The 2019 National Comprehensive Cancer Network (NCCN) guideline provides information on organ and musculoskeletal system toxicities that occur as side effects of immunotherapy and subsequent treatment decisions to be taken for immune-related adverse events (irAEs).

Increasing use of immunotherapy has led to a discrete group of immune-related adverse events (irAEs).

• Early recognition of symptoms and prompt action are essential for the effective management of immunotherapy-related toxicity
• Severe irAEs often require immunosuppression and hold or discontinuation of treatment

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Cancer immunotherapy has transformed the way cancer is treated. However, increasing use of immune-based therapies, such as immune checkpoint inhibitors (ICI), has exposed a discrete group of immune-related adverse events (irAEs).

The pharmacodynamics and pharmacokinetics of ICI immunotherapy differ greatly from that traditional cytotoxic chemotherapy. Traditional cytotoxic chemotherapy often results in acute-onset emetic and myelosuppressive effects; on the other hand, irAEs tend to have a relatively delayed onset and may be inflammatory or autoimmune in nature.

Even though the exact pathophysiology of ICI-mediated irAEs is unknown, translational research suggests that irAEs result from combination of autoreactive T cells, autoantibodies, and proinflammatory cytokines.

Dermatologic and gastrointestinal AEs are commonly observed with CTLA-4 agents, however, in some cases, endocrine and hepatic AEs are also observed. Colitis, liver toxicity, rash, hypothyroidism, and pneumonitis are some well-known AEs which occur with PD-1 inhibitors and PD-L1 inhibitors.

Combination ICI regimens offers enhanced efficacy, however, the toxicity with combination regimens is also greater than that observed for ICI monotherapy.

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Management of ICI-related toxicity

Early recognition of symptoms and prompt intervention are essential for effective management of immunotherapy-related toxicity. The primary aspect of toxicity management includes:

• Recognition and grading of toxicity and immunosuppression
• Individualized modification to ICI administration

Significant irAEs may require holding immunotherapy; while permanent discontinuation of the class of agent may be required in certain severe irAEs.

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Considerations for Patients on Immunosuppressants

Hyperglycaemia, gastritis, opportunistic bacterial or fungal infections, and osteoporosis can occur with long-term systemic corticosteroid; hence the following supportive care measures are needed for patients receiving an immunosuppressive regimen:

• Blood glucose monitoring
• For patients at higher risk of developing gastritis, histamine 2 blockers or proton pump inhibitors can be given during steroid therapy
• Prophylactic antimicrobial and antifungal agents
• Prophylaxis against pneumocystis jiroveci pneumonia and fungal infections for patients receiving a prednisone
• Prophylaxis against zoster reactivation
• Vitamin D and calcium supplementation to reduce the risk of osteoporosis
• Testing for hepatitis B and C virus before TNF inhibition
• Testing for latent/active tuberculosis before start of infliximab therapy

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Managing irAEs in special patient populations

ICI therapy must be approached cautiously among patients with prior irAEs or pre-existing autoimmune conditions. Ipilimumab can be safely used in organ transplant recipients. The following points should be considered in organ transplant recipients who may require ICI therapy:

• The elapsed time between transplant and initiation of immunotherapy
• The strength of maintenance immunosuppressive therapy required to prevent graft rejection
• The immunogenicity of the transplanted organ

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Infusion-Related Reactions

Infusion reactions are most commonly observed with the PD-L1 inhibitor avelumab. Acetaminophen and diphenhydramine are prescribed before avelumab infusion during the first 4 treatment cycles.

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Dermatologic Toxicity

Dermatologic toxicities are the most prevalent irAEs with ICI therapy. Inflammatory skin conditions typically present within the first 2 cycles of treatment. Ipilimumab has the highest rates of all-grade dermatologic irAEs than PD-1/PD-L1 inhibitors.

Maculopapular rash, with or without pruritus, is the most common presentation. Vitiligo is observed in patients with melanoma on PD-1 inhibitors. Inflammatory skin conditions such as eczematous, lichenoid, and psoriasiform manifestations, as well as bullous dermatitis are also reported. Some cases of alopecia and hair repigmentation have also been reported.

Treatment: The majority of dermatologic irAEs are low grade and resolve with appropriate care without requiring interruption of ICI. However, severe cutaneous reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis and drug rash with eosinophilia and systemic symptoms require hospitalization. Systemic immunosuppressive therapy and ICI discontinuation is suggested in such severe cases.

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Gastrointestinal Toxicity

GI irAEs may present as diarrhea or symptoms of colitis, such as watery diarrhea, cramping, and urgency. GI symptoms develop within 6 to 8 weeks of starting treatment. GI irAEs have been reported more frequently with anti-CTLA-4 monotherapy than with PD-1/PD-L1 inhibitors.

