What is the mechanism of action, administration, dosing, and indications for Rituximab (rituximab)?

Rituximab: Mechanism, Administration, Dosing, and Indications

Mechanism of Action

Rituximab is a chimeric monoclonal antibody that targets the CD20 antigen expressed on pre-B and mature B-lymphocytes, mediating B-cell lysis through complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). 1

• CD20 is expressed on >90% of B-cell non-Hodgkin's lymphomas and to a lesser degree on chronic lymphocytic leukemia cells, but not on hematopoietic stem cells, allowing for B-cell recovery after depletion 2
• In rheumatoid arthritis, B cells contribute to pathogenesis through production of rheumatoid factor and autoantibodies, antigen presentation, T-cell activation, and proinflammatory cytokine production 1
• Rituximab depletes circulating B cells within 3 days of administration, with circulating CD19-positive B cells depleted within the first three weeks 3, 1
• B-cell depletion is sustained for 6-12 months in most patients, with recovery beginning at approximately 6 months and median B-cell levels returning to normal by 12 months 4, 3, 1

Administration

Rituximab is administered as an intravenous infusion with specific premedication requirements to minimize infusion reactions. 1

Pre-Treatment Requirements

• Obtain immunoglobulin levels (IgG, IgM, IgA) before initiating therapy 5
• Screen for hepatitis B and C antibodies, including occult hepatitis B infection 5, 6
• Perform latent tuberculosis screening 5
• Obtain complete blood count with differential 5

Infusion Precautions

• Infusion reactions occur in up to 77% during first infusion, primarily mild to moderate flu-like symptoms that decrease with subsequent infusions 5, 2
• Severe infusion reactions (bronchospasm, hypotension) develop in approximately 10% of patients but are usually reversible with appropriate interventions 2
• Premedication with acetaminophen and antihistamines is recommended to manage infusion reactions 5

Dosing Regimens by Indication

Non-Hodgkin's Lymphoma

Standard schedule: 375 mg/m² IV once weekly for 4 weeks 4, 2

• Overall response rates of 30-60% with duration of response of 8-11 months in relapsed/refractory indolent NHL 4
• Extended schedule: 375 mg/m² IV once weekly for 4 weeks, followed by 4 additional weekly infusions at weeks 12-16 for responsive patients 4
• Extended schedule achieves overall response rates of 35-45% with duration of response exceeding 16-29 months 4

Waldenström's Macroglobulinemia

Standard schedule: 375 mg/m² IV once weekly for 4 weeks 4

• Critical warning: Patients with baseline serum IgM ≥4000 mg/dL should undergo prophylactic plasmapheresis or avoid rituximab during first 1-2 courses until IgM decreases to safer levels 4
• IgM flare occurs in approximately 50% of patients during first months of treatment and can lead to hyperviscosity-related complications in patients with high baseline IgM 4, 3
• The IgM flare is not associated with treatment failure and should not be interpreted as disease progression 4

Rheumatoid Arthritis

1000 mg IV on day 0, repeated on day 15 5

• Maintenance dosing of 1000 mg IV every 24 weeks based on clinical response 5
• Peripheral B-cell depletion (CD19 counts <20 cells/µL) occurs within 2 weeks after first dose in the majority of patients 1
• Re-treatment may be considered when clinical symptoms recur, typically every 6 months 5

Inflammatory Myositis

Primary regimen: 1000 mg IV on day 0, repeated on day 15 5

• This regimen showed 83% favorable response in 200 pediatric and adult patients with refractory disease over 44 weeks 5
• Alternative regimen: 375 mg/m² IV once weekly for 4 consecutive weeks 5
• Muscle strength improvement is progressive over 12 weeks following administration 3, 5
• Indicated for patients with refractory inflammatory myositis despite corticosteroids and at least one conventional immunosuppressant 5

Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA)

375 mg/m² IV once weekly for 4 weeks 1

• Peripheral blood CD19 B-cells deplete to <10 cells/µL following the first two infusions and remain at that level in 84% of patients through month 6 1
• B-cell return with counts >10 cells/µL occurs in 81% of patients by month 12 1

Bullous Pemphigoid

375 mg/m² IV once weekly for 4 weeks, with repeat infusions in some cases 4

• Improvement usually seen after 4 weeks of treatment 4
• Used for refractory disease, often allowing gradual withdrawal of other immunosuppressants 4
• Serious adverse events occurred in 3 of 8 cases in reported series, including fatal infections 4

FDA-Approved Indications

Rituximab is FDA-approved for multiple B-cell malignancies and autoimmune conditions 1:

• Relapsed or refractory low-grade or follicular CD20-positive B-cell non-Hodgkin's lymphoma 2, 7
• CD20-positive diffuse large B-cell lymphoma in combination with CHOP chemotherapy 2
• Chronic lymphocytic leukemia (in combination with chemotherapy) 1
• Rheumatoid arthritis inadequately responsive to TNF antagonists 1, 6
• Granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis 1
• Pemphigus vulgaris 1

Critical Safety Monitoring

Immunoglobulin Monitoring

• At week 24 of first course, 10% of RA patients experienced decreases in IgM, 2.8% in IgG, and 0.8% in IgA below lower limit of normal 1
• With repeated treatment, 23.3% experienced decreases in IgM, 5.5% in IgG, and 0.5% in IgA below normal at any time 1
• Hypogammaglobulinemia may increase risk of serious infections with repeated treatment 6

Hematologic Monitoring

• Monitor complete blood count at 2-4 month intervals during treatment for cytopenias 5
• Late-onset neutropenia can occur, particularly when combined with chemotherapy 4
• Grade 3-4 neutropenia rates are higher in patients ≥70 years old compared to younger patients 1

Infection Risk

• Screen for hepatitis B (including occult infection) before treatment, as reactivation has been reported 5, 6
• No significant increase in tuberculosis incidence observed in RA patients 6
• Progressive multifocal leukoencephalopathy is a rare but fatal complication requiring vigilance 5, 6
• Serious infections may occur, particularly with prolonged B-cell depletion or hypogammaglobulinemia 4, 6

Special Population Considerations

• In patients ≥70 years old, rates of serious adverse reactions including infections, neutropenia, and pancytopenia are higher 1
• Elderly patients may receive lower dose intensity of rituximab and concomitant chemotherapy 1
• A small proportion (~4%) of RA patients had prolonged peripheral B-cell depletion lasting >3 years after a single course 1