Clinical Pearls: Immune-Related Adverse Events from Immune Checkpoint Inhibitors
October 10, 2023
By Huy Pham
This article is part of a series appearing in
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Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target and bind to immune checkpoint molecules, either blocking co-inhibitory receptors or stimulating co-stimulatory receptors to enhance antitumour immunity. There are eight ICIs currently available in Canada. These ICIs either target cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death program-1 (PD-1), or programmed death-ligand 1 (PD-L1) and are primarily used in several cancers including but not limited to non-small-cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, and melanoma. They have differing mechanisms of action compared to conventional chemotherapies and thus, have different spectrums of adverse effects with varying clinical presentations, onsets, durations and severities. These are collectively called “immune-related adverse effects” (irAEs) and are autoimmune toxicities arising from the augmentation of the immune system and reduced immune tolerance. IrAEs can affect any organ or system in the body but are predominantly gastrointestinal, dermatologic, hepatic, endocrine, and pulmonary toxicities.1 The severity of irAEs is graded using the National Cancer Institute’s Common Terminology Criteria for Adverse Events2 and ranges from 1–5, with Grade 3 adverse events being those that are severe or medically significant and where hospitalization or prolongation of hospitalization is needed and Grade 4 adverse events being those with life-threatening consequence and where urgent interventions are needed.
IrAEs typically occur within weeks to 3 months of treatment though there may be a possible delayed onset of up to 1 year.3-6 They may persist for months beyond their initial onset. The incidence of irAES is generally higher with anti-CTLA-4 antibodies (occurring in up to 90% of patients) compared to anti-PD-1/PD-L1 antibodies (occurring in up to 70% of patients), with combination therapies having irAEs of greater incidence and severity. Between the two types, gastrointestinal irAES such as colitis and endocrine irAEs such as hypophysitis are more common in anti-CTLA-4 antibodies while thyroid dysfunction, myocarditis and pneumonitis are more common in anti-PD-1/PD-L1 antibodies.5,7-9 Anti-PD-1/PD-L1 antibodies have a grade ≥3 irAE incidence of 6%, anti-CTLA-4 antibodies a grade ≥3 irAE of 24%, and combination therapy a grade ≥3 irAE of 55%.10 There may be a possible correlation between immune-related adverse events from ICIs and positive clinical outcomes such as greater ICI efficacy and increased overall survival.11-15
Given the growing prevalence of ICIs in the treatment of cancers such as non-small cell lung cancers, the high incidences of irAEs associated with ICIs, and the variable nature of irAEs, it is imperative for pharmacists to comprehend how to manage irAEs.
General Principles of Treatment
Regardless of the specific organs affected by the irAEs, there are general principles of treatment depending on the degree of severity. In cases of Grade 1 irAEs of mild severity, ICI therapy can be continued with close monitoring except for some cardiac, hematologic, and neurologic toxicities such as aseptic meningitis. For most Grade 2 toxicities, clinicians should consider holding ICIs and resuming therapy when the symptoms and/or laboratory values have reverted to Grade ≤1. The patient may also be given prednisone at an initial dose of 0.5–1 mg/kg/day or equivalent. For Grade 3 toxicities, ICIs should be held and high doses of corticosteroids such as prednisone at 1–2 mg/kg/day should be started then tapered over 4–6 weeks once symptoms resolve to Grade 1 or lower. Infliximab 5 mg/kg IV every 2 weeks until symptom resolution may be administered for grade ≥3 toxicities if symptoms do not improve after 48–72 hours of corticosteroid therapy. Patients may be rechallenged with ICIs (either the same ICI or a different ICI) once symptoms and/or laboratory values revert to grade ≤1 and the benefits of therapy outweigh the risks. PD-1/PD-L1 monotherapy may be started in patients who experienced an irAE from PD-1/PD-1 and CTLA-4 combination therapy once symptoms resolve to grade ≤1. For grade 4 toxicities, ICIs should be permanently discontinued except for endocrine toxicities that can be managed with hormone replacement.1,16
Patients on high-dose corticosteroids or other immunosuppressants are at risk of opportunistic infections and may benefit from antimicrobial prophylaxis. Pneumocystis jirovecii pneumonia (PJP) prophylaxis should be started in patients taking prednisone 20 mg or more (or equivalent) for 4 weeks or more. The recommended therapy for PJP prophylaxis is sulfamethoxazole/trimethoprim. If the patient has a sulfa allergy, dapsone 100 mg once daily or atovaquone 750 mg BID may be used.17,18 Patients on prolonged steroid therapy (≥4 weeks) post-discharge should also be educated on the signs and symptoms of adrenal insufficiency such as fatigue and abdominal pain, the increased risk of osteoporosis and osteonecrosis, monitoring for hyperglycemia if the patient has pre-diabetes or existing diabetes, potential volume overload resulting in edema and weight gain, and the increased risk of peptic ulcers and gastrointestinal bleeding. Steroid-induced osteoporosis may be limited with adequate calcium and vitamin D intake of calcium 1000 mg daily if age 19–50 or 1200 mg daily if age <50 and vitamin D 400 units daily if age <50 or 800–2000 units daily if age >5019,20 with the option of bone-modifying agents such as alendronate 10 mg once daily or alendronate 70 mg once weekly if on steroid therapy for over 3 months.1 To reduce the risk of peptic ulcers and gastrointestinal bleeds, NSAIDs should be avoided and patients may be started on proton-pump inhibitor prophylaxis such as pantoprazole 40 mg once daily for 4–8 weeks as prophylaxis if they have risk factors for peptic ulcers such as a history of GI bleeds.1 If the patient is continued on steroid therapy beyond 4–8 weeks, deprescribing may be considered before or at the end of steroid therapy.
