What are the acute adverse effects of rituximab and how should they be prevented and managed?

Acute Adverse Effects of Rituximab

Rituximab causes fatal infusion reactions in a small percentage of patients, primarily during the first infusion, characterized by hypoxia, pulmonary infiltrates, respiratory distress, myocardial infarction, ventricular fibrillation, and cardiogenic shock, requiring immediate premedication with antipyretics, antihistamines, and corticosteroids, along with continuous monitoring during administration. 1

Infusion-Related Reactions (Most Common Acute Adverse Effect)

Incidence and Timing

• 77% of patients experience infusion reactions during the first administration, decreasing to 3-8% in subsequent infusions 2
• Severe reactions (grade 3-4) occur in approximately 10% of patients 2
• In rheumatoid arthritis patients, 32% experienced adverse reactions during or within 24 hours of the first infusion, with acute infusion-related reactions occurring in 27% 3
• Most reactions occur within 30-120 minutes of infusion start, though severe hypotension can develop as rapidly as 5 minutes after initiation 2, 4

Clinical Manifestations by Severity Grade

Grade 1 (Mild): 2

• Primarily cutaneous symptoms: rash, urticaria, pruritus
• Back pain or transient hypertension
• Fever, myalgia, headache, rigors, chills 5

Grade 2 (Moderate): 2

• Urticaria, nausea, vomiting
• Throat tightness, dyspnea
• Asymptomatic bronchospasm

Grade 3 (Severe): 2

• Symptomatic bronchospasm with wheezing
• Dyspnea requiring intervention
• Hypoxia

Grade 4 (Life-Threatening): 1, 2

• Anaphylaxis
• Hypotension/cardiogenic shock
• Myocardial infarction
• Ventricular fibrillation
• Respiratory failure with pulmonary infiltrates

Cardiovascular Complications

• Acute hypotension can occur within 5 minutes of infusion start, even in treatment-naïve patients 4
• Myocardial infarction, ventricular fibrillation, and cardiogenic shock are documented fatal complications 1
• In RA patients, 1.7% experienced serious cardiovascular reactions, with 3 cardiovascular deaths (0.4%) during controlled trials 3
• Chest pain, irregular heartbeats, and cardiogenic shock are recognized acute cardiac manifestations 2

Cytokine Release Syndrome

• More common with high tumor burden (lymphocyte count >25 × 10⁹/L) 2
• Presents with fever, rigors, chills, and constitutional symptoms within 12-24 hours of first infusion 2
• Can progress to tumor lysis syndrome with kidney failure, abnormal heart rhythm, and electrolyte disturbances 6
• Associated with elevated TNF-alpha levels (IL-6 and IL-1 typically not significantly elevated) 7

Acute Hematologic Toxicity

• Acute thrombocytopenia and leukopenia can develop rapidly following rituximab administration 7
• Most commonly occurs in patients with mantle cell lymphoma, bone marrow involvement, or splenomegaly 7
• Usually not associated with bleeding manifestations despite low platelet counts 7
• Pathogenesis involves cytokine release syndrome and complement activation 7

Pulmonary Complications

• Interstitial pneumonitis has been reported, with some cases proving fatal 1
• Hypoxia and pulmonary infiltrates are features of severe infusion reactions 1
• Bronchospasm, cough, rhinitis, nasal congestion, wheezing, and dyspnea occur acutely 2

Gastrointestinal Manifestations

• Nausea and vomiting are common during infusion reactions 2
• In RA patients, 8% experienced nausea (vs 5% with placebo) 3
• Diarrhea and abdominal pain can occur as part of mast cell-mediated reactions 2

Prevention and Management Strategies

Mandatory Premedication Protocol

Standard premedication (administer 30 minutes before infusion): 2, 3

• Diphenhydramine 25-50 mg IV or PO
• Acetaminophen 650-1000 mg PO
• Methylprednisolone 100 mg IV (especially for first infusion, reduces severe reactions from 4.7% to 1%) 2

Infusion Rate Protocol

First infusion: 2

• Start at 50 mg/hour for first 30 minutes
• Increase by 50 mg/hour every 30 minutes if tolerated
• Maximum rate: 400 mg/hour

Subsequent infusions (if first tolerated): 2

• Can use 90-minute rapid infusion protocol for NHL patients 8
• Not recommended for CLL patients due to insufficient safety data 8

High-Risk Patient Precautions

Patients with circulating malignant cells ≥25,000/mm³: 6

• Increased risk of cytokine release syndrome
• Consider prophylactic plasmapheresis if IgM ≥4000 mg/dL
• Reduced infusion rate mandatory

Patients with high tumor burden or lymphocyte count >25 × 10⁹/L: 2

• Reduced infusion rate required
• Enhanced monitoring for tumor lysis syndrome

Reaction Management by Grade

Grade 1 reactions: 2, 6

• Stop or slow infusion to 50%
• Administer symptomatic treatment
• Resume at 50% of previous rate once symptoms resolve
• Same-day rechallenge is safe

Grade 2 reactions: 2, 6

• Stop infusion immediately
• Administer methylprednisolone 40 mg IV if not already given
• Resume at 50% of previous rate after complete symptom resolution
• Shared decision-making regarding future infusions

Grade 3 reactions: 2, 6

• Stop infusion immediately and permanently discontinue for that session
• Aggressive symptomatic treatment
• Mandatory allergy specialist consultation before any rechallenge
• Formal desensitization protocols required for future doses

Grade 4 reactions: 2, 6

• Permanently discontinue rituximab
• Full resuscitative measures per anaphylaxis protocols
• Epinephrine, IV fluids, oxygen, airway management as needed

Monitoring Requirements

During infusion: 2, 6

• Continuous monitoring for at least 2 hours
• Vital signs every 15-30 minutes
• Immediate assessment if any symptoms develop
• Emergency equipment readily available

Post-infusion: 2

• Continue monitoring 1-2 hours after completion
• Most reactions occur within 30-120 minutes of start

Laboratory monitoring: 2

• Daily CBC and hepatic/renal function during therapy initiation
• Periodic monitoring based on clinical response thereafter

Critical Pitfalls to Avoid

• Never assume subsequent infusions are safe after a Grade 3 reaction - all such patients had recurrent reactions upon rechallenge 6
• Do not overlook hepatitis B screening before initiating therapy, as reactivation can cause fulminant hepatic failure and death 2, 9
• Never resume infusion at full rate after a reaction - always reduce to 50% 2, 6
• Do not attempt desensitization outside specialized centers - requires experienced staff and intensive monitoring 6
• Severe hypotension can occur within 5 minutes (not just 30 minutes to 2 hours as commonly cited) - vigilance is required from infusion start 4
• Patients with splenomegaly and bone marrow involvement who develop cytokine release syndrome should be closely monitored for acute cytopenia 7

Special Populations

Rheumatoid arthritis patients: 3, 5

• Adverse events are similar in type but less severe and less frequent compared to lymphoma patients
• Infusion reactions still occur in 32% during first infusion
• Serious infusion-related reactions in <1% of patients

CLL patients: 8

• Rapid infusion NOT recommended due to lack of safety evidence
• Standard infusion protocols should be maintained