What are the indications, dosages, and potential side effects of advanced monoclonal antibodies (mAbs), such as rituximab (Rituxan) and trastuzumab (Herceptin), in treating conditions like metastatic cancer, multiple sclerosis, and rheumatoid arthritis?

Advanced Monoclonal Antibodies: Clinical Applications and Management

Trastuzumab (Herceptin) for HER2-Positive Metastatic Breast Cancer

For first-line treatment of HER2-positive metastatic breast cancer, trastuzumab combined with pertuzumab plus a taxane (docetaxel or paclitaxel) for at least six cycles is the standard of care, regardless of hormone receptor status. 1

Indications and Dosing

• First-line setting: Applies to patients with de novo metastatic disease or those whose disease relapsed ≥12 months after prior HER2-targeting adjuvant therapy 1
• Standard regimen: Trastuzumab + pertuzumab + taxane for ≥6 cycles, followed by maintenance with trastuzumab + pertuzumab (plus endocrine therapy if HR-positive) 1
• Patients with chemotherapy contraindications: Trastuzumab + pertuzumab alone (HR-negative disease) or with endocrine therapy (HR-positive disease) 1

Critical Safety Considerations

• Cardiotoxicity: The primary dose-limiting toxicity; use with anthracyclines is problematic due to cardiac dysfunction risk 2
• Cerebral metastases: The rate of brain metastases development is 2.8-times higher in patients receiving trastuzumab 2
• Contraindications: Avoid in patients with pre-existing cardiac dysfunction or recent cardiovascular disease 1

Treatment Sequencing After Progression

• Second-line: Trastuzumab deruxtecan (T-DXd) is preferred following progression on trastuzumab/pertuzumab/taxane 1
• Alternative second-line: T-DM1 when T-DXd is unavailable or unsuitable (e.g., interstitial lung disease) 1

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Rituximab (Rituxan) for Rheumatoid Arthritis

Rituximab should be reserved for rheumatoid arthritis patients who have failed TNF inhibitors due to inadequate response, or as first-line biologic therapy only under specific circumstances including recent lymphoma, latent tuberculosis with contraindications to chemoprophylaxis, TB-endemic regions, or prior demyelinating disease. 1

Indications and Patient Selection

• Standard indication: After inadequate response to TNF inhibitors 1
• First-line biologic use (specific circumstances only): 1
  • Recent history of lymphoma
  • Latent tuberculosis with contraindications to chemoprophylaxis
  • Living in TB-endemic region
  • Previous demyelinating disease
  • Recent history of any malignancy (no evidence rituximab is associated with cancer occurrence) 1

Dosing and Administration

• Combination therapy required: Must be used with methotrexate or other conventional synthetic DMARDs for optimal efficacy 1
• Monotherapy: Has not been consistently superior to methotrexate alone 1

Mandatory Pre-Treatment Screening

All patients must undergo tuberculosis screening before initiating rituximab: 1

• Tuberculin skin test (TST) or interferon-gamma release assay (IGRA) required regardless of risk factors 1
• Use IGRA over TST in patients with prior BCG vaccination (high false-positive TST rates) 1
• Positive TST/IGRA requires chest radiograph and sputum examination if radiograph suggests TB exposure 1

Contraindications in Rheumatoid Arthritis

Do not use rituximab in patients with: 1

• Untreated chronic Hepatitis B 1
• Treated chronic Hepatitis B with Child-Pugh Class B or higher 1
• Active hepatitis requiring treatment 1

Safety Profile

• Infusion reactions: Most common adverse event (77% with first infusion, decreasing with subsequent infusions) 3
• Infections: Serious infections occur in <5% of patients; overall infection rate 31% (bacterial 19%, viral 10%) 3
• Cytopenias: Grade 3-4 cytopenias in 48% (lymphopenia 40%, neutropenia 6%) 3
• Hypogammaglobulinemia: Monitor immunoglobulin levels; median lymphopenia duration 14 days 3
• Serious cardiopulmonary reactions: Fatal in approximately 0.04-0.07% of patients 4

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Rituximab for Multiple Sclerosis (Off-Label Use)

