Adverse Effects of Monoclonal Antibodies

Overview of Adverse Event Profile

Monoclonal antibodies cause two distinct categories of adverse effects: immune-related adverse events (irAEs) arising from their mechanism of action, and protein administration-related reactions including infusion reactions and hypersensitivity. 1, 2, 3

The incidence and severity of adverse effects varies substantially based on which immune checkpoint is targeted, with anti-CTLA-4 agents causing more frequent and severe toxicities than anti-PD-1/PD-L1 agents. 1

Infusion-Related Reactions and Hypersensitivity

Acute Infusion Reactions

Infusion reactions occur in 77% of patients during first rituximab administration, decreasing in subsequent infusions, with severe reactions in 10% of patients (80% occurring during first infusion). 1
Reactions include headache, rash, pyrexia, nausea, urticaria, pruritus, chills, flushing, fatigue, dyspnea, chest discomfort, and tachycardia. 1
For immune checkpoint inhibitors (anti-PD-1/PD-L1), infusion reactions comprise less than 1% of adverse events in phase III studies. 1
Premedication with antipyretics and antihistamines should always be given for rituximab; however, premedication is not recommended for bevacizumab or atezolizumab. 1

Hypersensitivity and Anaphylaxis

Presumed hypersensitivity reactions including urticaria, pruritus, bronchospasm, and anaphylaxis occurred in 18% of patients receiving murine monoclonal antibodies. 4
Bronchospasm and anaphylaxis episodes occurred in patients treated more than once, at least 2 weeks after previous treatment, suggesting sensitization. 4
The risk of allergic reactions increases with the murine content of the antibody (murine > chimeric > humanized > fully human). 3

Immune-Related Adverse Events by Organ System

Incidence by Agent Type

Ipilimumab (anti-CTLA-4) at 3 mg/kg causes irAEs in 60-85% of patients, with grade 3-4 toxicities in 10-27% and a 2.1% treatment-related mortality rate. 1
At the higher adjuvant dose of 10 mg/kg, ipilimumab causes grade 3-4 irAEs in 41.6% and grade 5 irAEs in 1.1% of patients. 1
Anti-PD-1 agents (nivolumab, pembrolizumab) cause high-grade toxicities less commonly than ipilimumab. 1
Combination therapy with nivolumab plus ipilimumab causes grade 3-4 irAEs in 55% of melanoma patients. 5

Dermatologic Toxicities

Skin adverse events occur in 43-45% of ipilimumab-treated patients and 34% of anti-PD-1-treated patients, usually developing within the first few weeks. 1
Rash occurs in 24% with ipilimumab, 15% with anti-PD-1, and 40% with combination therapy, though grade 3-4 rashes are rare (<3-5%). 1
Pruritus is reported in 25-35% with ipilimumab, 13-20% with anti-PD-1, and 33% with combination therapy. 1
Vitiligo occurs in up to 25% of melanoma patients and appears associated with good clinical responses to anti-PD-1 therapy. 1

Gastrointestinal Toxicities

Severe colitis (grade 3-4) occurs in 30-40% of patients receiving nivolumab/ipilimumab combination therapy, often requiring corticosteroids and/or immunosuppressive agents. 5
Diarrhea is the most common immune-related gastrointestinal reaction; severe cases require high-dose corticosteroids. 1
Nausea and diarrhea occur in at least 15% of patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). 6

Endocrine Toxicities

Hypothyroidism, hypophysitis, and type 1 diabetes can develop and may be potentially permanent, requiring lifelong hormone replacement therapy. 5
Fatigue is the most frequently reported adverse event with anti-PD-1/PD-L1 (16-37% for anti-PD-1,12-24% for anti-PD-L1), though only a minority can be attributed to hypothyroidism. 1

Hepatic Toxicities

Hepatotoxicity is among the most frequently occurring irAEs, though specific incidence rates vary by agent. 1
Alanine aminotransferase elevation is a grade 3 or higher adverse event in more than 15% of pediatric patients with B-cell non-Hodgkin lymphoma receiving rituximab with chemotherapy. 6

Pulmonary Toxicities

Pneumonitis is an infrequent but potentially serious irAE that can be lethal. 1
Dyspnea occurs as part of infusion reactions and as an immune-related pulmonary toxicity. 1

Musculoskeletal Toxicities

Myositis with associated myocarditis carries high mortality and requires prompt recognition with immediate checkpoint inhibitor discontinuation. 1
Muscle spasms occur in at least 15% of GPA and MPA patients. 6
Immune-related arthritis may be permanent, particularly concerning after potentially curative surgery in the adjuvant setting. 5
The majority of checkpoint inhibitor-associated myositis patients will not have typical dermatomyositis rash. 1
Bulbar symptoms (dysphagia, dysarthria, dysphonia) and/or respiratory failure may indicate myositis or associated myasthenia gravis, which occurs in 12.5% of myositis cases. 1

