Real-World Treatment Patterns and Clinical Outcomes in Canadian Patients with AML Unfit for First-Line Intensive Chemotherapy

Round 1

Reviewer 1 Report

In this submission by Sanford et al, a subgroup of 170 Canadian patients from a larger CURRENT study are described. The authors describe the characteristics and outcomes of patients with AML who were not eligible for aggressive induction chemotherapy. Overall, the information provided is recent and comprehensive and informs the community about the current situation facing these patients. It may even serve as a control group for the future to assess the impact of newer interventions or treatment approaches. A few comments are provided that could improve the message and impact of this paper:

1. In the introduction, the author state that 5 year outcomes for AML in general are just 19 - 29%. Perhaps it is worth distinguishing the outcomes of patients treated aggressively (aggressive induction with transplant when appropriate) to provide a spectrum and rationale - that AML, if treated aggressively, has better outcomes than when it cannot be treated aggressively. Otherwise, the reader may be confused as the outcomes seem dismal whether patients are treated aggressively or not.

2. Perhaps a brief word about the goal of induction therapy is worthwhile. It may not inherently need to be "aggressive" to be effective. Treatment for APL is an example where effective treatment may not need to be aggressive or toxic (ATO and ATRA). As stated briefly in the conclusion, it would seem there is an urgent need for less aggressive yet more effective treatments to allow more patients to be benefit from treatment.

3. While patients may not receive aggressive induction, they could still be candidates for transplant if they could achieve remission (for instance, with HMA agents). It is surprising that this is not described or mentioned as a possibility. It may be an increasing option with HMA + venetoclax.

4. Throughtout the results (and in abstract), the author provide percentages of two separate groups without stating whether these are different. A simple chi-squared for comparing mean values could be considered to provide some insight about different groups contrasted with regard to various characteristics and outcomes. This appears to be lacking throughout. Moreover, some comparison to the larger CURRENT study should be considered and presented in the Results section, rather that in the DIscussion section.

5. More space in the Discussion should be used to address aspects of the observations and how this should be interpreted, rather than repeating results. In particular, do the authors suggest that more patients should be considered for HMA therapy since BAC did not really save on hospitalizations or visits? Perhaps this would add more quality of life and be worthy of further study?

6. In the Conclusion paragraph, the authors state in the last line: "use of novel therapies in Canada has increased, improving outcome for such patients" but there is no data to support this statement in the paper and it should be removed or changed. The introduction of newer therapy options in Canada that may be better tolerated by this population is worthy of further study with the goal of improving outcomes.

Author Response

1. In the introduction, the author state that 5 year outcomes for AML in general are just 19 - 29%. Perhaps it is worth distinguishing the outcomes of patients treated aggressively (aggressive induction with transplant when appropriate) to provide a spectrum and rationale - that AML, if treated aggressively, has better outcomes than when it cannot be treated aggressively. Otherwise, the reader may be confused as the outcomes seem dismal whether patients are treated aggressively or not.
   • We thank the reviewer for highlighting this oversight. We have added a sentence presenting a more granular breakdown of age-related survival: A recent US-based population study estimated 5-year survival rates to be 63% for patients aged 15 to 39 years, but declining to 22% in those aged 60 to 69 years and to 5% amongst those aged over 70 years at the time of diagnosis [1], and also included results from the CIBMTR US summary slides, 2021: Induction chemotherapy followed by post-remission (consolidation) therapy or allogeneic stem cell transplant (SCT) is the standard of care for those who can tolerate such intensive treatment, resulting in three-year overall survival rates of 54–58% [2-4].
2. Perhaps a brief word about the goal of induction therapy is worthwhile. It may not inherently need to be “aggressive” to be effective. Treatment for APL is an example where effective treatment may not need to be aggressive or toxic (ATO and ATRA). As stated briefly in the conclusion there is a need for less aggressive yet more effective treatments to allow more patients to benefit from treatment.
   • We agree with the sentiment expressed here by the reviewer and have added the statement in parentheses to the introduction: …and an inability to physically tolerate intensive chemotherapy due to comorbidities or frailty (the latter serving to highlight the need for less aggressive yet effective treatment regimens to extend benefit to those currently considered unsuitable for existing options).
3. While patients may not receive aggressive induction, they could still be candidates for transplant if they could achieve remission (for instance, with HMA agents). It is surprising that this is not described or mentioned as a possibility. It may be an increasing option with HMA + venetoclax.
   • We thank the reviewer for raising this excellent point. We trust following statement, added to the discussion section, reflects their thoughts suitably: Indeed, the advent of novel therapies may enable patients considered unfit for existing intensive treatment options to still achieve remission thereby enabling them to be considered as candidates for transplant.
4. Throughout the results (and in abstract), the author provide percentages of two separate groups without stating whether these are A simple chi-squared for comparing mean values could be considered to provide some insight about different groups contrasted with regard to various characteristics and outcomes. This appears to be lacking throughout. Moreover, some comparison to the larger CURRENT study should be considered and presented in the Results section, rather that in the Discussion section.
   • While we appreciate the sentiment of the reviewer, The CURRENT study (both the global and Canadian dataset) were observational in nature and not designed for such statistical inferences.
   • We have referenced the global study results where they differ notably from those of the Canadian dataset throughout the results section, and also discussed these in the discussion section.
5. More space in the Discussion should be used to address aspects of the observations and how this should be interpreted, rather than repeating results. In particular, do the authors suggest that more patients should be considered for HMA therapy since BAC did not really save on hospitalizations or visits? Perhaps this would add more quality of life and be worthy of further study?
   • We thank the reviewer for this insight and have added further discussion around interpretation of the results, in particular clarifying our thoughts on how the healthcare resource utilization data should be interpreted.
6. In the Conclusion paragraph, the authors state in the last line: "use of novel therapies in Canada has increased, improving outcome for such patients" but there is no data to support this statement in the paper and it should be removed or changed. The introduction of newer therapy options in Canada that may be better tolerated by this population is worthy of further study with the goal of improving outcomes.
   • We apologize for this oversight and have deleted this statement.