For relapsing MS as first-choice treatment, rituximab likely delays relapse compared to interferon beta/glatiramer acetate and may delay relapse compared to dimethyl fumarate and natalizumab, though evidence on disability worsening remains uncertain. 5

Efficacy as First-Choice Treatment

• Versus interferon beta/glatiramer acetate: Likely delays relapse (HR 0.14,95% CI 0.05-0.39) 5
• Versus dimethyl fumarate: May delay relapse (HR 0.29,95% CI 0.08-1.00) 5
• Versus natalizumab: May delay relapse (HR 0.24,95% CI 0.06-1.00) 5
• Disability worsening: Evidence remains uncertain across all comparisons 5

Efficacy as Switching Treatment

• Versus interferon beta/glatiramer acetate: Likely delays relapse (HR 0.18,95% CI 0.07-0.49) 5
• Versus fingolimod: Likely delays relapse (HR 0.08,95% CI 0.02-0.32) 5
• Versus natalizumab: May result in little to no difference in relapse (HR 0.96,95% CI 0.83-1.10) 5

Critical Safety Concern in MS

Rituximab likely increases serious common infections compared to interferon beta/glatiramer acetate (OR 1.71,95% CI 1.11-2.62) and natalizumab (OR 1.58,95% CI 1.08-2.32), though absolute risk remains low. 5

Primary Progressive MS

• Rituximab likely results in little or no difference in disability worsening compared to placebo (OR 0.71,95% CI 0.45-1.11) 5
• Evidence on other outcomes remains very uncertain 5

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COVID-19 Pandemic Considerations for Monoclonal Antibodies

Rituximab Dosing Modifications

During periods requiring reduced healthcare contact, extend rituximab dosing intervals: 1

• Maintenance therapy in follicular lymphoma: Consider reporting or removing maintenance cycles 1
• Avoid rituximab in chronic lymphocytic leukemia induction when combined with venetoclax; prefer alternative therapies 1

Trastuzumab Considerations

• Cardiotoxic agents including trastuzumab should be reconsidered if alternatives are available, given cardiac involvement prevalence with COVID-19 1
• Treatment continuation with monitoring via telemedicine is appropriate for stable patients 1

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Immunotherapy in Special Populations

Autoimmune Disease

For patients with pre-existing autoimmune disease requiring medication, 94% of expert consensus recommends against combination immunotherapy (e.g., nivolumab/ipilimumab) for intermediate/poor risk metastatic renal cell carcinoma. 1

• Retrospective data in melanoma showed 20% objective response rate with ipilimumab in patients with autoimmune disorders 1
• 50% experienced neither autoimmune flare nor grade ≥3 immune-related adverse events 1
• Anti-PD-1 therapy showed 33% objective response rate with manageable toxicity (30% developed additional immune-related adverse events) 1

Corticosteroid Use

• 75% of expert consensus recommends against treating patients receiving >10 mg/day prednisone equivalent with combination immunotherapy 1

Viral Infections

HIV, Hepatitis B/C patients can receive immune checkpoint inhibitors with appropriate monitoring: 1

• HIV patients: 24% any-grade immune-related adverse events, 10% grade ≥3,29% objective response rate 1
• HBV/HCV patients: 50% any-grade immune-related adverse events, 26% grade ≥3,21% objective response rate, no viral reactivation noted 1

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Common Pitfalls and Critical Warnings

Hepatitis B Reactivation

• Screen all patients for hepatitis B before initiating rituximab 3
• Fulminant hepatitis with hepatic failure and death can occur 3

Progressive Multifocal Leukoencephalopathy (PML)

• JC virus infection causing PML can occur with rituximab 3
• Monitor for new neurological symptoms 3

Tumor Lysis Syndrome

• Occurs within 12-24 hours after first rituximab infusion 4
• Estimated incidence 0.04-0.05% of patients 4
• Higher risk with high circulating malignant cell counts, pulmonary infiltrates, or prior cardiovascular disease 4

Severe Mucocutaneous Reactions

• Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with rituximab 3
• Discontinue rituximab and consider dermatologic consultation 3

Bowel Obstruction and Perforation

• Can occur with rituximab, particularly in lymphoma patients 3
• Evaluate patients with abdominal pain promptly 3