Review Reports - Canada’s First Joint Oncology-Allergy Clinic: Successful Desensitization to Trastuzumab Following Severe Anaphylactic Reaction in Which Epinephrine Was Inappropriately Withheld

Round 1

Reviewer 1 Report

This is a well-written case presentation describing an anaphylactic reaction to trastuzumab leading to the development of a medical oncology and allergy multidisciplinary clinic.

The manuscript contains an appropriate description of the case but could be strengthened with the addition of the following:

1. literature review of recommendations for trastuzumab hypersensitivity reaction/anaphylaxis protocols. Many Canadian centres may not include acute administration of epinephrine in their protocols so this is an important point to highlight.

2. Literature review of trastuzumab desensitization protocols and allergy clinics outside of Canada (a quick pubMed review did suggest some other jurisdictions have such clinics)

3. Further details about the clinic would be helpful. GIven such reaction?s are uncommon and unpredictable the need for a regular clinic could be questioned. How often does the clinic run, how many referrals a month I would assume it includes referrals for allergies to any oncology therapeutic. do the authors have details of the patients seen, time to referral and time to rechallenge with offending therapeutic?

Author Response

Dear Reviewer,

Thank you for your time and suggestions. Please see below for our description of the changes we have implemented in response.

Point 1: literature review of recommendations for trastuzumab hypersensitivity reaction/anaphylaxis protocols. Many Canadian centres may not include acute administration of epinephrine in their protocols so this is an important point to highlight.

Response: The EAACI guidelines on anaphylaxis [5] are the best source for recommendations regarding administration of epinephrine when anaphylaxis is suspected. The guidelines apply to oncology settings and reactions to monoclonal antibody therapies, chemotherapy agents, and other drugs or allergens. We have added a sentence clarifying this to the discussion (lines 192-198):

There are limited studies informing trastuzumab-specific guidelines around treatment protocols when adverse reactions occur. However, the current anaphylaxis guidelines for diagnosis and treatment of suspected anaphylactic reactions applies to all instances of anaphylaxis [5]. This includes reactions to monoclonal antibody therapies like trastuzumab, chemotherapy agents, and other drugs [5]. The treatment guidelines should therefore be implemented in oncology settings like the one described in this case, and epinephrine should always be the recommended treatment.

Point 2: Literature review of trastuzumab desensitization protocols and allergy clinics outside of Canada (a quick pubMed review did suggest some other jurisdictions have such clinics).

Response: We have included additional case series with trastuzumab desensitization, some of which had generalized protocols. We have added the following paragraph to the introduction to further elaborate (lines 72-89):

Trastuzumab has potential tremendous benefit and when hypersensitivity reactions occur, rechallenge with desensitization protocols has become more common [10-13] and have been included in small numbers in several case series of desensitization to oncology treatments [11-13]. There are currently no formal guidelines or recommendations concerning Trastuzumab rechallenge, but desensitization protocols have been published in the literature [11-13]. A recent European Academy of Allergy and Clinical Immunology (EAACI) position paper proposed an algorithm for the evaluation of hypersensitivity reactions to chemotherapeutic agents [14]. It recommends serum tryptase levels and immunologic skin testing for patients with immediate hypersensitivity reactions in order to assess their risk in continuing treatment [14]. If deemed low risk, patients can undergo a challenge in which the drug is administered in a monitored environment [14]. If hypersensitivity is suspected and the patient is deemed to have moderate to high risk of reaction on further exposure, they can undergo rapid drug desensitization [14]. During desensitization, the drug is administered in diluted amounts according to a multi-step protocol that increases to the target dose over time, resulting in a temporary state of tolerance [7]. While the mechanism is incompletely understood, this immunologic tolerization to the offending drug is induced by inhibiting mast cell activation responses and thus preventing anaphylaxis [15].

