Short summary

Drug hypersensitivity reactions commonly complicates critical treatments involving chemotherapeutics and biologicals. If culprit drugs cannot be substituted, patients risk to face suboptimal treatments or hazardous re-exposures. Allergy expertise have proven useful in ruling out/confirming drug hypersensitivity, finding safe drug alternatives or inducing tolerance to culprit drugs. The aim is to maintain best possible treatment options concomitantly with improving safety for the patient.

Rationale

INTRODUCTION This ph.d. project investigates patients experiencing immediate drug hypersensitivity reactions (IDHRs) elicited by chemotherapeutics and biologicals (Ch/Bi). The primary target group is cancer patients together with patients suffering from chronic inflammatory diseases or diabetes. The aim is to maintain best possible treatment options in patients suffering from IDHRs in critical treatments concomitantly with improving safety for the patient.

BACKGROUND Adverse drug reactions (ADR) are common and complicates medical treatments especially in cases of critical treatments with Ch/Bi. Most ADRs can be classified as expected side effects (type-A reactions). Some reactions occur only in predisposed individuals reacting to doses, normally tolerated by the majority of recipients (type-B reactions). The classical approach when managing drug hypersensitivity reactions, (DHRs) is strict avoidance of the culprit drug. However, in some situations e.g. allergy to insulin in diabetics substitution is not possible. When Ch/Bi are culprits, cancer patients and patients with severe chronic diseases face the risk of receiving a suboptimal treatment potentially reducing quality of life and life expectancy. On the other hand, continuous use of a drug could jeopardize the patients' health, and in worst case, life. DHRs are categorized into allergic-immune reactions (T- and/or B-cell activation after sensitization), pharmacological interactions with immune receptors (p-i reactions) (direct stimulation of T-cells), and pseudo-allergic reactions (direct stimulation of cells of the immune system without prior sensitization) Immediate drug hypersensitivity reactions (IDHRs) occurs during or within 6 hours of the drug infusion and are mainly allergic-immune reactions and pseudo-allergic reactions. IDHRs range from classical allergic reactions with symptoms such as urticaria, angioedema, bronchospasm and anaphylactic shock (termed type-I reactions) to symptoms elicited by cytokine release such as flushing, dyspnea, hypertension, fever, back pain, vomiting and collapse (termed cytokine-release-reactions). While some reactions are mild and easily controllable, others are severe and reoccurring. The latter is termed Significant Immediate Drug Hypersensitivity Reactions. Non Immediate Drug Hypersensitivity Reactions (NIDHRs) encompass allergic-immune reactions and p-i-reactions and range from mild maculopapular exanthemas to Severe Cutaneous Adverse Reactions (SCAR) such as Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) IDHR is frequently encountered in departments treating patients with Ch/Bi with the rate of IDHRs to selected biologicals being reported to 5-10 % for rituximab, 2-3 % for infliximab, 3-22 % for cetuximab, and 0,6-5 % for trastuzumab. Concerning taxanes and platinum salts (the chemotherapeutics most prone to cause hypersensitivity) the incidence is 5-10 % and 1-46 % respectively. In Southern Europe and the US allergy centers are experienced in evaluating patients with suspected IDHRs to Ch/Bi, whereas such patients are rarely encountered in northern Europe including Denmark. While international studies have demonstrated the usefulness of an allergy work up in these patients, allergy experts do not routinely evaluate Danish patients. The aim of an allergy work up is to identify the culprit drug/excipient to avoid hazardous re-exposures or to rule out drug hypersensitivity thereby allowing patients to resume first choice of treatment. When the culprit drug responsible for the IDHR has been identified, the allergist can aid to reintroduce the culprit drug by inducing specific drug tolerance - or in finding a safe alternative. For several years, we have successfully induced tolerance in diabetic patients experiencing IDHRs to insulin preparations by using a procedure called rapid drug desensitization (RDD). Apart from the usefulness of RDD in treating insulin-allergic diabetics, RDD is found to be both safe and cost effective when treating patients experiencing IDHRs (classical allergic reactions and cytokine release reactions) elicited by Ch/Bi. RDD can be carried out in an outpatient allergy center[11,12] and allows according to the literature almost 100 % of patients to receive full therapeutic doses. Break Through Reactions happen, but they are generally mild in nature and limited to the first RDD cycle.

AIMS 1) To optimize the management of IDHRs elicited by drugs (in casu insulin allergy in diabetic patients), where drug substitution is not possible. 2) To investigate frequency and clinical spectrum of IDHRs elicited by antineoplastic treatments in Danish cancer patients. 3) To manage significant IDHRs elicited by Ch/Bi for facilitation of best treatment options.

Description of the cohort

Study 1: In the period from 2003-2021, 40 patients were diagnosed with insulin allergy at the Allergy Center at OUH. In 20 of those patients, tolerance to insulin was induced. Medical journals will be reviewed regarding case history, diagnostic tests and interim events. Insulin allergic diabetics will be offered a diagnostic re-evaluation at the Allergy Center.

Study 2: During 30 days, cancer patients experiencing Immediate Drug Hypersensitivity Reactions at the Departments of Hematology and Oncology at OUH will be observed by staff from the Allergy Center in real time. The total number of treatments administered on study days will be noted. The identified patients with IDHRs will be followed for a period of three months for evaluation of number and severity of reactions, change of therapy(-ies) and outcome.

Study 3: During a year, cancer patients- and patients with chronic inflammatory diseases experiencing significant IDHRs elicited by chemotherapeutics and biologicals will be included after referral to the Allergy Center at OUH. A controlled allergy work up will be initiated, and RDD will be performed whenever indicated.

Collaborating researchers and departments

Department of Oncology, OUH

Department of Hematology, OUH