What are the potential side effects of immune therapy and how are they managed?

Side Effects of Immune Therapy and Management

Immune checkpoint inhibitors cause immune-related adverse events (irAEs) that can affect any organ system, with the most common being gastrointestinal, dermatologic, hepatic, endocrine, and pulmonary toxicities, requiring a graded approach to management based on severity. 1

Common Side Effects

The most frequently reported adverse reactions include:

• Infections (upper respiratory, sinusitis, pharyngitis) occurring in >10% of patients 1
• Infusion-related reactions with symptoms including fever, chills, chest pain, blood pressure changes, shortness of breath, rash, and itching 2
• Headache and abdominal pain as common systemic symptoms 2
• Fatigue occurring frequently across all immunotherapy regimens 1

Organ-Specific Immune-Related Adverse Events

Gastrointestinal Toxicities

• Colitis and diarrhea are among the most common irAEs, occurring in approximately one-third of treated patients 3
• Severe colitis (grade 3-4) occurs in 30-40% of patients receiving combination therapy with nivolumab/ipilimumab, often requiring corticosteroids and/or immunosuppressive agents 1

Endocrine Disorders

• Hypothyroidism, hypophysitis, and type 1 diabetes can develop, with some being potentially permanent 1, 4
• These endocrinopathies may require lifelong hormone replacement therapy 1

Hepatic Toxicity

• Hepatitis with elevated liver enzymes can occur, with some cases progressing to severe hepatic reactions requiring liver transplantation 1, 2
• Jaundice and marked liver enzyme elevations warrant immediate discontinuation 2

Pulmonary Complications

• Pneumonitis and interstitial lung disease including rapidly progressive disease have been reported 1, 2

Dermatologic Reactions

• Skin rash, vitiligo, and new-onset or worsening psoriasis (all subtypes including pustular) can develop 2, 4
• Red scaly patches or raised bumps filled with pus may indicate psoriasis 2

Musculoskeletal Effects

• Immune-related arthritis which may be permanent, particularly concerning after potentially curative surgery 1
• Myositis and joint pain have been documented 1, 2

Neurologic Toxicities

• Peripheral neuropathies, Guillain-Barré syndrome, myasthenia gravis, and transverse myelitis have been reported 2, 4
• Changes in vision, weakness in arms or legs, numbness, tingling, and seizures require immediate evaluation 2
• Stroke can occur within 24 hours of infusion 2

Cardiovascular Events

• Myocardial infarction, arrhythmias, and cerebrovascular accidents occurring within 24 hours of infusion initiation 2
• Cardiac inflammation and pericardial effusion have been documented 1, 2

Renal Complications

• Nephritis is particularly concerning in patients with a single kidney 1

Hematologic Toxicities

• Neutropenia, thrombocytopenia, and anemia can develop, with patients needing to seek immediate attention if they bruise easily, bleed, or appear pale 2

Ophthalmologic Issues

• Uveitis and optic nerve complications requiring urgent ophthalmology referral for any visual disturbances 1

Severity and Timing

• 30-40% of patients receiving combination immunotherapy (nivolumab/ipilimumab) experience severe toxicities requiring corticosteroids 1
• 55% of patients in melanoma trials experienced grade 3-4 adverse effects related to dual-agent immunotherapy 1
• Onset varies by agent: ipilimumab causes cutaneous complications early followed by digestive symptoms, while nivolumab-related irAEs typically start around a few months after administration 4
• Delayed allergic reactions can occur 3-12 days after treatment 2

Management Algorithm by Grade

Grade 1 Toxicities

• Continue immunotherapy with close monitoring for most organ systems 1
• Exception: Hold therapy for certain neurologic, hematologic, and cardiac toxicities even at grade 1 1

Grade 2 Toxicities

• Hold immunotherapy for most grade 2 toxicities 1
• Initiate corticosteroids at 0.5-1 mg/kg/day prednisone equivalent 1
• Resume therapy when symptoms revert to grade 1 1
• For PD-1 monotherapy, 50% of experts recommend holding only for grade 3, while 50% support holding for worrisome grade 2 toxicities (diarrhea, arthritis, dyspnea, hepatitis) or multiple grade 2 toxicities 1

Grade 3 Toxicities

• Hold immunotherapy immediately 1
• Initiate high-dose corticosteroids at prednisone 1-2 mg/kg/day or equivalent 1
• Taper steroids over 4-6 weeks once symptoms resolve 1
• Consider infliximab if no improvement within 48-72 hours of high-dose steroids for certain toxicities 1
• 72% of experts recommend this approach for clinically-significant grade 3 irAEs (excluding stable endocrinopathies on replacement) 1

Grade 4 Toxicities

• Permanently discontinue immunotherapy in most cases 1
• Exception: Endocrinopathies controlled by hormone replacement allow continuation 1

Specific Management Considerations

Steroid-Refractory Colitis

• Up to 42% of severe colitis cases are steroid-refractory 3
• Infliximab is the first-line rescue therapy for steroid-refractory cases 3, 5
• Vedolizumab represents second-line therapy for infliximab-refractory cases 3
• Tofacitinib has limited data but may be considered in refractory cases 3

Combination Therapy Toxicity

• Chemotherapy plus immunotherapy creates diagnostic challenges as symptoms can mimic either cytotoxic effects or irAEs, requiring different management approaches 1
• No biomarkers currently exist to distinguish between these toxicity types 1

Pediatric Considerations

• Higher infection rates in pediatric patients compared to adults 2
• Children with Crohn's disease showed anemia, leukopenia, flushing, viral infections, neutropenia, bone fracture, and bacterial infections more frequently than adults 2
• Vaccine breakthrough infections including disseminated BCG have occurred in infants exposed in utero 2

Critical Pitfalls to Avoid

• Do not start corticosteroids before ophthalmologic evaluation for eye symptoms, as this may worsen infectious causes or mask accurate diagnosis 1
• Maintain high suspicion that any new symptoms are treatment-related, as irAEs can affect any organ system 1
• Monitor for delayed reactions occurring days to weeks after treatment 2
• Screen for hepatitis B before starting therapy, as reactivation can occur 2
• Avoid live vaccines during and after treatment; wait at least 6 months after birth before administering live vaccines to infants exposed in utero 2
• Do not combine with anakinra or abatacept due to increased infection risk 2

Long-Term Considerations

• Permanent side effects including diabetes and immune-related arthritis are particularly concerning in the adjuvant setting after potentially curative surgery 1
• Constant vigilance required as adverse events may occur late, even after terminating active treatment 1
• Lupus-like syndrome may develop with chest pain, shortness of breath, joint pain, and sun-sensitive rash, requiring discontinuation 2