Treatment: Corticosteroids are typically the first line of treatment of GI irAEs. However, long-duration corticosteroid without infliximab is associated with an increased infection risk compared with short-duration steroid plus infliximab; hence early initiation of nonsteroid immunosuppressive therapy may lead to better outcomes. Vedolizumab can be used in infliximab-resistant inflammation of the small intestine and colon.

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Hepatic Toxicity

Hepatotoxicity is another well-documented ICI-mediated irAE that is typically mild but can be severe or even fatal in rare cases.

Asymptomatic elevations in AST and alanine transaminase are the most commonly observed hepatic AEs with PD-1/PD- inhibitors. Combination regimens are associated with a considerably higher incidence of hepatotoxicity.

Treatment: Corticosteroids are commonly recommended in ICI-mediated hepatotoxicity. Mycophenolate may be used to treat severe persistent hepatitis despite corticosteroid therapy. Cyclosporine is another alternative for steroid-refractory hepatotoxicity. Infliximab is not recommended given concerns for liver toxicity.

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Pancreatic Toxicity

Amylase and/or lipase elevations can occur with ICI therapy. These elevations are asymptomatic and it is not recommended to discontinue therapy based on this sole finding. In rare cases, acute pancreatitis can also occur.

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Endocrine Toxicity

Immune-mediated endocrine gland dysfunction may cause hypothyroidism, hyperthyroidism, hypophysitis, type I diabetes, and primary adrenal insufficiency. As the symptoms overlap with other conditions, diagnosis can be challenging. Review of imaging features of endocrine irAEs at presentation and after treatment may aid differential diagnosis.

Hypophysitis is generally observed with ipilimumab, whereas thyroid dysfunction is commonly seen with PD-1/PD-L1 inhibitors. Combination ICI therapy is associated with the highest incidence of endocrinopathy.

Treatment: ICI-mediated endocrine toxicity often results in permanent organ damage and typically requires life-long hormonal supplementation. Corticosteroids may help to alleviate symptoms of acute inflammation in hypophysitis, adrenalitis and thyrotoxicosis; however, it cannot mitigate organ damage.

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Pulmonary Toxicity

Pneumonitis has been associated with ICI therapy.

Treatment: Mild cases can be managed with oral corticosteroid, whereas moderate and severe cases require oral or intravenous corticosteroid. Patients with grade 3 or higher pneumonitis, often require additional immunosuppression with infliximab alone or infliximab with cyclophosphamide. Rarely, pneumonitis worsens despite immunosuppression, and may result in infection and/or death

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Renal Toxicity

Renal toxicity may present as acute tubulointerstitial nephritis. Kidney injury is usually preceded with an extrarenal irAE and pyuria.

Treatment: Use of corticosteroid, usually show recovery of renal function, hemodialysis may be required in some cases.

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Ocular Toxicity

Dry eye and uveitis are the most frequently reported ocular ICI-associated events.

Treatment: Mild irAEs are generally managed by a topical steroid; severe conditions may require systemic corticosteroid therapy and discontinuation of ICI therapy.

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Nervous system toxicity

Neurologic irAEs can be challenging to diagnose due to nonspecific symptoms, variability in presentation, and the wide range of differential diagnoses to consider. Myasthenia gravis, Guillain–Barré syndrome (GBS)-like syndrome, central and/or peripheral neuropathy, aseptic meningitis, encephalitis, and transverse myelitis are some documented irAEs.

Treatment:

• Most of the irAEs (except peripheral neuropathies) of the nervous system are high grade events. High-dose intravenous corticosteroids and ICI discontinuation is recommended for such high-grade events
• Alternative immunosuppressive therapies such as IVIG, plasmapheresis, rituximab, and cyclosporine are often required for progressive and steroid-refractory cases
• Fatalities have been reported in patients who developed encephalitis and myasthenia gravis; prompt treatment is critical for reducing long-term morbidity and mortality

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Cardiovascular toxicity

Cardiac irAEs have been associated with ipilimumab, pembrolizumab, and nivolumab. Manifestations of cardiovascular irAEs include myocarditis, cardiomyopathy, cardiac fibrosis, heart failure, and cardiac arrest. Myocarditis is often observed in patients receiving combination ICI therapy and in patients with diabetes.

Treatment: Corticosteroids and/or supportive care measures are helpful to improve symptoms in most cases, however, despite prompt interventions; there is a high propensity for permanent cardiotoxicity and fatalities.

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Musculoskeletal toxicity

Musculoskeletal and rheumatic irAEs include inflammatory arthritis, myositis, and myalgias. Severe myositis, in rare cases, can be fatal and has been documented more commonly in patients receiving PD-1/PD-L1 inhibitor.

Treatment: Immunosuppressive therapy with corticosteroids is usually prescribed for inflammatory arthritis or other rheumatologic irAEs; however, some cases may require additional lines of therapy beyond corticosteroid.