Rituximab: Indications, Dosing, and Side Effects
Primary Indications
Rituximab is FDA-approved for CD20-positive B-cell malignancies (non-Hodgkin's lymphoma, chronic lymphocytic leukemia) and autoimmune conditions (rheumatoid arthritis, ANCA-associated vasculitis, pemphigus vulgaris), with off-label use in immune thrombocytopenia and chronic graft-versus-host disease. 1
Hematologic Malignancies
- Non-Hodgkin's Lymphoma (NHL): Standard first-line therapy in combination with chemotherapy regimens (R-CHOP, R-CVP, R-bendamustine) for both indolent and aggressive B-cell lymphomas 2, 3
- Chronic Lymphocytic Leukemia (CLL): Approved in combination with fludarabine and cyclophosphamide for treatment-naïve and relapsed disease 1, 4
- Follicular Lymphoma: Rituximab with chemotherapy is the standard treatment for patients requiring therapy, with maintenance therapy significantly prolonging remission 2
Autoimmune Conditions
- Rheumatoid Arthritis: Indicated for patients with inadequate response to TNF inhibitors, used in combination with methotrexate 5
- ANCA-Associated Vasculitis (GPA/MPA): Effective for induction and maintenance of remission 6
- Immune Thrombocytopenia (ITP): Used off-label for refractory disease, though not FDA-approved for this indication 2
- Chronic Graft-versus-Host Disease: Particularly effective for skin manifestations of steroid-refractory disease 2
Standard Dosing Regimens
Non-Hodgkin's Lymphoma
- Standard dose: 375 mg/m² IV once weekly for 4 consecutive weeks 3, 1
- Maintenance therapy (high tumor burden): 375 mg/m² every 8 weeks for 12 doses 3
- Consolidation (after single-agent rituximab): 375 mg/m² every 8 weeks for 4 doses 3
Chronic Lymphocytic Leukemia
- Approved dose: 500 mg/m² IV in combination with fludarabine and cyclophosphamide 1, 4
- This higher dose compared to NHL (375 mg/m²) was adopted because single-agent rituximab at the NHL dose showed poor response rates in CLL 4
Rheumatoid Arthritis
- Standard regimen: Two 1,000 mg IV infusions separated by 2 weeks, in combination with methotrexate 1
- Alternative lower dose: Two 500 mg IV infusions separated by 2 weeks 1
ANCA-Associated Vasculitis
- Induction: 375 mg/m² IV once weekly for 4 weeks 6
- Maintenance options:
Immune Thrombocytopenia (Off-Label)
- Typical dose: 375 mg/m² IV weekly for 4 consecutive infusions 2
- Lower doses may be sufficient but optimal dosing remains undefined 2
- Important caveat: Complete response rate at 6 months is 47% versus 32.5% with standard care, but long-term benefit beyond 1.5 years is not statistically significant 2
- Exception: Adult females with newly diagnosed or persistent ITP (<1 year duration) treated with rituximab plus high-dose dexamethasone achieved 79% durable remission at >48 months, suggesting gender and disease duration influence outcomes 2
Chronic GVHD (Off-Label)
- Standard dose: 375 mg/m² IV once weekly for 4-8 infusions 2
- Alternative lower dose: 50 mg/m² weekly for 4 weeks showed similar efficacy (69% overall response rate) 2
Administration Protocol
Mandatory Premedication
- All patients: Acetaminophen and antihistamine (e.g., diphenhydramine) 30-60 minutes before each infusion 1
- RA, GPA/MPA, and pemphigus vulgaris patients: Methylprednisolone 100 mg IV (or equivalent) 30 minutes prior to each infusion 1
- NHL patients receiving 90-minute infusion: Glucocorticoid component of chemotherapy should be administered prior to rituximab 1
Infusion Preparation
- Dilute to final concentration of 1-4 mg/mL in 0.9% sodium chloride or 5% dextrose 1
- Diluted solutions stable for 24 hours at room temperature or 48 hours refrigerated (2-8°C) 1
Infusion Rate Modifications
- Grade 1-2 reactions: Slow or temporarily stop infusion, provide symptomatic treatment 6
- Grade 3-4 reactions: Stop infusion immediately, provide aggressive symptomatic management 6
- Resume at minimum 50% rate reduction after symptom resolution 1
Prophylactic Medications
Infection Prophylaxis
- CLL patients: Pneumocystis jirovecii pneumonia (PCP) prophylaxis during treatment and up to 12 months following completion 1
- GPA/MPA patients: PCP prophylaxis during treatment and at least 6 months after last infusion 1
- Pemphigus vulgaris patients: Consider PCP prophylaxis during and after treatment 1
- High-risk patients: Herpes virus prophylaxis for CLL patients 1
Tumor Lysis Syndrome Prevention
