Royal North Shore Hospital

A protocol for pre-treatment testing for antibodies to galactose-alpha-1,3-galactose to mitigate the risk of cetuximab hypersensitivity reactions - a retrospective cohort review.

Cetuximab improves survival in KRAS wildtype metastatic colorectal cancer. However, high rates of hypersensitivity reactions (HSRs) limit its use, with HSR rates up to 10-20 %. A major driver of cetuximab HSR is from pre-formed IgE antibody response to galactose-1,3-alpha-galactose (alpha-gal). Evidence from retrospective studies supports alpha-gal pre-screening in this setting. This study reports the impact of prospective alpha-gal antibody screening on cetuximab HSR. Records were reviewed across three medical oncology centres that have adopted alpha-gal antibody screening measures. Data for patients with metastatic colorectal cancer treated with cetuximab were retrieved. All centres assessed alpha-gal levels using the ImmunoCAP® immunoassay. Due to variability in alpha-gal screening practices across study sites, a standardised protocol was applied to all cases. This protocol allowed cetuximab administration if alpha-gal levels were ≤0.10 kUA/L, but prohibited it if alpha-gal levels were >0.10 kUA/L in favour of panitumumab administration. Patients were allocated to either the Alpha-gal Pre-screening Applied ('Pre-screening') or Alpha-gal Pre-screening Not Applied ('Reference') cohorts based on protocol requirements being met. The primary outcome between these patient groups was the incidence of cetuximab HSRs. Of 254 assessable patients, 39 underwent the pre-treatment screening protocol. Of the Pre-screening group, 3% (n=1/39) experienced a cetuximab HSR compared to 16% (n=35/215) in the Reference group (Odds ratio (OR) 0.14; 95% CI 0.0033-0.86, p= 0.02). Patients with alpha-gal antibody titres >0.10 kUA/L were more likely to experience a cetuximab HSR (OR 69.71; 95% CI 5.18-4296.81, p=0.0001). Pre-treatment screening for alpha-gal antibodies significantly reduces the incidence of cetuximab HSRs. A testing threshold of 0.10 kUA/L is effective in identifying patients at risk. Implementing this protocol can improve the safety of cetuximab therapy in high-risk populations. Hypersensitivity reactions (HSRs) limit cetuximab use in KRAS wildtype advanced colorectal cancer, with a significant driver being pre-formed IgE antibodies against galactose-1,3-alpha-galactose (alpha-gal). Our multicentric retrospective study assessed the impact of prospective alpha-gal antibody screening on HSR incidence following cetuximab administration. Of 254 assessable patients, pre-treatment alpha-gal antibody screening significantly reduced the incidence of cetuximab HSRs (3% vs 16%; OR 0.14, p=0.02). Our findings support pre-treatment alpha-gal screening to improve safety of cetuximab therapy in high-risk populations.

Immunoglobulin E Sensitization to Mammalian Oligosaccharide Galactose-α-1,3 (α-Gal) Is Associated With Noncalcified Plaque, Obstructive Coronary Artery Disease, and ST-Segment-Elevated Myocardial Infarction.

Treating known risk factors for coronary artery disease (CAD) has substantially reduced CAD morbidity and mortality. However, a significant burden of CAD remains unexplained. Immunoglobulin E sensitization to mammalian oligosaccharide galactose-α-1,3-galactose (α-Gal) was recently associated with CAD in a small observational study. We sought to confirm that α-Gal sensitization is associated with CAD burden, in particular noncalcified plaque. Additionally, we sort to assess whether that α-Gal sensitization is associated with ST-segment-elevated myocardial infarction (STEMI) Methods: We performed a cross-sectional analysis of participants enrolled in the BioHEART cohort study. We measured α-Gal specific-immunoglobulin E antibodies in serum of 1056 patients referred for CT coronary angiography for suspected CAD and 100 selected patients presenting with STEMI, enriched for patients without standard modifiable risk factors. CT coronary angiograms were assessed using coronary artery calcium scores and segmental plaque scores. α-Gal sensitization was associated with presence of noncalcified plaque (odds ratio, 1.62 [95% CI, 1.04-2.53], =0.03) and obstructive CAD (odds ratio, 2.05 [95% CI, 1.29-3.25], =0.002), independent of age, sex, and traditional risk factors. The α-Gal sensitization rate was 12.8-fold higher in patients with STEMI compared with matched healthy controls and 2.2-fold higher in the patients with STEMI compared with matched stable CAD patients (17% versus 1.3%, =0.01 and 20% versus 9%, =0.03, respectively). α-Gal sensitization is independently associated with noncalcified plaque burden and obstructive CAD and occurs at higher frequency in patients with STEMI than those with stable or no CAD. These findings may have implications for individuals exposed to ticks, as well as public health policy. Registration: URL: https://www.anzctr.org.au; Unique identifier: ACTRN12618001322224.

Increased rates of cetuximab reactions in tick prevalent regions and a proposed protocol for risk mitigation.