We have also added additional information about allergy-oncology clinics in other jurisdictions, including the two clinics in the United States, and a comment regarding current collaboration efforts in Europe (lines 211-226):

The EAACI gave Task Force status to the interdisciplinary field of AllergoOncology in 2014, which aims to encourage exchange of expertise in order to further understanding of both topics [14]. The field focuses on the relationship between allergic responses and cancer, immunomodulation, including Ig-E mediated responses, and aims to provide new insights into treatments like cancer immunotherapies [14]. While allergic reaction to anti-cancer agents is not a new problem, the management of allergy and allergic disease in daily clinical oncology is an emerging area that falls under this interdisciplinary umbrella [14].
Reactions to chemotherapy agents and monoclonal antibody therapies are increasingly common in the last several decades and have become more clinically significant as the number and efficacy of therapies has increased [7]. While there is abundant collaboration between allergists and oncologists in many European jurisdictions as a result the EAACI’s efforts in the expanding field of AllergoOncology [14], there are only a handful of examples in North America. Only two such clinics have been established in the United States, out of the Brigham and Women’s Hospital in Boston and the Albert Einstein College of Medicine in New York.

Point 3: Further details about the clinic would be helpful. Given such reactions are uncommon and unpredictable the need for a regular clinic could be questioned. How often does the clinic run, how many referrals a month. I would assume it includes referrals for allergies to any oncology therapeutic. do the authors have details of the patients seen, time to referral and time to rechallenge with offending therapeutic?

Response: We have included additional details regarding the clinic as per your recommendations (lines 227-266):

The Medical Oncology and Allergy Clinic in Winnipeg, Manitoba is the first formal collaboration in Canada with one of its goals to provide recommendations regarding acute management of hypersensitivity reactions and prevention of their recurrence (e.g., with administration via desensitization). When patients have adverse reactions to their cancer therapies, they are promptly referred to the clinic for urgent assessment, immunologic skin testing, and consideration of rechallenge or desensitization. The clinic deals with all allergy related issues experienced by current oncology patients. This not only includes infusion-related or anaphylactic reactions and subsequent skin testing and desensitization, but also suspected allergic reactions to oral anti-cancer drugs and contrast dye. Patients with penicillin or other antibiotic allergies are also seen, especially those being considered for allogenic stem cell transplant. Prior to the clinic’s establishment, local allergists and oncologists noticed there was a high frequency of often time-sensitive consultations for oncology patients. This led to involvement of the hospital Chief Medical Officer, department heads of medical oncology and allergy, and directors of the Systemic Therapies program and Provincial Oncology Drug Program. The data supporting allergist involvement in medical oncology was reviewed, along with the regular consults, leading to agreement that a dedicated clinic would the provide the time, place, and staff to prioritize management of oncology patients’ allergy-related problems. The clinic was established in September 2022 and runs one half-day per week, and approximately 5 patients are seen per clinic. The timing of referral is generally quick, and patients are seen within 5 business days.

Reviewer 2 Report

The authors present a case of anaphylaxis which should have led to a malpractice event: the diagnosis of anaphylaxis for missed, the treatment of anaphylaxis was not provided and the patient sustained a severe and potentially lethal injury and was finally rescued by the ER treatment. The voice of the patient is not hear throughout the case and it is likely that the patient has PTSD despite de successful desensitization. The impact of his initial hypersensitivity reaction is likely to impact the quality of life forever and should be evaluated and noted. Specific comments:

1. The title needs to be changed since indicating that the patient did not received epinephrine is discouraging its use during anaphylaxis and is against standard of care

2. The patient had no diagnosis of anaphylaxis and tryptase was not obtained. Due to the severity of the event it is possible that the patient has Hereditary Alpha Tryptasemia (tryptase > 8 ng/ML) (Lyons Nature Genetics 2016) or Mastocytosis (> 11,4ng/ml). A baseline tryptase level should be obtained and the patient should be evaluated for mast cell activation conditions if elevated as indicated.

3. Many cases of tratuzumab desensitization have been published and included in chemotherapy series such as in Sloane et al JACI In Practice 2016 and Isabwe et al JACI 2018 and the authors need to update the references and read the series.

Author Response

Dear Reviewer,

Thank you for your time and suggestions. Please see below for our description of the changes we have implemented in response.