Patients with pre-existing autoimmune diseases were excluded from the clinical trials of ICIs due to concerns about a higher risk of serious autoimmune toxicities in that population.10,21-23 Patients with autoimmune disorders who take ICIs do experience symptom flares and/or irAEs though these adverse events can be easily managed and usually do not lead to permanent discontinuation.22-25 One proposal for the use of ICIs in patients with autoimmune disorders is to first discontinue all non-selective immunosuppressants, initiate the appropriate selective immunosuppressants, and assess the patient prior to beginning ICI treatment . Afterwards, the patient is started on concomitant ICI therapy.26
Common irAEs and their management
This section provides a general overview of the management strategies for irAEs by the organ system affected and is derived from the guidelines by the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), and Cancer Care Ontario (CCO).1,3,16 The CCO and the ASCO guidelines provide recommendations on supportive therapies for patients experiencing an irAE. ASCO and ESMO guidelines cover a broader range of irAEs than the CCO guideline, discussing irAEs such as severe cutaneous adverse reactions, encephalitis, and pancreatitis.
The most common types of irAE are dermatologic toxicities that usually present as maculopapular rashes, pruritus (with or without eruptions), and vitiligo and have been reported in up to 71.5% of patients on ICIs.1 Dermatologic toxicities are usually the earliest observed irAEs, occurring within 3–6 weeks of treatment.10 The primary treatment strategy is the use of corticosteroids (topical or systemic) along with emollients, cool compresses for itches, and antipruritic drugs if necessary as supportive therapy. Systemic corticosteroids such as methylprednisolone dosed at 1 mg/kg IV once daily are to be initiated if lesions are severe and/or persistent and tapered down over 4–6 weeks once symptoms resolve to Grade 1 or less or return to baseline. The patient should be assessed for signs and symptoms such as fever, skin pain, and skin sloughing as these may indicate the presence of immune therapy-induced severe cutaneous adverse reactions. ICI discontinuation is warranted in these cases.1,3,16 Discontinuation should also occur if dermatologic symptoms do not improve after 12 weeks of supportive management.27 Patients may be rechallenged with the same ICI (or a different ICI as according to the cancer type) in a case-by-case basis. The decision to rechallenge a patient with ICI therapy depends on a multitude of factors. One factor to consider is the prior tumour response, where an objective response to the initial therapy renders resumption of therapy a less favourable choice as the antitumor response due to ICI therapy is likely sustained. Another factor is the type and severity of the presenting dermatologic irAE as more life-threatening irAEs makes rechallenging a less favourable option. Other factors include overall duration of cancer treatment, the efficacy, safety and availability of ICI alternatives, and the efficacy, safety and availability non-ICI alternatives such as traditional chemotherapy for the cancer type.1
Diarrhea and colitis
GI toxicities are also common complications of ICIs. Diarrhea and colitis are common GI toxicities, occurring at any grade in approximately 30% of patients on anti-CTLA-4 antibodies. Grade ≥3 diarrhea has an incidence of less than 10%.28,29 Although the onset can range from 1-107.5 weeks, the median time to onset is 6–8 weeks for anti-CTLA-4 antibodies and 2–3 months for anti-PD-1/PD-L1 antibodies.29 Infectious causes of diarrhea and or colitis such as C. difficile infections should be ruled out.16,27,30 The treatment of diarrhea and colitis are similar and will depend on the frequency of daily bowel movements, with mild cases involving antidiarrheal drugs (such as loperamide 4 mg then 2 mg every 4 hours or after every loose bowel movement until diarrhea-free for 12 hours with a maximum daily dose of 16 mg) as primary management. Oral rehydration and electrolyte supplementation using oral rehydration solutions such as Gatrolyte ® and dietary modifications towards a low-fiber diet may serve as supportive care. Corticosteroids such as prednisone taken as a daily oral 1 mg/kg dose followed by a minimum 4-week taper upon resolution are used in moderate to life-threatening cases and ICI therapy is withheld or permanently discontinued. Other immunosuppressants such as infliximab, which is taken as an intravenous 5 mg/kg dose every 2 weeks, or mycophenolate mofetil, which is taken in twice-daily 5000 mg doses until resolution, may be administered if symptoms are refractory to corticosteroids.1,16 Rechallenge with the same or different ICI may be a possible option with consideration for alternative antineoplastic therapies and the association between the severity of the initial diarrhea/colitis and the likelihood of recurrence
