Successful Treatment with Brigatinib after Alectinib-Induced Hemolytic Anemia in Patients with Metastatic Lung Adenocarcinoma—A Case Series
Round 1
Reviewer 1 Report
This paper deals with case series of alectinib-induced hemolytic anemia. The cases were well documented, and discussion was excellent. Since there are some issues to be solved, the article should be revised before publication.
Major comments
1. Although alectinib-induced hemolytic anemia is rare, it has been known enough among lung cancer specialists as several reports have been available. At first glance, this paper seems to lack novelty. However, it is a quite new report that brigatinib after alectinib can avoid alectinib-induced hemolytic anemia. Therefore, I recommend authors to remove patient (4) and revise the title as “Successful treatment with brigatinib after alectinib-induced hemolytic anemia in patients with metastatic lung adenocarcinoma – A Case Series”.
2. The introduction is well written but a bit too redundant. Line 6-19 should be deleted because other mutations are not relevant to this paper. Instead, the authors should describe (1) the incidence of ALK-positive lung cancer, (2) the standard treatment strategy for ALK-positive lung cancer, (3) the position of alectinib in the strategy, and (4) the common adverse events of alectinib and the incidence of anemia during alectinib as the authors have already described in the introduction section. It will help readers to focus on ALK and anemia.
3. What would the authors like to indicate by showing Figure 2, 3, 6 and Table 1? The authors should show the response of alectinib and the peripheral smear for each patient as figures. Namely, figure 1, 2, and 3 should show response in patient (1), (2), and (3), respectively. Figure 4A-C should show peripheral smear of patient (1)-(3). Furthermore, table 1 should show the summarized patients’ laboratory data (including Hb, MCV, Plt, LDH, Bil T, Bil I, Haptoglobin, Retic, Coombs tests, G6PD test, etc) at the diagnosis of hemolytic anemia. If the data of ferritin and iron are available, the authors should add text.
4. The PD-L1 expressions of all patients were over 50%. What do the authors think is the relation between high PD-L1 expression and alectinib induced hemolytic anemia? Please discuss.
5. Why does alectinib not brigatinib cause hemolytic anemia? Is the phenomenon specific for alectinib? If it is not specific for alectinib, line 227-241 should be revised because the supposed mechanism is common in ALK-TKIs.
6. Conclusion should not include discussion. Please reconstruct the discussion and conclusion section.
Minor comments
1. Please describe the race of all patients.
2. Is upper part of figure 1 (March 2020) left-right reverse?
3. Please write "Figure 1" instead of "Figure-1" as the author's instructions.
4. Can you provide peripheral smear images for all patients?
5. How did the authors exclude paroxysmal nocturnal anemia? It is important to investigate PNH in patients with negative Coombs hemolytic anemia.
6. Line 131: PDL-1 => PD-L1
Author Response
Thank you so much for reviewing our paper entitled: Alectinib-induced hemolytic anemia in patients with metastatic lung adenocarcinoma- A Case Series. We appreciate the time and effort you made to help us enhance our manuscript and have taken your comments into serious consideration.
Reviewer 1:
This paper deals with case series of alectinib-induced hemolytic anemia. The cases were well documented, and discussion was excellent. Since there are some issues to be solved, the article should be revised before publication.
Many changes were performed according to your highly appreciated suggestions.
Major comments
- Although alectinib-induced hemolytic anemia is rare, it has been known enough among lung cancer specialists as several reports have been available. At first glance, this paper seems to lack novelty. However, it is a quite new report that brigatinib after alectinib can avoid alectinib-induced hemolytic anemia. Therefore, I recommend authors to remove patient (4) and revise the title as “Successful treatment with brigatinib after alectinib-induced hemolytic anemia in patients with metastatic lung adenocarcinoma – A Case Series”.
Title, introduction and discussion were adjusted accordingly to highlight the successful treatment with Brigatinib while keeping patient 4 for pertinence: similar pattern, asian origin, negative PD-L1 status,etc.
- The introduction is well written but a bit too redundant. Line 6-19 should be deleted because other mutations are not relevant to this paper. Instead, the authors should describe (1) the incidence of ALK-positive lung cancer, (2) the standard treatment strategy for ALK-positive lung cancer, (3) the position of alectinib in the strategy, and (4) the common adverse events of alectinib and the incidence of anemia during alectinib as the authors have already described in the introduction section. It will help readers to focus on ALK and anemia.
