Why is rituximab (CD20 monoclonal antibody) prescribed?

Why Rituximab is Prescribed

Rituximab is prescribed to deplete CD20-positive B-lymphocytes in patients with B-cell malignancies (non-Hodgkin lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia) and autoimmune diseases (rheumatoid arthritis, vasculitis, cryoglobulinemia) where pathogenic B-cells drive disease progression. 1

Mechanism of Action

Rituximab is a chimeric monoclonal antibody that binds to the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes, but not on hematopoietic stem cells. 1 Upon binding CD20, rituximab triggers B-cell death through three primary mechanisms:

• Complement-dependent cytotoxicity (CDC): Activates the complement cascade leading to cell lysis 1, 2
• Antibody-dependent cellular cytotoxicity (ADCC): Recruits immune effector cells to destroy antibody-coated B-cells 1, 3
• Direct apoptosis induction: Triggers programmed cell death pathways in malignant B-cells 3, 4

The drug also sensitizes chemotherapy-resistant tumor cells to conventional cytotoxic agents, enhancing the efficacy of combination regimens. 2, 3

Primary Clinical Indications

B-Cell Malignancies

Non-Hodgkin Lymphoma (NHL)

• Diffuse large B-cell lymphoma: Rituximab combined with CHOP chemotherapy is the standard first-line treatment, achieving 76% complete response rates versus 63% with CHOP alone, with 2-year overall survival of 70% versus 57%. 5, 2
• Follicular lymphoma: As monotherapy in relapsed/refractory disease, rituximab achieves 48% overall response rates with median time to progression of 13 months. 2, 6
• Mantle cell lymphoma: Approved in combination with chemotherapy backbones such as CODOX-M/IVAC or dose-adjusted EPOCH. 7

Chronic Lymphocytic Leukemia (CLL)

• The FCR regimen (fludarabine + cyclophosphamide + rituximab) is the standard first-line chemo-immunotherapy for fit CLL patients. 7
• In relapsed/refractory CLL, fludarabine + rituximab or high-dose methylprednisolone + rituximab are acceptable salvage options. 7

Acute Lymphoblastic Leukemia (ALL)

• In CD20-positive B-cell precursor ALL, adding rituximab to standard chemotherapy improves molecular remission rates (90% by week 16 versus 59% with chemotherapy alone) and 5-year overall survival (71%). 5
• Rituximab is recommended when CD20 expression is ≥20% of leukemic blast cells, though some evidence suggests benefit at lower expression levels (≥11.7%). 5
• The addition of 16-18 rituximab infusions significantly improves event-free survival by reducing relapse incidence. 5

Autoimmune and Inflammatory Conditions

Rheumatoid Arthritis

• Rituximab is indicated for patients with inadequate response to TNF inhibitors, achieving B-cell depletion within 2 weeks and sustained depletion for at least 6 months. 5, 1
• Treatment reduces inflammatory markers including IL-6, CRP, rheumatoid factor, and anti-citrullinated peptide antibodies. 1

ANCA-Associated Vasculitis (Granulomatosis with Polyangiitis and Microscopic Polyangiitis)

• Rituximab depletes peripheral CD19 B-cells to <10 cells/µL following the first two infusions, with sustained depletion through 6 months in 84% of patients. 1

HCV-Related Cryoglobulinemic Vasculitis

• Rituximab is especially recommended for severe clinical manifestations, improving purpura, ulcers, fatigue, arthralgias, glomerulonephritis, and peripheral neuropathy in 75-90% of cases. 5
• It effectively manages life-threatening complications including hyperviscosity syndrome. 5
• Rituximab decreases cryocrit, improves rheumatoid factor and C4 levels, and induces disappearance of bone marrow B-cell clonal expansion. 5

Waldenström's Macroglobulinemia

• Standard rituximab schedule (375 mg/m² weekly × 4 weeks) achieves 30-60% overall response rates with 8-11 months duration of response. 5
• Extended schedule (additional 4 weekly infusions at weeks 12-16) achieves 35-45% overall response with 16-29 months duration of response. 5
• Patients with baseline serum IgM ≥4000 mg/dL require prophylactic plasmapheresis before rituximab to prevent hyperviscosity complications. 5, 7

Pharmacodynamic Effects

B-Cell Depletion Kinetics

• Circulating CD19-positive B-cells are depleted within 2-3 weeks of the first infusion. 1, 2
• B-cell recovery typically begins around 6 months, with median levels returning to normal by 12 months post-treatment. 8, 1, 2
• A small proportion (~4%) of patients experience prolonged B-cell depletion lasting >3 years after a single course. 1

Immunoglobulin Effects

• IgM and IgG serum levels are reduced from 5-11 months following rituximab administration, with 14% of NHL patients developing levels below normal range. 1
• In rheumatoid arthritis, 23.3% of patients develop IgM below lower limit of normal, 5.5% develop low IgG, and 0.5% develop low IgA during repeated treatment. 1

Critical Safety Considerations

Mandatory Pre-Treatment Screening

• Hepatitis B screening: All patients must be tested for HBV before initiating rituximab, as reactivation can cause fulminant liver failure and death; HBV-positive patients require preemptive antiviral therapy. 7, 1
• Complete blood count with differential: Required to identify baseline cytopenias. 7
• Comprehensive metabolic panel: Assesses hepatic and renal function. 7
• Pregnancy testing: Mandatory for women of childbearing potential. 7

Infusion-Related Reactions

• Occur in 77% of patients during first infusion, decreasing to 3-8% in subsequent infusions. 9
• Severe reactions (grade 3-4) occur in approximately 10% of patients. 9, 2
• Fatal infusion reactions are characterized by hypoxia, pulmonary infiltrates, respiratory distress, myocardial infarction, ventricular fibrillation, and cardiogenic shock. 9, 7
• Mandatory premedication: Antihistamine (diphenhydramine 25-50 mg) and antipyretic (acetaminophen 650-1000 mg) 30 minutes before infusion, with strong consideration for methylprednisolone 100 mg IV. 9

Infection Risk

• Significantly increased risk of pneumocystis pneumonia, particularly with concomitant immunosuppression; prophylaxis should be considered. 7
• Progressive multifocal leukoencephalopathy (PML), a lethal JC polyomavirus encephalitis, has been reported with increasing frequency. 9
• Antibody responses to recall antigens are dramatically reduced, with median recovery time of 9 months (range 5.9-14.4 months). 9

High Tumor Burden Precautions

• Patients with high tumor burden or lymphocyte count >25 × 10⁹/L are at increased risk for cytokine release syndrome and require reduced infusion rate and close monitoring. 9, 8

Common Pitfalls to Avoid

• IgM flare in Waldenström's macroglobulinemia: Occurs in 50% of patients during the first months of treatment; this is not treatment failure and should not be misinterpreted as progression. 5
• Diagnostic interference: Rituximab masks surface CD20 epitopes, causing false-negative immunohistochemistry; use alternative pan-B-cell markers such as CD79a when evaluating post-rituximab tissue specimens. 8
• Concurrent biologic agents: Explicitly contraindicated due to increased infection risk without additional benefit. 7
• Severe cutaneous reactions: DRESS, AGEP, Stevens-Johnson syndrome, and toxic epidermal necrolysis require permanent drug avoidance. 7