Point 1: The title needs to be changed since indicating that the patient did not received epinephrine is discouraging its use during anaphylaxis and is against standard of care

Response: Thank you for your suggestion. It is true that epinephrine is the standard of care and that withholding it is against said standard. However, we included the fact that epinephrine was not administered in this case for that very reason. We felt it highlights the problem in many oncology treatment rooms where epinephrine is sometimes inappropriately withheld when patients develop anaphylaxis. We do not to discourage its use, so we have amended the wording of the title (lines 2-4):

Canada’s first joint Oncology-Allergy Clinic: successful desen-sitization to Trastuzumab following severe anaphylactic reaction in which epinephrine was inappropriately withheld.

Point 2: The patient had no diagnosis of anaphylaxis and tryptase was not obtained. Due to the severity of the event it is possible that the patient has Hereditary Alpha Tryptasemia (tryptase > 8 ng/ML) (Lyons Nature Genetics 2016) or Mastocytosis (> 11,4ng/ml). A baseline tryptase level should be obtained and the patient should be evaluated for mast cell activation conditions if elevated as indicated.

Response: We have clarified that a tryptase was not drawn due to patient refusal (line 135).

We have added a section to the introduction discussing the importance of drawing a serum tryptase following reaction and a baseline tryptase level for comparison (lines 47-59):

Other tests can be used to further support diagnosis in patients with atypical symptoms. Current guidelines recommend measuring serum tryptase one half to two hours after onset of anaphylaxis, in addition to measurement of baseline tryptase 24 hours after resolution of all anaphylaxis symptoms [5]. During anaphylaxis, serum tryptase concentrations increase as a result of mast cell degranulation, and while measuring levels during a clinical emergency will not help diagnose anaphylaxis, if elevated above baseline it can be helpful confirming the diagnosis of anaphylaxis retrospectively [5]. A serum tryptase 1.2 times higher than baseline tryptase +2 μg/L supports a diagnosis of anaphylaxis [5]. The baseline tryptase also permits exclusion of other conditions associated with an elevated tryptase that can contribute to severe anaphylactic reactions, such as Mastocytosis and Hereditary Alpha Tryptasemia [5-6]. Skin-prick or intradermal testing post-reaction can also be conducted to evaluate for IgE-mediated disease when used in correlation with clinical history [7].

We have emphasized that anaphylaxis is a clinical diagnosis (line 150) and have also added a section to the discussion with regard to tryptase and these conditions. We acknowledged the disadvantage of tryptase not being drawn (acutely or for baseline comparison), discuss the utility of the test in the context of this case, and why authors felt Mastocytosis was unlikely given the patient’s absent history previous anaphylaxis or symptoms indicative of a mast cell disorder (lines 173-184):

Serum tryptase can also be used retrospectively to confirm anaphylaxis in the event of clinical uncertainty and is recommended by current guidelines [5]. While the patient did meet the clinical criteria for anaphylaxis [5], a serum tryptase was unfortunately not drawn due to patient-refusal which is a disadvantage. The lack of baseline tryptase also means that confounding conditions like Mastocytosis and Hereditary Alpha Tryptasemia could not be evaluated, especially given the severity of the patient’s reaction. However, genetic testing for Hereditary Alpha-Tryptasemia is not currently available in Manitoba, locally or as an external test. Furthermore, even if a Tryptase was drawn, a normal level would not have ruled out Mastocytosis and the patient ultimately would have required a bone marrow biopsy to diagnose the condition [18]. Authors were reassured by the patient’s absent history of prior anaphylaxis or other symptoms indicative of mast cell disorder and felt that the condition was unlikely in this case.

Point 3: Many cases of tratuzumab desensitization have been published and included in chemotherapy series such as in Sloane et al JACI In Practice 2016 and Isabwe et al JACI 2018 and the authors need to update the references and read the series.

Response: Thank you for your suggestion, we have read the case series and included the following comments with the appropriate references (line 72-89):

Trastuzumab has potential tremendous benefit and when hypersensitivity reactions occur, rechallenge with desensitization protocols has become more common [10-12] and have been included in small numbers in several case series of desensitization to oncology treatments [11-12]. There are currently no formal guidelines or recommendations con-cerning Trastuzumab rechallenge, but desensitization protocols have been published in the literature [11-13]. A recent European Academy of Allergy and Clinical Immunology (EAACI) position paper proposed an algorithm for the evaluation of hypersensitivity reactions to chemotherapeutic agents [14]. It recommends serum tryptase levels and immunologic skin testing for patients with immediate hypersensitivity reactions in order to assess their risk in continuing treatment [14]. If deemed low risk, patients can undergo a challenge in which the drug is administered in a monitored environment [14]. If hypersensitivity is suspected and the patient is deemed to have moderate to high risk of reaction on further exposure, they can undergo rapid drug desensitization [14]. During desensitization, the drug is administered in diluted amounts according to a multi-step protocol that increases to the target dose over time, resulting in a temporary state of tolerance [7]. While the mechanism is incompletely understood, this immunologic tolerization to the offending drug is induced by inhibiting mast cell activation responses and thus preventing anaphylaxis [15].

