multivariate analysis. Results I don’t understand this sentence : “Forty-five patients (45/90, 50.0%) showed HI in absolute neutrophil count (29/78, 37.2%)” because you describe 18 patients with HI. I think you should rephrase or add punctuation. --> Those 18 patients did not achieve an objective response (CR or PR), but they showed hematologic improvements (His). We revised the sentences more clearly as following: “18 patients (21.2%) who did not achieve an objective response demonstrated hematologic improvement (HI) in PB. Thus, the clinical benefit rate (CR + CRi + PR + HI only) was 52.9% (45/85). Regardless of achieving an objective response, 45 patients (45/90, 50.0%) showed HI in absolute neutrophil count (29/78, 37.2%), hemoglobin (32/78, 41.0%) and/or platelet count (28/77, 36.4%).” Explain in materiel and methods your definition of “infectious complications”. It included bacterial infections and fungal infection complications? --> We added a sentence, “Infectious complications included any bacterial, viral, fungal, and miscellaneous infection such as Pneumocystis jiroveci during decitabine treatment.” in the Patients and Methods section. Discussion The most limiting point is the identification of the MNA-SF, which is unreliable. Its identification as a prognostic factor must be taken with caution. --> We accepted your suggestions and emphasized the limitations of the use of MNA-SF by retrospective measures. We also mentioned the need for prospective studies for confirming the value of MNA-SF in elderly AML. You do not enough compare your results (cut-offs, results) with other existing publications (10-12) and I added new references: “Decitabine as a First-Line Treatment for Older Adults Newly Diagnosed with Acute Myeloid Leukemia” Hyunsung Park et al. “Decitabine improves outcomes in older patients with acute myeloid leukemia and higher blast counts“ Kadia et al. “Multivariate and subgroup analyses of a randomized, multinational, phase 3 trial of decitabine vs treatment choice of supportive care or cytarabine in older patients with newly diagnosed acute myeloid leukemia and poor- or intermediate-risk cytogenetics.” Mayer J et al. --> Many thanks for the list of existing publications. We added a comparison of survival and cut-offs and reason for including PB blasts in multivariate analysis rather than BM blasts in the part of discussion. Figures Poor quality figures due to a pixel problem, impossible to read --> The resolution of original figures satisfies the guidelines. The Supplement figures shown in the PDF are too small, so it is difficult to see. You can download the original files from the link at the top right of figure pages in the PDF. Reviewer #2: 1. The authors stated in the “treatment and evaluation paragraph” that “considering the palliative nature of the HMA treatment, disease evaluation was often not performed unless clear signs of disease progression”. I think that treatment with HMA is not a palliative treatment but an active therapy for elderly AML that can be performed when the patient is considered unfit for aggressive therapy; Unfit patient must be defined based on a multidimensional geriatric assessment that distinguish them clearly from a frail patient for which best supportive care is suggested. --> We intended “palliative nature” as a meaning of different mechanism and responses from traditional intensive chemotherapy. As the reviewer pointed out, the meaning of “palliative nature” is unclear, so we corrected this phrase as follows: “considering the mechanism of action of decitabine and delayed responses different from intensive chemotherapy,” In absence of a systematic disease evaluation for all patient population with bone marrow aspirate/biopsy how could you determine properly disease response ( es CR/CRi)? --> Patients with new presence of leukemic blasts in peripheral blood or lack/loss of hematologic improvement during treatment were thought of disease progression or no response. In that cases, bone marrow (BM) biopsy were not needed to confirm CR or PR. This study was a retrospective study, and it reflected a real-world practice. However, every patients with CR or PR in our study were confirmed by BM biopsy. In Table 1 which describes the patients characteristics their multidimensional geriatric assessment is missing. Thus how did you decided that patients were unfit for aggressive chemotherapy or frail? I do not think that ECOG performance status assessment in sufficient for a correct fitness evaluation --> This study is a retrospective study from multicenter. Thus, a uniform multidimensional geriatric assessment was not performed, and physicians of each center individually decided to start decitabine treatment. This might reflect the actual situation of our clinical practice. 2. The highlight and the novelty of the study is that MNA-SF assessment ≥8 predicts improved survival in decitabine treated AML patients. I think that it should be specified when MNA-SF score was performed. If was performed at diagnosis and/or every how many months during decitabine treatment. In fact a dynamic assessment is more significative because the score value can change a lot along treatment and on the base of disease response to therapy --> All the MNA-SF-related indicators were collected only once at the time of diagnosis of AML. We absolutely agreed with the reviewer’s point-out, and we discussed more about necessity of a dynamic assessment of MNA-SF, by prospective approach. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0235503.r002
22 Apr 2020 Decision Letter - Francesco Bertolini, Editor PONE-D-20-00626R1 Real world outcomes of decitabine treatment for newly diagnosed acute myeloid leukemia in older adults PLOS ONE Dear Dr. Hong, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses all the points raised during the review process by Reviewer #1, an expert in the field. We would appreciate receiving your revised manuscript by Jun 06 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Francesco Bertolini, MD, PhD Academic Editor PLOS ONE [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Article that has improved since the last time, but there are still points that need to be clarified. Materiels and Methods : Change title Definition of real word : Real world data (RWD) in medicine is data derived from a number of sources that are associated with outcomes in a heterogeneous patient population in real-world settings, such as patient surveys, clinical trials, and observational cohort studies.