Cardiovascular Toxicities

Cardiac inflammation, pericardial effusion, and myocarditis have been documented and can be life-threatening. 5
Myocarditis associated with myositis has high mortality; normal cardiac enzymes cannot always rule out myocarditis. 1
Cardiac adverse reactions require discontinuation of infusions in cases of serious or life-threatening events. 6

Neurologic Toxicities

Neurological disorders are very infrequent but may be very serious and even lethal. 1
Headache occurs in at least 15% of GPA, MPA, and pemphigus vulgaris (PV) patients. 6

Ophthalmologic Toxicities

Uveitis and optic nerve complications require urgent ophthalmology referral for any visual disturbances. 5
Do not start corticosteroids before ophthalmologic evaluation for eye symptoms, as this may worsen infectious causes or mask accurate diagnosis. 5

Renal Toxicities

Nephritis is particularly concerning in patients with a single kidney. 5
Renal toxicity can occur, requiring discontinuation in patients with rising serum creatinine or oliguria. 6
Renal toxicity risk increases when rituximab is used in combination with cisplatin. 6

Infectious Complications

General Infection Risk

Infections including upper respiratory, sinusitis, and pharyngitis occur in more than 10% of patients. 5
Upper respiratory tract infection and nasopharyngitis occur in at least 10% of rheumatoid arthritis patients and at least 15% of PV patients. 6
Urinary tract infection and bronchitis occur in at least 10% of rheumatoid arthritis patients. 6
Infections occur in at least 15% of GPA and MPA patients. 6

Serious and Opportunistic Infections

Serious infections are an important adverse reaction in rheumatoid arthritis patients treated with rituximab. 6
Bispecific antibodies carry increased infection risk compared to conventional multiple myeloma regimens due to cytopenias, hypogammaglobulinemia, and direct immunosuppression. 1
Febrile neutropenia, sepsis, and enteritis are grade 3 or higher adverse events in more than 15% of pediatric B-cell non-Hodgkin lymphoma patients. 6

Specific Infection Management Recommendations

Universal herpes simplex and varicella zoster virus prophylaxis is recommended for patients receiving bispecific antibody therapy. 1
Universal pneumocystis jirovecii pneumonia prophylaxis is recommended; routine anti-fungal prophylaxis is not recommended. 1
Screening for hepatitis B virus reactivation risk should be performed in all patients. 1
Monthly intravenous immunoglobulin treatment is recommended for immunoparesis in the absence of life-threatening infectious manifestations. 1

Hematologic Toxicities

Neutropenia occurs in at least 25% of chronic lymphocytic leukemia patients treated with rituximab. 6
Lymphopenia and fever are common adverse reactions in non-Hodgkin lymphoma patients (≥25%). 6
Anemia occurs in at least 15% of GPA and MPA patients. 6
Colony-stimulating factors should be used in patients with grade 3 neutropenia. 1
A 25% decrease in white blood cells was associated with side effects in 40/66 courses, whereas only 9/81 courses with less than 25% WBC decrease were associated with toxicity. 4

Cytokine Release Syndrome

In March 2006, TGN1412 (a CD28-specific superagonist monoclonal antibody) caused life-threatening cytokine release syndrome during first-in-human study, resulting in recommendations to improve safety of initial clinical studies. 2
Cytokine release syndrome is thought to cause infusion reactions with immunotherapy agents. 1
Patients with high tumor burden are at higher risk of severe cytokine release syndrome with rituximab. 1

Oncologic Risks

Tumor lysis syndrome can occur; aggressive intravenous hydration, anti-hyperuricemic agents, and renal function monitoring are required. 6
Long-term effects of monoclonal antibodies may include possible derangement of immune response and/or increase in neoplasms, though data are limited. 7
Development of tumors is a potential secondary effect arising from immunosuppression mechanisms. 3

Autoimmune Phenomena

Flares in Pre-existing Autoimmune Disease

Patients with pre-existing autoimmune disease experience flares in approximately 50% of cases: 47/86 with rheumatoid arthritis, 4/8 with psoriatic arthritis, 64% with polymyalgia rheumatica, 31% with systemic lupus erythematosus, and 43% with Sjögren's syndrome. 1
Less than 10% of patients with pre-existing autoimmune disease flares had to stop checkpoint inhibitor therapy. 1
Patients with history of autoimmune disease or actively treated autoimmune disease are at risk for worsening while on immune checkpoint blockade. 1
Patients with prior irAEs on ipilimumab are at risk of developing irAEs following anti-PD-1 treatment and vice versa, with up to 35% experiencing grade 3-4 toxicity and over 20% developing grade 3-4 irAEs when sequencing is reversed. 1

De Novo Autoimmune Disease

Development of autoimmune phenomena is a secondary effect arising from mechanisms of action. 3
Exacerbations of autoimmune disease temporally related to influenza vaccination have been reported, though prospective controlled trials do not support cause-and-effect relationships. 1