Reviewer 3 Report

30 January 2023

Aleksandar Šekerović

Section Managing Editor, MDPI Novi Sad

E-Mail: sekerovic@mdpi.com

MDPI Branch Office, Novi Sad

Bulevar oslobođenja 83, 21000 Novi Sad, Serbia

Tel: +381 21 300 14 49

www.mdpi.com

Dear Editors.

I would like to thank you for the opportunity to review the article entitled " Canada’s first joint Oncology-Allergy clinic: successful desensitization to trastuzumab following severe anaphylactic reaction in which epinephrine was not administered curroncol-2206107 by Madeline Robinson *, Marc Geirnaert, Brady Anderson, Lundy McKibbin" to Current Oncology

This is a case presentation about successful desensitization in a 43-year-18 old female with locally advanced HER2 positive breast cancer following severe anaphylactic reaction to trastuzumab in which epinephrine was not administered. The case has been reported by Medical Oncology and Allergy Clinic, Canada’s first multidisciplinary clinic.They have proposed this multidisciplinary clinic model as a treatment framework moving forward, with the goal of continuing first-line therapies in cancer patients who develop drug-hypersensitivity (i.e., through desensitization).

I agree that the lack of such clinic is an unmet need for the management of oncology patients who experience hypersensitivity reactions and I want to thank the authors that they bring the topic to daily practice, but there are major problems before accepting as indicated below.

1-I do not think the Table showing anaphylaxis criteria is necessary. They are very well known, and you can just indicate reference as ref no:5

2-The blood sample was not taken for tryptase, and this should be pointed out as a disadvantage

3-There is no information about skin test with Trastuzumab that should be done before desensitization to understand underlying mechanism. please indicate as another disadvantage

4-Line 104-108: Please indicate clearly which protocol for desensitization was used

5-Line 118-120: The case is clearly anaphylaxis and the sentence between these lines should be revised like that.

6-Delay in giving adrenaline is a common problem worldwide and it is an important problem in especially drug induce anaphylaxis even leading to death and please briefly discuss that point

7-I do not think that there is no need Table 2 with desensitization protocol which is a well-known 12 steps desensitization protocol for allergists. But if the readers of the journal are not so familiar that protocol you can keep it

8- Please add information if there is any Oncology and Allergy Clinic somewhere in the world

And you can briefly put information how you established a multi-disciplinary Medical Oncology and Allergy Clinic. That might be helpful for physicians for seeking help in this issue

Author Response

Dear Reviewer,

Thank you for your time and suggestions. Please see below our description of the changes we have made in response.

Point 1: I do not think the Table showing anaphylaxis criteria is necessary. They are very well known, and you can just indicate reference as ref no:5

Response: Table 1 showing anaphylaxis criteria has been removed, and instead indicated only as a reference.

Point 2: The blood sample was not taken for tryptase, and this should be pointed out as a disadvantage

Response: We have added a section to the introduction discussing the importance of drawing a serum tryptase following reaction (lines 47-54):

Point 3: There is no information about skin test with Trastuzumab that should be done before desensitization to understand underlying mechanism. please indicate as another disadvantage.