Hepatitis is another common irAE that typically presents as an asymptomatic elevation of aspartate transaminase, alanine transaminase, and occasionally bilirubin. The incidence in monotherapy is 1–10% and usually appears 8–12 weeks into therapy. Severe hepatitis may occur in 1–2% of cases with symptoms of fatigue, fever, nausea, and abdominal pain.1,16,28 Ideally, liver function tests (LFTs) are done at baseline and before each dose of ICIs. Other causes of hepatotoxicity and LFT elevation like viral or drug-induced hepatitis should be investigated before starting irAE management. The mainstay therapy for immune-mediated hepatitis is corticosteroids (for instance, oral prednisone 1 mg once daily for Grade 2 hepatitis) with the option of additional immunosuppression such as mycophenolate mofetil dosed at 500–1000 mg BID or tacrolimus dosed at 0.10–0.15 mg/kg/day if the LFTs remain elevated despite corticosteroid therapy in patients with Grade ≥3 hepatitis. Infliximab should be avoided as hepatotoxicity has been reported.31 Rechallenge with the same or a different ICI may be considered for patients, especially if there are no suitable antineoplastic alternatives. LFT monitoring once or twice weekly may be needed (especially if ICI therapy is continued) since rebound elevation may occur and resolution typically occurs in 4–9 weeks, with higher grade hepatitis having a greater time to resolution.1,16,32,33
Endocrine irAEs are fairly common, occurring in 5–20% of patients at any grade. Symptoms usually occur within 12–24 weeks of therapy but can arise months into the therapy.16 The more common endocrine irAEs are thyroiditis, hypophysitis (inflammation of the pituitary gland), diabetes and adrenal insufficiency. Lifelong hormone replacement therapy is likely needed due to endocrine deficiencies resulting from the adverse event.26 Hypothyroidism and hyperthyroidism can occur in patients using ICIs though hypothyroidism is more common. Immune-related hypothyroidism is managed with levothyroxine at an initial dose of 0.5-1.5 mcg/kg daily with methylprednisolone 1–2 mg/kg IV once daily or equivalent and supportive care for cardio-respiratory symptoms for severe cases. Symptoms of immune-related hyperthyroidism may be managed with beta-blockers such as propranolol dosed at 10–40 mg PO QID, or if urgent and Grave’s Disease is present, methimazole or propylthiouracil. The initial dose of methimazole will depend on the severity of hyperthyroidism, ranging from 15 mg for mild cases and 60 mg for severe cases, divided into 2–3 doses daily, with a gradual reduction over 4–6 weeks to a maintenance dose of 5–15 mg daily. Propylthiouracil may be started at 50–100 mg PO TID and titrated until euthyroidism is achieved, after which the dose should be gradually reduced by 33% every 4–6 weeks to a lowest effective maintenance dose. Patients may be continued on therapy for 12–18 months with possible discontinuation if thyroid function is normal.34 If hyperthyroidism is due to autoimmune thyroiditis, hypothyroidism may follow after hyperthyroidism has been treated and would require thyroid hormone replacement.1,3,16 Hypophysitis has an incidence of ~10% and may present with non-specific symptoms of headache, nausea, fatigue, weakness, visual impairments, insomnia, temperature intolerance, sexual dysfunction, and memory loss. Low levels of TSH, LH, FSH, GH, ACTH, and cortisol may be indicative of hypophysitis.29 Unlike hypothyroidism, hypophysitis presents with low free T4. High-dose corticosteroids such as methylprednisione dosed at 1 mg/kg IV daily are used to reverse the inflammatory process and prevent long-term hormone deficiencies.16 Immune-mediated adrenal insufficiency is an urgent condition characterized by electrolyte imbalance, severe hypotension, and dehydration. Sepsis should be ruled out prior to starting treatment with IV high-dose steroids such as hydrocortisone 100 mg IV QID.16,27,28 Fludrocortisone 50–100 mcg PO daily may be used for postural hypotension until symptom resolution or as indefinite hormone replacement in primary adrenal insufficiency.35,36 For patients with endocrine irAEs, they may be restarted on the same or different ICI upon recovering to Grade ≤1 symptoms.