Cetuximab is an anti-epidermal growth factor receptor mouse-human chimeric monoclonal antibody used to treat advanced colorectal cancers. Initial data suggest that severe infusion reactions occurred in 4.5%, many on first exposure. The majority of those with anaphylactic reactions possess predeveloped IgE antibodies to galactose-alpha-1,3-galactose. It is thought that the vector for preexposure to alpha-gal is antigen inoculation via tick bites. This retrospective study reviews the experience of two community cancer centers in high tick exposure areas in Sydney with cetuximab anaphylaxis and proposes a protocol to avoid this. Severe cetuximab infusion reactions occurring in the Northern Cancer Institute Frenchs Forest and St Leonards clinics, Sydney, from May 2014 to February 2019 were recorded. Area of residence was then compared to areas of known high tick prevalence. A total of 87 patients received cetuximab in this period. Six patients (6.9%) experienced at least a grade 3 reaction, three females, age range 41-72 years (median 57.5 years). All were receiving cetuximab for metastatic colorectal cancer and their anaphylaxis occurred with the first infusion in all cases. These cases support the existing theory of increased rates of cetuximab anaphylaxis in areas of high tick prevalence. Given this, we recommend the following protocol for patients being considered for cetuximab therapy: known mammalian meat allergy as an absolute contraindication; all patients receiving cetuximab should have RAST (ImmunoCAP ) testing for alpha-gal specific-IgE-specific antibodies before first infusion and those who test positive to be considered alternate therapy.

Mammalian meat allergy - beyond urticaria?

Specific-IgE to galactose-α-1,3-galactose (alpha-gal) has limited utility in diagnosing meat allergy in a tick-endemic population.

Tick-induced allergies: mammalian meat allergy and tick anaphylaxis.

Mammalian meat allergy after tick bites and tick anaphylaxis are the most serious tick-induced allergies. They are often severe, should be largely avoidable and offer fascinating insights into the development and prevention of allergies. Australian clinicians reported the first cases of tick anaphylaxis and discovered the association between tick bites and the development of mammalian meat allergy. The subsequent finding of the allergen epitope within the meat responsible for the allergic reaction, α-gal (galactose-α-1,3-galactose), stimulated further interest in this emergent allergy. Reports of mammalian meat allergy associated with bites from several tick species have now come from every continent where humans are bitten by ticks. The number of diagnosed patients has continued to rise. Clinically, mammalian meat allergy and tick anaphylaxis present quite differently. The prominent role of cofactors in triggering episodes of mammalian meat allergy can make its diagnosis difficult. Management of mammalian meat allergy is complicated by the manifold potential therapeutic implications due to the widespread distribution of the mammalian meat allergen, α-gal. Exposures to α-gal-containing medications have proved lethal in a minority of people, and fatal tick anaphylaxis has been reported in Australia. Prevention of tick bites is prudent and practicable; killing the tick in situ is crucial to both primary and secondary prevention of allergic reactions. Mechanisms in the development of mammalian meat allergy constitute a paradigm for how allergies might arise.

Tick-induced allergies: mammalian meat allergy, tick anaphylaxis and their significance.

Serious tick-induced allergies comprise mammalian meat allergy following tick bites and tick anaphylaxis. Mammalian meat allergy is an emergent allergy, increasingly prevalent in tick-endemic areas of Australia and the United States, occurring worldwide where ticks are endemic. Sensitisation to galactose-α-1,3-galactose (α-Gal) has been shown to be the mechanism of allergic reaction in mammalian meat allergy following tick bite. Whilst other carbohydrate allergens have been identified, this allergen is unique amongst carbohydrate food allergens in provoking anaphylaxis. Treatment of mammalian meat anaphylaxis involves avoidance of mammalian meat and mammalian derived products in those who also react to gelatine and mammalian milks. Before initiating treatment with certain therapeutic agents (e.g., cetuximab, gelatine-containing substances), a careful assessment of the risk of anaphylaxis, including serological analysis for α-Gal specific-IgE, should be undertaken in any individual who works, lives, volunteers or recreates in a tick endemic area. Prevention of tick bites may ameliorate mammalian meat allergy. Tick anaphylaxis is rare in countries other than Australia. Tick anaphylaxis is secondarily preventable by prevention and appropriate management of tick bites. Analysis of tick removal techniques in tick anaphylaxis sufferers offers insights into primary prevention of both tick and mammalian meat anaphylaxis. Recognition of the association between mammalian meat allergy and tick bites has established a novel cause and effect relationship between an environmental exposure and subsequent development of a food allergy, directing us towards examining environmental exposures as provoking factors pivotal to the development of other food allergies and refocusing our attention upon causation of allergy in general.

An association between tick bite reactions and red meat allergy in humans.

Twenty-five patients living in a tick-endemic region of Sydney, New South Wales developed red meat allergy after experiencing large local reactions to tick bites. This represents a potentially novel cross-reaction between an arthropod and a food protein. (MJA 2009; 190: 510-511).