Venous Thromboembolic Risk Does Not Increase After a Third Dose of SARS-CoV-2 mRNA-BNT162b2 Vaccine in Cancer Patients Receiving Active Systemic Therapies: Updated Results from the Vax-On-Third-Profile Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript entitled "Innovative Screening Methods to Reduce the Misdiagnosis of Lyme Disease: Public Health Implications and Global Perspective”, explored the current landscape of Lyme disease management, emphasizing the need for improved diagnostic strategies and public health interventions. Despite the good structure of the manuscript, there are some concerns which should be addressed.

1. You reported an overall incidence rate of 7.2% for TEEs. How does this compare to baseline rates in similar populations of cancer patients not receiving mRNA vaccines?
2. The median follow-up time was 10.6 months. Do you believe this duration was sufficient to capture all relevant thromboembolic events post-vaccination?

Author Response

The manuscript entitled "Innovative Screening Methods to Reduce the Misdiagnosis of Lyme Disease: Public Health Implications and Global Perspective”, explored the current landscape of Lyme disease management, emphasizing the need for improved diagnostic strategies and public health interventions. Despite the good structure of the manuscript, there are some concerns which should be addressed.

Although the incorrect reference to the title of the article is clearly attributable to a misprint mistake, we sincerely thank you for subsequent insightful comments.

You reported an overall incidence rate of 7.2% for TEEs. How does this compare to baseline rates in similar populations of cancer patients not receiving mRNA vaccines?

The lack of a control group of unvaccinated subjects is a major limitation of this and every study of COVID-19 vaccination in cancer patients. Almost all patients diagnosed with active cancer received COVID-19 vaccination during the historical period of the study, precluding the possibility of identifying a control group for reliable direct comparisons. An indirect comparative evaluation of our data could refer to observational studies that have evaluated the occurrence of thromboembolic events in patients with active cancer undergoing systemic therapies. These studies included unvaccinated cancer patients with clinical features similar to our case series. The most recent research with an observation timeframe of at least 12 months has estimated a cumulative incidence of TTEs between 6.6% and 7.7%, or from 5.8 to 9.6 per 100 person-years. The latter figures appear consistent with our findings, suggesting that receipt of the third dose of tozinameran did not affect the onset of TEEs over a 12-month period. The Discussion section of the article already included a detailed reference to this interpretive key to our findings.

The median follow-up time was 10.6 months. Do you believe this duration was sufficient to capture all relevant thromboembolic events post-vaccination?

We believe the latter is a very pertinent observation because current evidence does not provide an established timeline for monitoring adverse events following COVID-19 vaccination. However, the median follow-up period in our study appears reliable for two main reasons. First, most TTEs in our case series occurred within six months of booster vaccination, and only a minority occurred beyond this time frame. Second, available vaccine safety studies usually refer to adverse events that occurred within 12 months or earlier.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors in this paper investigate thromboembolic events (TEEs) following the third dose of the SARS-CoV-2 mRNA-BNT162b2 vaccine in cancer patients undergoing systemic therapy. Analyzing 429 patients, they found a 7.2% TEE incidence, with higher rates in those receiving targeted therapies (11.3%) and immune checkpoint inhibitors (16.2%). NK cell response, prior TEEs, and central venous catheters were identified as independent risk factors.

The study concludes that while the vaccine does not broadly increase TEE risk, specific immune and clinical factors warrant further monitoring in cancer patients. 

The analysis in this study appears methodologically rigorous, employing a prospective cohort design with clear eligibility criteria and well-defined endpoints.

The statistical approach includes univariate and multivariate regression analyses to assess correlations between thromboembolic events (TEEs) and immune responses, ensuring robustness in identifying independent risk factors.

However, while the study reports significant correlations, particularly between high NK cell responses and TEE risk, causality remains uncertain.

The reliance on observational data limits definitive conclusions about whether immune alterations directly contribute to thrombosis or if pre-existing conditions predispose certain patients.

Additionally, the sample size for some subgroups, such as those on immune checkpoint inhibitors, may be limited, affecting statistical power.

Overall, the study provides valuable insights but would benefit from further validation through larger, controlled studies or mechanistic investigations to clarify the biological pathways linking vaccination, immune modulation, and thromboembolic risk.

Author Response

The authors in this paper investigate thromboembolic events (TEEs) following the third dose of the SARS-CoV-2 mRNA-BNT162b2 vaccine in cancer patients undergoing systemic therapy. Analyzing 429 patients, they found a 7.2% TEE incidence, with higher rates in those receiving targeted therapies (11.3%) and immune checkpoint inhibitors (16.2%). NK cell response, prior TEEs, and central venous catheters were identified as independent risk factors.

The study concludes that while the vaccine does not broadly increase TEE risk, specific immune and clinical factors warrant further monitoring in cancer patients.

The analysis in this study appears methodologically rigorous, employing a prospective cohort design with clear eligibility criteria and well-defined endpoints.

The statistical approach includes univariate and multivariate regression analyses to assess correlations between thromboembolic events (TEEs) and immune responses, ensuring robustness in identifying independent risk factors.

However, while the study reports significant correlations, particularly between high NK cell responses and TEE risk, causality remains uncertain.

The reliance on observational data limits definitive conclusions about whether immune alterations directly contribute to thrombosis or if pre-existing conditions predispose certain patients.

According to the Reviewer’s suggestions, we placed greater emphasis on the uncertainty surrounding the causal link between immune changes triggered by vaccination and venous thromboembolism. Additionally, we noted that the observational design of this study restricts our ability to draw definitive conclusions about whether changes in NK cell responses post-vaccination directly lead to venous thromboembolism.