Pneumonitis is an infrequent and potentially life-threatening irAE that occurs more frequently with anti-PD-1/PD-L1 therapy (1–5%) than with anti-CTLA-4 therapy (<1%).10 The time to onset has a broad range with a median onset of approximately 3–6 months.16 Patients with pneumonitis present with symptoms of new or worsening shortness of breath, chest pain, cough, and hypoxia. Corticosteroid therapies are the main therapeutic options with infliximab 5 mg/kg IV every 2 weeks, mycophenolate mofetil 500–1000 mg PO BID, cyclophosphamide 1–2 mg/kg once daily, or IV immunoglobulins 2 g/kg over a period of 2–5 days in divided doses of 400–500 mg/kg as possible choices if symptoms do not improve or worsen. Empiric antibiotics may be considered if concurrent community-acquired pneumonia is suspected (for instance, ceftriaxone 1 g IV Q24H for 5 days) and prophylactic antibiotics for patients on immunosuppression for >4 weeks, specifically sulfamethoxazole/trimethoprim 800mg/160mg PO daily for PJP prophylaxis during the period when the daily corticosteroid dose exceeds prednisone 20 mg (or equivalent).1,3,16 Rechallenging with the same or different ICI may be considered if the patient has had a grade ≤2 pneumonitits or grade 3 pneumonitits if the benefits of continuing the ICI for cancer treatment outweigh the risks of a recurrent pneumonitis or other irAEs. Rechallenging should not be offered to patients with grade 4 pneumonitis.
Neurotoxicity associated with ICIs have incidences of <5% and encompasses a heterogeneous spectrum of irAEs including paresthesias, encephalitis, aseptic meningitis, and Guillain-Barré–like syndrome.1,26 They may occur within 1–6 weeks of treatment.10,37 Patients with grade 1 irAEs (asymptomatic or mild symptoms) are to be continued on ICI and monitored. Patients with grade ≥2 irAEs should have their ICI therapy withheld with discontinuation for patients with severe symptoms. Corticosteroids (such as prednisone 1 mg/kg PO daily or equivalent for moderate cases) are used to manage these irAEs with the introduction of other immunosuppressants like infliximab 5 mg/kg IV every 2 weeks if symptoms worsen.16 Immunosuppressive therapy is to continue until symptom resolution to Grade 1 or less.
Hospital pharmacists play numerous roles in the management of irAEs and, by extension, ICI therapy.38 Pharmacists can provide patient education on ICIs, particularly on how the adverse event profiles of ICIs are different from that of conventional chemotherapies and how these irAEs generally resolve if managed in a prompt and appropriate manner.
Pharmacists also have a role in the continuous monitoring of patients for irAEs, whether it is during the initiation of ICI treatment, during therapy, or during the post-therapy follow-up period. Pharmacists could provide an immunotherapy consult service for the early identification and management of irAEs in patients taking ICIs.39 One cancer centre implemented a proof-of-concept pharmacist-driven immune checkpoint inhibitor management program with an enrolment of 47 patients.40 In addition, an evaluation of intensive pharmacist follow-ups and interventions in outpatients receiving ICIs over three years observed 1664 recommendations made by pharmacists, which included recommendations on supportive care, educational sessions, and medication initiation and adjustments. Pharmacist interventions were associated with reduced odds of therapy discontinuation secondary to irAEs.41
Finally, pharmacists can be involved with the management of irAEs, where they can evaluate the benefit-risk balance and individualize therapy for the management of irAEs. A retrospective chart review of the implementation of an irAE pharmacy protocol involving 17 patients observed that the pharmacists started 21 new therapies for the management of irAEs including hypothyroidism, hepatotoxicity, rashes, and colitis. The pharmacist-led protocol also reduced the time physicians spent on irAE management and increased their confidence in the pharmacist management of irAEs.42 Pharmacists may also formulate a steroid taper schedule for hospitalized patients who are on corticosteroid therapy.
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