What are the side effects of Rituximab (rituximab)

Rituximab Side Effects

Rituximab causes infusion-related reactions in up to 77% of patients during the first infusion, with severe reactions occurring in approximately 10% of cases, and carries risks of serious infections, B-cell depletion lasting 9-12 months, and rare but potentially fatal complications including progressive multifocal leukoencephalopathy and hepatitis B reactivation. 1, 2

Infusion-Related Reactions (Most Common)

Infusion reactions are the most frequent adverse effect, occurring in 50-87% of patients, predominantly during the first infusion. 3, 4

• Mild to moderate flu-like symptoms include fever, chills, rigors, nausea, and constitutional symptoms that typically resolve within 3 hours 3, 5
• Severe reactions (10% of patients) include bronchospasm, hypotension, hypoxia, pulmonary infiltrates, and respiratory distress 6, 7
• Fatal infusion reactions have been reported, characterized by hypoxia, pulmonary infiltrates, respiratory distress, myocardial infarction, ventricular fibrillation, and cardiogenic shock 6, 1
• Cytokine release syndrome is more common with high tumor burden and presents with fever, rigors, chills, and constitutional symptoms 5, 6

Management of Infusion Reactions

• All patients should receive premedication with antihistamines (e.g., diphenhydramine 25-50 mg) and acetaminophen (650 mg) 30 minutes before infusion 6, 1, 4
• For Grade 1 reactions (primarily cutaneous): same-day rechallenge at reduced infusion rate 5
• For Grade 2 reactions (urticaria, nausea, vomiting, dyspnea): shared decision-making regarding rechallenge versus desensitization 5
• For Grade 3-4 reactions (symptomatic bronchospasm, anaphylaxis, hypotension): stop infusion immediately and consider desensitization protocols for future doses 5, 1

Infectious Complications

Infections occur in 47.9% of patients, with severe infections in 17.9%, due to profound B-cell depletion and impaired humoral immunity. 8, 9

Specific Infection Risks

• Hepatitis B reactivation is the most critical infection risk, potentially causing fulminant liver failure and death—all patients must be screened for HBV before treatment and receive preemptive antiviral therapy if positive 9, 6
• Progressive multifocal leukoencephalopathy (PML), a lethal encephalitis caused by JC polyomavirus, has been reported with increasing frequency 6, 9, 6
• Pneumocystis pneumonia risk is increased, particularly with concomitant immunosuppression 6
• Fatal sepsis has been reported, especially in transplant patients and those with hypogammaglobulinemia 6
• Atypical bacterial, fungal (including Pneumocystis), and viral infections (including CMV) are more common 6

Risk Factors for Infection

• Concurrent use of intravenous chemotherapy increases infection risk 8
• Treatment of systemic lupus erythematosus is associated with higher infection rates 8
• Neutropenia and use of intravenous immunoglobulin correlate with increased infection risk 8
• Concomitant severe immunodeficiency (HIV infection or fludarabine use) significantly elevates risk 9

Hematologic Adverse Effects

• Neutropenia occurs in 14-49% of patients (Grade 3-4), with higher rates when combined with chemotherapy 2, 6
• Thrombocytopenia develops in 9-11% of patients 2
• Anemia affects 20-35% of patients 2
• Leukopenia occurs in 12-23% of patients 2
• Febrile neutropenia develops in 9-15% of patients receiving rituximab with chemotherapy 2

Immunologic Effects and Recovery

B-cell depletion is profound and prolonged, with median recovery time of 9 months (range 5.9-14.4 months), though 51% of patients have persistently low B-cell counts beyond one year. 8, 7

• CD19+ or CD20+ B cells are depleted by approximately 90% within 3 days 3
• CD27+ memory B cells recover more slowly, with median time of 15.7 months 8
• Hypogammaglobulinemia develops in 23.2% of patients (low IgG) and 40.8% (low IgM), with persistent low levels in 13.7% and 33.9% respectively beyond 12 months 8
• Antibody responses to recall antigens are dramatically reduced 6

Pulmonary Complications

• Interstitial pneumonitis has been reported, with some cases proving fatal 6
• Pulmonary toxicity occurs in 18% of patients in some studies 2
• Cough, rhinitis, nasal congestion, wheezing, and dyspnea can occur 5

Serum Sickness-Like Reactions (SSLRs)

SSLRs occur more commonly in autoimmune diseases (78-85% of cases) and present with the classic triad of arthritis, fever, and cutaneous manifestations (purpura, urticaria, erythema). 6

• Rechallenge can be considered after shared decision-making, as 2 of 4 and 6 of 7 rechallenges were well tolerated in reported series 6
• Premedication with H1-antihistamines and systemic glucocorticoids has been used, though no large validated studies exist 6

Serious Non-Immediate Adverse Reactions

The following severe reactions are not amenable to desensitization and require drug avoidance: 6

• DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)
• AGEP (Acute Generalized Exanthematous Pustulosis)
• Stevens-Johnson syndrome (SJS)
• Toxic epidermal necrolysis (TEN)
• Myocardial infarction
• Arrhythmia (including supraventricular arrhythmias and atrial fibrillation)
• Shock
• Cardiogenic shock

Other Common Adverse Effects

• Upper respiratory tract infections (>10% of patients) 2
• Nasopharyngitis and bronchitis (>10% of patients) 2
• Hypertension, nausea, arthralgia, pyrexia, and pruritus (≥5% of patients) 2
• Peripheral sensory neuropathy (30% when combined with chemotherapy) 2
• Hepato-biliary toxicity (17% in some studies) 2
• Rash and/or pruritus (17% in some studies) 2

Pediatric-Specific Considerations

In pediatric patients, anaphylaxis occurs in 3.6% and adverse events associated with infusion in 15.4%, with infections being common (47.9%) but long-term adverse events like prolonged neutropenia and leukoencephalopathy being absent. 8

Critical Monitoring Recommendations

• Screen all patients for hepatitis B before initiating rituximab 9
• Monitor during and after infusion for infusion-related reactions 1
• Obtain CBC count and hepatic/renal function periodically during therapy 6
• Consider Pneumocystis pneumonia prophylaxis, especially with concomitant immunosuppression 6
• Monitor for signs of infection throughout treatment and during prolonged B-cell recovery period 8
• Assess immunoglobulin levels in patients with recurrent infections 8