Additionally, the sample size for some subgroups, such as those on immune checkpoint inhibitors, may be limited, affecting statistical power.

The lack of stratification at baseline is a major limitation of this study. As much as the health emergency of COVID-19 warranted “all-comer” enrollment to ensure vaccination for as many patients as possible, this modality resulted in heterogeneity in the composition of the subgroups. Such a disproportion was particularly evident in the sample size of subgroups defined by different active treatments, implying limited statistical power of the univariate comparison. As much as the multivariate analysis minimized the risk of false positives with respect to possible correlation with TTEs, the latter remains the main limitation of the study and the first one we acknowledged in the dedicated section.

Overall, the study provides valuable insights but would benefit from further validation through larger, controlled studies or mechanistic investigations to clarify the biological pathways linking vaccination, immune modulation, and thromboembolic risk.

The uncertainty of this potential interaction would benefit from further validation through larger, controlled studies or mechanistic investigations to elucidate the biological pathways linking COVID-19 vaccination, immune modulation, and venous thromboembolic risk. We have added these considerations in the final part of the “Discussion” section.

Reviewer 3 Report

Comments and Suggestions for Authors

The paper presents data on the risk of venous thromboembolism development in cancer patients who received booster dose of tozinameran against SARS-CoV-2 infection. Prospective observation within 12 months revealed a relatively high incidence of VTE which was not surprising taking into account patient’s characteristics. At the same time there was no connection between vaccination and VTE risks.

The study is conducted and presented in clear and detailed way. I believe it can be of some interest for those involved in cancer patient’s management even if the current situation with SARS-CoV-2 infection is different from the time of the first two-three years of pandemic.

I have some remarks.

1. Please, change the definition “thromboembolic events” to “venous thromboembolism”. You registered only deep vein thrombosis and pulmonary embolism which are parts of venous thromboembolism. I believe using more specific definition would help to find the paper for those who are interested in cancer-associated DVT. Please, change TEE for VTE also.
2. Please, change the title in the way reader could immediately see the main finding of the study. I mean something of that kind “VTE risk doesn’t increase after the third dose of SARS-CoV-2 2

mRNA-BNT162b2 vaccine in cancer patients receiving active systemic therapies”

3. Please, shorten Conclusions significantly. This part should be of two to three sentences where only the results are repeated. No any kind of discussion of the results or future perspectives.
4. I believe that previous anticoagulation treatment has to be presented in more details. Was it VTE prevention in patients receiving chemotherapy? Or it was a treatment of VTE episode? When it stopped? Were there some patients who received anticoagulants after third dose of vaccine?

Author Response

The paper presents data on the risk of venous thromboembolism development in cancer patients who received booster dose of tozinameran against SARS-CoV-2 infection. Prospective observation within 12 months revealed a relatively high incidence of VTE which was not surprising taking into account patient’s characteristics. At the same time there was no connection between vaccination and VTE risks.

The study is conducted and presented in clear and detailed way. I believe it can be of some interest for those involved in cancer patient’s management even if the current situation with SARS-CoV-2 infection is different from the time of the first two-three years of pandemic.

I have some remarks.

Please, change the definition “thromboembolic events” to “venous thromboembolism”. You registered only deep vein thrombosis and pulmonary embolism which are parts of venous thromboembolism. I believe using more specific definition would help to find the paper for those who are interested in cancer-associated DVT. Please, change TEE for VTE also.

We think this is a very insightful observation. The definition of thromboembolic events could also include arterial vascular events, the evaluation of which is beyond the scope of this study and experimental design. We have therefore replaced the term thromboembolic events (TEEs) with the more appropriate venous thromboembolism (VTE) throughout the manuscript.

Please, change the title in the way reader could immediately see the main finding of the study. I mean something of that kind “VTE risk doesn’t increase after the third dose of SARS-CoV-2 mRNA-BNT162b2 vaccine in cancer patients receiving active systemic therapies”

According to the Reviewer's suggestion, we have revised the article's title to “Venous thromboembolic risk does not increase after a third dose of SARS-CoV-2 mRNA-BNT162b2 vaccine in cancer patients receiving active systemic therapies: updated results from the Vax-On-Third-Profile study”. This change aims to highlight the study's primary finding more clearly.

Please, shorten Conclusions significantly. This part should be of two to three sentences where only the results are repeated. No any kind of discussion of the results or future perspectives.

We have significantly shortened the length of the “Conclusions” section, removing redundant comments on the study results. We have also moved considerations about future perspectives or further investigation to a more appropriate part of the “Discussion” section.

I believe that previous anticoagulation treatment has to be presented in more details. Was it VTE prevention in patients receiving chemotherapy? Or it was a treatment of VTE episode? When it stopped? Were there some patients who received anticoagulants after third dose of vaccine?

We agree with the Reviewer that our initial description of antiplatelet and anticoagulant therapies was too broad and lacked detail. Consequently, we have included a comprehensive description of the therapeutic indications for both treatments in Table 1, titled “Patient characteristics at baseline”. While heart was the predominant reason for these therapies, previous VTE and primary prophylaxis of cancer-related VTE accounted for 5.6% and 2.1% of cases, respectively. Notably, no patients received additional antiplatelet or anticoagulant agents for prophylaxis of thromboembolic events potentially related to vaccination. The latter observations have been added as additional remarks to the “Patient characteristics at baseline” subsection.