Timing and Duration of Adverse Events

irAEs usually start within the first 8-12 weeks of treatment initiation, with skin toxicities often being first to develop. 1
First onset of irAEs has been documented as long as 1 year after discontinuation of treatment. 1
Constant vigilance is required as adverse events may occur late, even after terminating active treatment. 5
For ipilimumab, onset varies but typically begins within the first 8-12 weeks. 1

Management Algorithm by Toxicity Grade

Grade 1 Toxicities

Continue immunotherapy with close monitoring for most organ systems. 5

Grade 2 Toxicities

Hold immunotherapy and initiate corticosteroids at 0.5-1 mg/kg/day prednisone equivalent. 5
For infusion reactions: stop or slow the infusion rate and provide symptomatic treatment. 1

Grade 3 Toxicities

Hold immunotherapy immediately, initiate high-dose corticosteroids, and taper steroids over 4-6 weeks once symptoms resolve. 5
For infusion reactions: stop the infusion and provide aggressive symptomatic treatment. 1

Grade 4 Toxicities

Permanently discontinue immunotherapy in most cases. 5
For infusion reactions: stop the infusion, provide aggressive symptomatic treatment, and permanently discontinue the agent. 1

Refractory Cases

High-dose systemic glucocorticoids (1-2 mg/kg/day, median 70 mg/day) are first-line treatment for severe myositis; 10% receive intravenous methylprednisolone pulses. 1
Up to 20% of myositis patients receive intravenous immunoglobulins, and approximately 10% undergo plasma exchanges. 1
Second-line therapies for glucocorticoid-refractory cases include mycophenolate mofetil, methotrexate, and abatacept (which successfully resolved severe glucocorticoid-refractory myocarditis). 1
Alemtuzumab has been successfully used in glucocorticoid-refractory myocarditis as rescue therapy. 1

Special Populations and Considerations

Patients with Pre-existing Autoimmune Disease

Pre-existing autoimmune rheumatic and/or systemic disease should not preclude use of cancer immunotherapy. 1
Baseline immunosuppressive regimen should be kept at lowest dose possible (for glucocorticoids, below 10 mg prednisone per day if possible). 1

Pregnancy and Lactation

Monoclonal antibodies can cause fetal harm; advise females of reproductive potential of potential risk to fetus and use of effective contraception. 6
Advise not to breastfeed during rituximab treatment. 6
Pregnancy is a contraindication to monoclonal antibody therapy. 7

Geriatric Patients

In chronic lymphocytic leukemia patients older than 70 years, exploratory analyses suggest no benefit with addition of rituximab to fludarabine-cyclophosphamide. 6

Pediatric Patients

Hypokalemia is a grade 3 or higher adverse event in more than 15% of pediatric B-cell non-Hodgkin lymphoma patients. 6

Vaccination Considerations

Live virus vaccinations prior to or during rituximab treatment are not recommended. 6
Live vaccines should not be administered to patients with chronic inflammatory diseases on maintenance immunosuppression. 1
Other recommended vaccines, including inactivated influenza vaccine and hepatitis B vaccine, should not be withheld because of concerns about exacerbation of chronic immune-mediated or inflammatory illness. 1

Critical Diagnostic and Management Pitfalls

Diagnostic Challenges

Chemotherapy plus immunotherapy creates diagnostic challenges as symptoms can mimic either cytotoxic effects or irAEs, requiring different management approaches. 5
No biomarkers currently exist to distinguish between these toxicity types. 5
Maintain high suspicion that any new symptoms are treatment-related, as irAEs can affect any organ system. 5

Biopsy Considerations

Tissue biopsy in higher grade (3-4) toxicity should be considered when there is diagnostic doubt about etiology and management would be altered by biopsy results. 1
The reporting pathologist must be informed of specific reasons for biopsy procedure. 1

Baseline Assessment Requirements

Before starting treatment, assess patient history (including family history), general physical condition, autoimmune diseases, baseline laboratory tests, and radiological exams. 1
Patients should be informed of potential adverse events before treatment initiation and report directly to treating physician or team. 1

Long-Term and Permanent Effects

Permanent side effects including diabetes and immune-related arthritis are particularly concerning in the adjuvant setting after potentially curative surgery. 5
Some endocrine toxicities may require lifelong hormone replacement therapy. 5
Little is known about long-term effects of monoclonal antibodies in humans. 7

Contraindications and Precautions

Rituximab has no absolute contraindications listed in FDA labeling. 6
Contraindications to monoclonal antibodies generally include allergic diseases, neoplastic diseases, infective diseases, hypertension, cardiac failure, and pregnancy. 7
Bowel obstruction and perforation should be considered and evaluated for with abdominal pain, vomiting, or related symptoms. 6

What are the potential adverse effects of monoclonal antibodies (mAbs) in patients with a history of autoimmune diseases, such as rheumatoid arthritis (RA) or cancer?

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