Response: The patient did not undergo intradermal testing upon initial referral to the Medical Oncology & Allergy clinic due to patient-refusal; this was omitted in error. The following has been added with appropriate references (157-170):

After the reaction, the patient was referred to the Medical Oncology & Allergy clinic for evaluation. The patient declined intradermal skin testing to confirm Trastuzumab hypersensitivity as she understood that regardless of positive or negative results, she would proceed with desensitization given the severity of her reaction. Immunologic skin-prick or intradermal testing is always recommended but is sometimes unavailable or does not change management. In the case of some chemotherapy agents, it may not be feasible due to cutaneous toxicity [15]. The tests are also poorly validated as there is limited information about their sensitivity and specificity [15]. There are currently no standardized skin-prick or intradermal testing doses for many chemotherapy agents and monoclonal antibody therapies [15]; some concentrations have been recommended but evidence is limited [17], including for trastuzumab [10]. Therefore, even when available, the immunologic skin tests are not always reliable in confirming hypersensitivity after a reaction occurs. In this particular case of severe anaphylaxis, desensitization is the appropriate intervention for further oncologic therapy regardless of intradermal test results.

Background regarding skin-testing was also added to the introduction (lines 57-59):

Skin-prick or intradermal testing post-reaction can also be conducted to evaluate for IgE-mediated disease when used in correlation with clinical history [7].

Point 4: Line 104-108: Please indicate clearly which protocol for desensitization was used.

Response: The source for the desensitization protocol has been cited in the appropriate locations and added to the references.

Point 5: Line 118-120: The case is clearly anaphylaxis and the sentence between these lines should be revised like that.

Response: We have clarified the indicated sentence that the patient’s reaction was anaphylaxis.

Point 6: Delay in giving adrenaline is a common problem worldwide and it is an important problem in especially drug induce anaphylaxis even leading to death and please briefly discuss that point.

Response: We have added a section to the discussion about how delay in giving epinephrine is a common problem worldwide, particularly drug-induced anaphylaxis, and have included appropriate references (lines 185-191)

Delay in epinephrine administration is a common issue worldwide, particularly with drug-induced anaphylaxis. There is often failed or delayed recognition in hospital and emergency room settings, and even when recognized, epinephrine is under-used, and patients are inappropriately treated with only fluids and antihistamines [19-20]. One Canadian study postulated that healthcare provider concerns about epinephrine side effects were sometimes a barrier to its administration [19], but there are no absolute contraindications to the administration of epinephrine when treating anaphylaxis [8].

Point 7: I do not think that there is no need Table 2 with desensitization protocol which is a well-known 12 steps desensitization protocol for allergists. But if the readers of the journal are not so familiar that protocol you can keep it

Response: We elected to continue to include the desensitization protocol described in Table 2 (amended to Table 1 after anaphylaxis criteria removed). While allergists may be familiar with the protocol or similar protocols, oncologists reading the journal may not be, so we felt it best to include it for the sake of completeness.

Point 8: Please add information if there is any Oncology and Allergy Clinic somewhere in the world. And you can briefly put information how you established a multi-disciplinary Medical Oncology and Allergy Clinic. That might be helpful for physicians for seeking help in this issue.

Response: We have added additional information about allergy-oncology clinics in other jurisdictions, including the two clinics in the United States, and a comment regarding current collaboration efforts in Europe (lines 211-226):

We have added the following information about how the clinic was established (232-266):

The clinic deals with all allergy related issues experienced by current oncology patients. This not only includes infusion-related or anaphylactic reactions and subsequent skin testing and desensitization, but also suspected allergic reactions to oral anti-cancer drugs and contrast dye. Patients with penicillin or other antibiotic allergies are also seen, especially those being considered for allogenic stem cell transplant. Prior to the clinic’s establishment, local allergists and oncologists noticed there was a high frequency of often time-sensitive consultations for oncology patients. This led to involvement of the hospital Chief Medical Officer, department heads of medical oncology and allergy, and directors of the Systemic Therapies program and Provincial Oncology Drug Program. The data supporting allergist involvement in medical oncology was reviewed, along with the regular consults, leading to agreement that a dedicated clinic would the provide the time, place, and staff to prioritize management of oncology patients’ allergy-related problems. The clinic was established in September 2022 and runs one half-day per week, and approximately 5 patients are seen per clinic. The timing of referral is generally quick, and patients are seen within 5 business days.

Round 2

Reviewer 1 Report

Thank you for addressing the initial comments.

Reviewer 2 Report

The authors have answered all the criticism and improved the manuscript which is now of clinical interest

Reviewer 3 Report

I want to thank the authours, they adressed the comments and responded appropriately*