- Consider prophylaxis in patients with high tumor burden (≥25,000 circulating malignant cells/mm³) 7
Major Adverse Effects and Safety Monitoring
Infusion-Related Reactions (Most Common)
- Incidence: Up to 77% during first infusion, decreasing with subsequent infusions 6, 1
- Manifestations: Fever, chills, rigors, pruritus, urticaria, rash, hypotension, bronchospasm 1
- ITP-specific: 20% experience infusion reactions including rash, urticaria, fever, myalgia, headache, transient hypertension 2
- RA-specific: 32% experienced reactions during or within 24 hours of first infusion, decreasing to 11% after second infusion 1
- Severe reactions: Hypoxia, pulmonary infiltrates, respiratory distress, myocardial infarction, ventricular fibrillation, cardiogenic shock can occur within 30-120 minutes of infusion onset 1
Life-Threatening Complications
Hepatitis B Reactivation (Black Box Warning)
- Risk: Can result in fulminant hepatitis, hepatic failure, and death 1, 7
- Screening requirement: Measure HBsAg and anti-HBc before initiating treatment in ALL patients 1
- High-risk populations: Both HBsAg-positive patients AND HBsAg-negative but anti-HBc-positive patients 1
- Management: Preemptive antiviral therapy for HBV-positive patients 7
Progressive Multifocal Leukoencephalopathy (PML)
- Characteristics: Rare but potentially fatal JC virus reactivation causing brain infection 2, 7
- Monitoring: Maintain vigilance for neurological symptoms throughout treatment 5
Severe Mucocutaneous Reactions (Black Box Warning)
- Types: Stevens-Johnson syndrome, toxic epidermal necrolysis, paraneoplastic pemphigus, DRESS, AGEP, lichenoid dermatitis, vesiculobullous dermatitis 1, 7, 8
- Onset: Variable, including reports on first day of exposure 1
- Management: Permanently discontinue rituximab; safety of re-administration not established 1, 7
Immunologic Complications
Hypogammaglobulinemia
- Risk factors: Multiple courses of rituximab increase risk 2
- Monitoring: Check serum immunoglobulin levels before and periodically after rituximab 2
- Clinical significance: May increase infection risk, though relationship not fully established 5
Increased Infection Risk
- Mechanism: B-cell depletion and immunosuppression 7
- Common infections: Nasopharyngitis, upper respiratory tract infections, urinary tract infections, bronchitis, sinusitis 1
- RA-specific: 39% experienced infections versus 34% with placebo 1
- Serious infections: Pneumocystis pneumonia risk elevated, particularly with concomitant immunosuppression 7
Hematologic Toxicity
- CLL-specific Grade 3-4 events: Neutropenia (30-49%), febrile neutropenia (9-15%), leukopenia (23%), thrombocytopenia (11%), pancytopenia (3%) 1
- Monitoring: Complete blood count with differential at baseline and every 2-4 months during treatment 6
Cardiovascular and Other Toxicities
- Hyperviscosity risk: Patients with baseline IgM ≥4,000 mg/dL require prophylactic plasmapheresis or avoidance during first 1-2 courses 7
- Cardiac monitoring: Close observation required for patients with pre-existing cardiac conditions 1
Critical Pre-Treatment Screening
Mandatory Assessments
- Hepatitis B screening: HBsAg and anti-HBc in ALL patients 1
- Hepatitis C screening: Antibody status 6
- Latent tuberculosis screening 6
- Baseline immunoglobulin levels 6
- Complete blood count with differential 6
- Pregnancy status (contraindicated in pregnancy) 5
- Hypersensitivity to murine proteins 5
- Congestive heart failure assessment 5
Vaccination Considerations
- Administer all indicated vaccinations BEFORE initiating rituximab whenever possible 6, 5
- For patients already on rituximab, continue other immunosuppressive medications around time of vaccination per American College of Rheumatology conditional recommendation 6
Important Clinical Caveats
ITP-Specific Limitations
- Long-term efficacy concerns: Only 21% response rate at 5 years in retrospective analysis 2
- Mortality signal: Meta-analysis revealed 3% death rate in uncontrolled trials, though causality unclear 2
- Not FDA-approved for ITP indication 2
Drug Interaction Warnings
- Contraindication: Concurrent treatment with multiple biologic agents explicitly contraindicated due to increased infection risk without additional benefit 7
- RA-specific: Not recommended as first-line therapy without prior TNF inhibitor trial 7