[1] Real-world data refer to observational data as opposed to data gathered in an experimental setting such as a randomized controlled trial (RCT). Remove real word in the text I am very dubious about the retrospective evaluation of the MNA-SF, which for me will inevitably be subjective due to its retrospective character and therefore unreliable. You say that the people have partly made a prospective and retrospective evaluation, so why didn't you do the questionnaire from the beginning ? You said that the classification was done according to the 2016 classification, but what about before 2016? Did you reclassify the AML? The detail of the univariate/multivariate analysis are missing in methods: which criteria, which p... PFS and OS should be describe in statistical analysis Results The description of the results on prognostic factors, the most important one, is confusing: for example: "age, PS, absence of PB... were associated to prolonged OS" Does it involve univariate, multivariate analysis? Figures: p and months are missing Tables : HR and 95%CI are missing in univariate analysis Discussion Difficult in the discussion to see the original points of the article with numbers digits of the publication appearing. In a recent publication (Fili et al. 2019, leukemia research) found : The ORR in real-world setting was 33% and median OS in responders was 22.6 mths. Which is more than you, how can you explain the difference ? Reviewer #2: The authors have adequately addressed my comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0235503.r003
Revision 2
5 Jun 2020 Author Response Reviewer #1: Article that has improved since the last time, but there are still points that need to be clarified. Materiels and Methods : Change title Definition of real word : Real world data (RWD) in medicine is data derived from a number of sources that are associated with outcomes in a heterogeneous patient population in real-world settings, such as patient surveys, clinical trials, and observational cohort studies.[1] Real-world data refer to observational data as opposed to data gathered in an experimental setting such as a randomized controlled trial (RCT). Remove real word in the text --> We removed “real world” in the title and introduction section. I am very dubious about the retrospective evaluation of the MNA-SF, which for me will inevitably be subjective due to its retrospective character and therefore unreliable. You say that the people have partly made a prospective and retrospective evaluation, so why didn't you do the questionnaire from the beginning? --> MNA-SF-related factors were obtained by physicians, nurses, and nutritionists in participating institutions. They were recorded on hospitalization records, baseline nursing records, and nutritional records for purposes unrelated to this study. As reviewers pointed out, MNA-SF scores were retrospectively calculated by reviewing medical records, therefore the reliability of MNA-SF score is inevitably lower than that of prospective studies. Since the predictive power of this score was expected to be weak, it was only described as an additional content according to recommendations. We also described this limitation in discussion section. You said that the classification was done according to the 2016 classification, but what about before 2016? Did you reclassify the AML? --> AML was initially categorized by WHO classification of myeloid neoplasms and acute leukemia at the time of diagnosis in each patient (i.e., either version 2008 or 2016). We reclassified the category according to the 2016 revision of WHO classification when we obtained and analyzed these data. The detail of the univariate/multivariate analysis are missing in methods: which criteria, which p... --> We added detailed description about the methods of analysis in statistical analysis section. PFS and OS should be described in statistical analysis. --> Definition of PFS and OS was moved to statistical analysis section from treatment and evaluation section. Results The description of the results on prognostic factors, the most important one, is confusing: for example: "age, PS, absence of PB... were associated to prolonged OS" Does it involve univariate, multivariate analysis? --> As a reviewer pointed out, methods of statistics were unclear. We added a clear explanation in methods section and tailed additional markers (univariate/multivariate) in the sentences of result section. Figures: p and months are missing --> Figure 1A and 1B: Survival duration (months) and 95% CI were already presented in Figure legends. --> Figure S1 and S2: P-value was given in lower left corner of each graph. We added survival duration (months) and 95% CI of each curve. Tables: HR and 95%CI are missing in univariate analysis --> Univariate analysis of survival was conducted by using log-rank test. Thus, univariate P was presented in Table 4, but hazard ratio cannot be calculated in univariate analysis. Discussion Difficult in the discussion to see the original points of the article with numbers digits of the publication appearing. --> We expressed the exact number of survivals from other studies more clearly (reference 9-12, 18) to compare with the results of ours. In a recent publication (Fili et al. 2019, leukemia research) found : The ORR in real-world setting was 33% and median OS in responders was 22.6 months. Which is more than you, how can you explain the difference? --> In the publication (Fili et al. 2019, leukemia research), the ORR was 42% and median OS was 12.7 months in patients treated with first line decitabine (n = 75). These numbers seemed better than our results, but they involved more proportion of better performance status (ECOG PS 1-2 was 88%) than ours. We added explanation about this in the first paragraph of discussion section. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0235503.r004
17 Jun 2020 Decision Letter - Francesco Bertolini, Editor Outcomes of decitabine treatment for newly diagnosed acute myeloid leukemia in older adults PONE-D-20-00626R2 Dear Dr. Hong, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Francesco Bertolini, MD, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0235503.r005
Formally Accepted
23 Jul 2020 Acceptance Letter - Francesco Bertolini, Editor PONE-D-20-00626R2 Outcomes of decitabine treatment for newly diagnosed acute myeloid leukemia in older adults Dear Dr. Hong: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Francesco Bertolini Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0235503.r006

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .