Management of Acute Myeloid Leukemia: A Review for General Practitioners in Oncology

Round 1

Reviewer 1 Report

This is a well organized review of AML treatment in the modern era including integrating other disciplines to help support patients through the new therapies to achieve the maximal quality of life possible under challenging circumstances.

There are some minor grammatical  edits

below are a few specific suggestions. 

I would also suggest updating the WHO and ELN classifications and risk stratifications given that they were just updated otherwise this review will be out of date as soon as it published.

ref 18 should be replaced with ELN which defines refractory in recent times.

this statement should be clarified

"Notably, this meta-analysis reported less toxicity with a lower dose of 3 147 mg/m2 with equivalent efficacy outcomes[28]." should be clarified to say equivalent to what? ie the previous higher single dose regimen

I would also suggest breaking up the paragraph with midostaurin and gemtuzumab

The definition of  CR is not correct. it doesn't include transfusion dependence.

the following statement is not clear. It should just say "was not statistically significant"

"although 234 OS was numerically longer in the experimental arm the study did not meet its primary 235 endpoint (Median OS 7.2 months vs 4.1 months, 0.75 (95% CI, 0.52-1.07; P = .11)." 

the following statement is not quite correct. it is not correct to say "almost all". it should be "all progress". no cures.

"not considered curative and almost all patients will 241 eventually progress after an initial response." 

the first paragraph talking about repeat flt3 testing for R/R disease refers to clonal evolution. i don't think it is correct to mix clonal evolution with the appearance and disappearance of flt3 status.

"5.6 months for salvage chemotherapy (for death, HR 0.64, 95% CI 0.49-0.83, P<0.001)[23]." for death?

IDH mutations are very rare. this statement needs to be corrected.

"IDH1 or IDH2, are often found at the time of AML diagnosis, a" it is not correct that they are often found at diagnosis. IDH mutations are 10-15% at diagnosis

Author Response

This is a well organized review of AML treatment in the modern era including integrating other disciplines to help support patients through the new therapies to achieve the maximal quality of life possible under challenging circumstances.

There are some minor grammatical edits, below are a few specific suggestions.

1. I would also suggest updating the WHO and ELN classifications and risk stratifications given that they were just updated otherwise this review will be out of date as soon as it published.
   • As suggested, we have updated the relevant Table 1 to reflect the recently published 2022 version of the WHO and ELN classification schema. We have adjusted all references to the ELN Classification to the updated, 2022 version.

2. Ref 18 should be replaced with ELN which defines refractory in recent times.
   • Reference #18 has been adjusted to reflect the recently published ELN criteria

3. This statement should be clarified: "Notably, this meta-analysis reported less toxicity with a lower dose of 3 mg/m2 with equivalent efficacy outcomes [28]." should be clarified to say equivalent to what? ie the previous higher single dose regimen
   • Thank you for noting this, as you suggest we have revised this statement to be more clear, with the text reading as follows:
   • “Notably, this meta-analysis reported less toxicity with a lower dose of 3 mg/m2 with equivalent efficacy outcomes when compared to the higher 6 mg/m2 dose utilized in earlier trials.”

4. I would also suggest breaking up the paragraph with midostaurin and gemtuzumab
   • As suggested, we have separated these two paragraphs in the text

5. The definition of CR is not correct. it doesn't include transfusion dependence.
   • Thank you for noting this error, we have corrected this in the text, which now reads as follows:
   • “The initial goal of induction treatment is to obtain a complete remission (CR), which is defined as <5% blasts on a cellular bone marrow aspirate, count recovery (e.g., absolute neutrophil count (ANC) >1 x 109/L, platelets >100 x109/L)”

6. The following statement is not clear. It should just say "was not statistically significant": "although 234 OS was numerically longer in the experimental arm the study did not meet its primary 235 endpoint (Median OS 7.2 months vs 4.1 months, 0.75 (95% CI, 0.52-1.07; P = .11)."
   • Per your suggestion, we have revised this statement to read as follows:
   • “This study found a higher rate of CR/CRi with LDAC and venetoclax (48% vs. 13%); however, there was no statistically significant difference in OS (Median OS 7.2 months vs 4.1 months, 0.75 (95% CI, 0.52-1.07; P = .11).”

7. The following statement is not quite correct. it is not correct to say "almost all". it should be "all progress". No cures: "not considered curative and almost all patients will 241 eventually progress after an initial response."
   • Thank you for noting this misstatement; we have corrected the text to now read as “all progress” per your suggestion:
   • “Despite a significant improvement in survival with the introduction of azacitidine and venetoclax, this treatment alone is not considered curative and all patients will eventually progress after an initial response.”

8. The first paragraph talking about repeat flt3 testing for R/R disease refers to clonal evolution. I don't think it is correct to mix clonal evolution with the appearance and disappearance of flt3 status.
   • As per your suggestion, we have adjusted this paragraph to remove the reference to clonal evolution, with the text now reading as follows:
   • “It is important to recognize that, in patients with R/R AML, the cytogenetic and mutational profiles can change from the time of diagnosis, and are not necessarily fixed. In particular, the gain or loss of mutations in the driver gene FLT3 that were either not present or detectable at diagnosis has been well described.”

9. "5.6 months for salvage chemotherapy (for death, HR 0.64, 95% CI 0.49-0.83, P<0.001)[23]." for death?
   • Thank you for noting this, we have removed the “for death” portion of the text, this now reads:
   • “This translated into an improved median OS at 9.3 months in the gilteritinib arm versus 5.6 months for salvage chemotherapy (HR 0.64, 95% CI 0.49-0.83, P<0.001).”

10. IDH mutations are very rare. this statement needs to be corrected. "IDH1 or IDH2, are often found at the time of AML diagnosis, a" it is not correct that they are often found at diagnosis. IDH mutations are 10-15% at diagnosis.
    • Per your suggestion, we have revised this statement to read:
    • “Mutations in either of the isocitrate dehydrogenase (IDH) genes, IDH1 or IDH2, are found in 10-15% of patients at the time of AML diagnosis, and can rarely be acquired at the time of relapse.”

Reviewer 2 Report

This is a well-written general overview of status of AML treatment. 

Suggestions:

1. Would update the references to ELN categortization with the updated citation from BLOOD (2022 vs 2017). 

2. In Table 2, it is somewhat confusing as to whether it is showing upfront therapies vs approved agents.  References should be included for each agent. 

3.  In table 3, would again include references or state this is how you administer azacitidine/venetoclax at your center and provide justification. 

4.  The section on palliative care is fine, but since this review is directed to "general practitioners in oncology", it might be good to have a section on how a general oncologist might interface with AML therapy. This is probably different in Canada vs other countries, but might be worth commenting on referrals for clinical trials, helping with consolidations/transfusions/other supportive care/ giving azacitidine/venetoclax in the community, and other considerations. 

Minor:

Line 51: Patients; Line 154; "low in" ; Line 301 patients'  not patients

Author Response

Reviewer #2

This is a well-written general overview of status of AML treatment.

Suggestions:

1. Would update the references to ELN categortization with the updated citation from BLOOD (2022 vs 2017).
   • Thank you for this important suggestion. We have replaced the ELN categories in Table 1 to reflect the ELN 2022 guidelines, and updated all references and text to reflect the ELN 2022 guidelines.

2. In Table 2, it is somewhat confusing as to whether it is showing upfront therapies vs approved agents. References should be included for each agent.

• We agree that this is an important point to clarify in this table. We have added a column outlining the approval status and disease state of approval (ie, frontline, R/R) and also included references to the landmark trials for each agent.

3. In table 3, would again include references or state this is how you administer azacitidine/venetoclax at your center and provide justification.

• We have provided an appropriate reference that reinforces these recommendations on these practical aspects of managing venetoclax and azacytidine. (PMID 31628431)

4. The section on palliative care is fine, but since this review is directed to "general practitioners in oncology", it might be good to have a section on how a general oncologist might interface with AML therapy. This is probably different in Canada vs other countries, but might be worth commenting on referrals for clinical trials, helping with consolidations/transfusions/other supportive care/ giving azacitidine/venetoclax in the community, and other considerations.

• Thank you for this excellent suggestion; while we do not have additional room to extensively examine this topic within the word limit, we have addressed this in the conclusion as follows:
• “Given the increasing numbers of older adults with AML with aging populations, this pa-tient group will likely represent a growing portion of community oncology practices. It is important for general practitioners in oncology and community oncologists to be aware of the spectrum of treatment options available to patients with AML. Most of these patients will benefit from a close collaborative relationship between providers at the tertiary AML treatment center within their region and community oncologists. In particular, collabora-tion around referrals for clinical trials, administration of some aspects of therapy, and supportive care closer to home.”

Minor:

1. Line 51: Patients; Line 154; "low in" ; Line 301 patients' not patients
   1. Thank you, this has been corrected in the revised manuscript