Reviewer 2 Report

The manuscript by Dr. Sanford et al. entitled "Real-world treatment patterns and clinical outcomes in Canadian patients with AML unfit for first-line intensive chemotherapy" describes some parameters including overall survival free survival, time to treatment failure, healthcare resource utilization, etc in AML patients who are not eligible for first-line intensive therapy. The topic is exciting and has scientific merits. In order to improve the manuscript, the reviewer hopes that the following comments and suggestions will be addressed.

Major comments:

1.     The authors should mention the criteria for early intensive ineligibility in the method section.

2.     Several valuable measures have been evaluated in this study; however, the reviewer hopes that the authors describe each variable briefly in the method section (line 87-92).

3.     I am confused about the study called CURRENT, which is multinational, while the presented research has used Canadian data. I request that the authors clarify this issue.

4.     Presenting overall including and excluding criteria for the study is of interest.

5.     Table 1: It is desired and respectful not to classify gender only as male and female since there are many gender identities.

6.     Figure1 A: Are there any available data about types of infections in studied AML patients since IFIs are significant causes of morbidity and mortality in the case of AML.

7.     Line 195: In previous studies, fungal infections were considered common among AML patients. I hope the authors explain why Canadian MDs avoid using anti-fungal drugs or the infection pattern is different in Canada.

Minor comments:

1.     Some abbreviations need mentioning in the extended form, such as ECOG

2.     Line 131: I wonder if the authors clarify "other" in the middle of the following sentence: Among those who received BSC, the most common interventions were transfusions, other, infection management, and pain relief (Figure 1). 

Author Response

1. The authors should mention the criteria for early intensive ineligibility in the method section.
   • We thank the reviewer for this suggestion and have included this in the methods: Patients could be defined as ineligible for intensive induction therapy on the basis of their treating physician’s assessment of age, ECOG performance status, comorbidities, regional guidelines, or institutional practice, or all of the above [5].
2. Several valuable measures have been evaluated in this study; however, the reviewer hopes that the authors describe each variable briefly in the method section (line 87-92).
   • We are unsure of what additional information we should include to address the reviewer’s suggestion. We have added a citation to the ESMO guidelines which provides definitions for these endpoints.
3. I am confused about the study called CURRENT which is multinational, while the presented research has used Canadian data. I request that the authors clarify this issue.
   • We apologize to the reviewer for any confusion and have highlighted this in the methodology: Overall results of the global study have been published elsewhere[6]. The focus of this manuscript is the results for the Canadian dataset from the global study.
4. Presenting overall including and excluding criteria for the study is of interest.
   • We have added these to the methods section.
5. Table 1: It is desired and respectful not to classify gender only as male and female since there are many gender identities.
   • We thank the reviewer for pointing this out and have added a footnote to the table clarifying that all patients in the Canadian dataset identified as either male or female.
6. Figure1 A: Are there any available data about types of infections in studied AML patients since IFis are significant causes of morbidity and mortality in the case of AML.
   • We agree with the sentiment of the reviewer. Unfortunately for this chart review that level of data granularity was not available.
7. Line 195: In previous studies, fungal infections were considered common among AML patients. I hope the authors explain why Canadian MDs avoid using anti-fungal drugs or the infection pattern is different in Canada.
   • We are confused by the reviewer’s assertion that fungal infections were generally considered common among AML patients – perhaps this is within the setting of intensive treatment? For example, fungal infection was not listed as an adverse event occurring in >1 patient in the Phase 3 study of azacitidine in older patients with AML.[7] The low rates of anti-infective use in general may reflect local guidelines on anti-infective stewardship (which we have mentioned in the discussion section)

Minor comments

8. Some abbreviations need mentioning in the extended form, such as ECOG
   • Our apologies – we have included this now
9. Line 131: I wonder if the authors clarify "other" in the middle of the following sentence: Among those who received BSC, the most common interventions were transfusions, other, infection management, and pain relief (Figure 1).
   • Unfortunately we do not have that level of detail available in the dataset

REFERENCES

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