As suggested, other mutations were removed from the introduction to maintain focus on ALK-rearrangement positive NSCLC.
- What would the authors like to indicate by showing Figure 2, 3, 6 and Table 1? The authors should show the response of alectinib and the peripheral smear for each patient as figures. Namely, figure 1, 2, and 3 should show response in patient (1), (2), and (3), respectively. Figure 4A-C should show peripheral smear of patient (1)-(3). Furthermore, table 1 should show the summarized patients’ laboratory data (including Hb, MCV, Plt, LDH, Bil T, Bil I, Haptoglobin, Retic, Coombs tests, G6PD test, etc) at the diagnosis of hemolytic anemia. If the data of ferritin and iron are available, the authors should add text.
Figures were altered with the removal of figure 2, and addition of pulmonary disease response in patient 2 as figure 2 instead of 3. Figure 6 was renamed as figure 4 including the peripheral smear of patient 4 indicative of hemolytic processes. Unfortunately, peripheral smears of patients 1-3 were not available. Table 1 was maintained to portray changes in laboratory data suggesting hemolysis with Alectinib interruption, dose adjustment and discontinuation.
Table 2 was added in the end to include all 4 patients’ laboratory data at the diagnosis of Alectinib-induced hemolytic anemia.
Iron, and ferritin information were added to the text.
- The PD-L1 expressions of all patients were over 50%. What do the authors think is the relation between high PD-L1 expression and alectinib induced hemolytic anemia? Please discuss.
A discussion regarding PD-L1 expression and possible effects on response as well as adverse events was added.
- Why does alectinib not brigatinib cause hemolytic anemia? Is the phenomenon specific for alectinib? If it is not specific for alectinib, line 227-241 should be revised because the supposed mechanism is common in ALK-TKIs.
A comment regarding a possibility of a class effect and the differences of mechanism of action with brigatinib despite the role of ALK-inhibition to the formation of oxidative hemolysis was added.
- Conclusion should not include discussion. Please reconstruct the discussion and conclusion section.
A conclusion paragraph was added.
Minor comments
- Please describe the race of all patients.
All patient races were included.
- Is upper part of figure 1 (March 2020) left-right reverse?
Indeed, there was an unintentional inversion of images corrected.
- Please write "Figure 1" instead of "Figure-1" as the author's instructions.
Done!
- Can you provide peripheral smear images for all patients?
Unfortunately, peripheral smears of patients 1-3 are not available.
- How did the authors exclude paroxysmal nocturnal anemia? It is important to investigate PNH in patients with negative Coombs hemolytic anemia.
There was no clinical suspicion of PNH; however, no flow cytometry was performed. Elaboration added to the discussion.
- Line 131: PDL-1 => PD-L1
Corrected.
Reviewer 2 Report
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1. References 4,6,27,29,30 and 32 do not have output data, they should be entered.
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2. I believe that the authors should pay attention to the analysis of the activity of NOS (NO-synthetase) in patients during subsequent analyzes of the use of the drug. In the works that analyze the effect of the drug, oxidative stress is reported, but none deals with the level of nitrites, nitrates or nitric oxide. It can be assumed that nitrosative stress affects the hemolysis of erythrocytes in the body and this is directly related to the metabolism of the drug in the liver.
Author Response
Thank you so much for reviewing our paper entitled: Alectinib-induced hemolytic anemia in patients with metastatic lung adenocarcinoma- A Case Series. We appreciate the time and effort you made to help us enhance our manuscript and have taken your comments into serious consideration.
Reviewer 2:
Thank you for giving us the time and effort to review our manuscript.
- References 4,6,27,29,30 and 32 do not have output data, they should be entered.
Adjusted!
- I believe that the authors should pay attention to the analysis of the activity of NOS (NO-synthetase) in patients during subsequent analyzes of the use of the drug. In the works that analyze the effect of the drug, oxidative stress is reported, but none deals with the level of nitrites, nitrates or nitric oxide. It can be assumed that nitrosative stress affects the hemolysis of erythrocytes in the body and this is directly related to the metabolism of the drug in the liver.
A small paragraph discussing the possible oxidative stress, production of superoxides and the possible effect of nitrosative stress on hemolysis mentioned; nevertheless, without further elaboration regarding the role of NOS due to the absence of sufficient supporting data.
Round 2
Reviewer 1 Report
Great works.
In proofreading, you should correct double space and insert a space before each reference.
