What are the potential side effects of Rituximab (rituximab) in adult patients with a history of cancer or autoimmune diseases?

Rituximab Side Effects in Adult Patients

Rituximab causes infusion-related reactions in approximately 77% of patients during first administration (decreasing to 3-8% in subsequent infusions), with severe reactions occurring in ~10% of patients, and carries serious risks including fatal infections, hepatitis B reactivation, progressive multifocal leukoencephalopathy, and cardiac complications. 1, 2

Infusion-Related Reactions (Most Common)

Mild to Moderate Reactions (20-32% of patients)

• Rash, urticaria, fever, myalgia, headache, and transient hypertension occur most commonly during the first infusion 3
• Rigors, chills, and flu-like symptoms are typical manifestations 3, 1
• These reactions decrease dramatically in frequency with subsequent infusions 1

Severe Infusion Reactions (~10% of patients)

• Bronchospasm, hypotension, hypoxia, pulmonary infiltrates, and respiratory distress characterize severe reactions 1, 2
• Fatal reactions have been reported, presenting with myocardial infarction, ventricular fibrillation, and cardiogenic shock 1, 2
• Onset typically occurs within 30-120 minutes of infusion start 2
• Patients with high tumor burden (circulating malignant cells ≥25,000/mm³) or lymphocyte count >25×10⁹/L are at highest risk 1, 2

Cytokine Release Syndrome

• More common with high tumor burden, presenting with fever, rigors, chills, and constitutional symptoms 3, 1
• Can occur within 12-24 hours after first infusion 1

Serious Infectious Complications

Hepatitis B Reactivation (Critical Risk)

• Can result in fulminant hepatitis, hepatic failure, and death 3, 2
• Occurs in both HBsAg-positive patients and those who are HBsAg-negative but anti-HBc positive 3, 2
• All patients must be screened for HBsAg and anti-HBc before initiating rituximab 3, 2
• Patients testing positive require preemptive antiviral therapy 1

Progressive Multifocal Leukoencephalopathy (PML)

• Fatal encephalitis caused by JC polyomavirus reported with increasing frequency 3, 1
• Represents a lethal complication of B-cell depletion 1

General Infection Risk

• Serious bacterial, fungal, and viral infections can occur during and after treatment, leading to death 2
• Pneumocystis jirovecii pneumonia risk is increased, particularly with concomitant immunosuppression 1, 4
• Fatal sepsis has been documented 4

Hypogammaglobulinemia

• Risk increases with multiple courses of rituximab 3
• Some patients develop prolonged low antibody levels (>11 months), predisposing to infections 2
• Antibody responses to recall antigens are dramatically reduced, with median recovery time of 9 months (range 5.9-14.4 months) 1
• Serum immunoglobulin levels should be monitored before and periodically after rituximab 3, 1

Cardiovascular Complications

• Chest pain, irregular heartbeats, myocardial infarction, and cardiogenic shock can occur 1, 2
• Patients with pre-existing cardiac conditions require close monitoring during and after treatment 2

Severe Mucocutaneous Reactions (Rare but Fatal)

• Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, and AGEP have been reported 1, 2
• Paraneoplastic pemphigus, lichenoid dermatitis, and vesiculobullous dermatitis documented 2
• Onset variable, including reports on first day of exposure 2
• These reactions are not amenable to desensitization and require permanent drug discontinuation 1, 5

Hematologic Complications

Tumor Lysis Syndrome

• Occurs within 12-24 hours after first infusion 2
• Manifests as kidney failure requiring dialysis, abnormal heart rhythm, and electrolyte disturbances 2
• Symptoms include nausea, vomiting, diarrhea, and lack of energy 2

Thrombocytopenia

• Severe acute thrombocytopenia can develop rapidly after administration (platelet drop from 112,000/μL to 5,000/μL documented within 24 hours) 6
• Late-onset neutropenia is an uncommon but recognized complication 7

Gastrointestinal and Abdominal Complications

• Nausea, vomiting, diarrhea, and abdominal pain are recognized adverse effects 1, 2
• Severe bowel problems including blockage or tears can occur, sometimes leading to death, particularly when rituximab is combined with chemotherapy 2
• Intestinal perforation has been reported 7

Pulmonary Complications

• Interstitial pneumonitis has been reported, with some cases proving fatal 1, 4
• Rituximab itself can cause drug-induced hypersensitivity pneumonitis and interstitial lung disease (15% fatal in one systematic review) 4
• Cough, rhinitis, nasal congestion, wheezing, and dyspnea can occur 1

Renal Complications

• Severe kidney problems leading to death can occur, especially in patients receiving rituximab for NHL 2
• Kidney function should be monitored with blood tests throughout treatment 2

Mortality Data

• Death rate of 3% reported in meta-analysis of uncontrolled rituximab trials in ITP, though causality was unclear 3
• Fatalities primarily associated with severe infusion reactions, infections (particularly hepatitis B reactivation and PML), and severe mucocutaneous reactions 3, 1, 2

Risk Stratification by Disease Type

Adverse drug reactions are significantly more common in hematologic malignancies (25-35.9% in NHL/CLL) compared to autoimmune disorders (9.4-17.5%) 8

Essential Preventive Measures

Mandatory Premedication

• Acetaminophen (650-1000 mg) and antihistamine (diphenhydramine 25-50 mg) 30 minutes before each infusion 1, 2
• Methylprednisolone 100 mg IV 30 minutes prior for RA, GPA, MPA, and PV patients 1, 2
• For patients with prior grade 2+ reactions, corticosteroid premedication reduces severe reactions from 4.7% to 1% 1

Mandatory Screening

• HBsAg and anti-HBc testing before initiating treatment 3, 2
• Baseline immunoglobulin levels, hepatitis C antibodies, and latent tuberculosis screening 5
• Complete blood count and hepatic/renal function 1, 4

Prophylactic Therapy

• PCP prophylaxis for CLL patients during treatment and up to 12 months following 2
• PCP prophylaxis for GPA/MPA patients during treatment and at least 6 months after last infusion 2
• Consider PCP prophylaxis for PV patients and those on concomitant immunosuppression 4, 2

Critical Monitoring Requirements

• Continuous vital sign monitoring for at least 2 hours during infusion, particularly for high-risk patients 1
• Monitoring should continue 1-2 hours after infusion completion, as most reactions occur within 30-120 minutes 5
• Emergency equipment must be readily available 5
• Serial monitoring of immunoglobulin levels, particularly with multiple courses 3, 1

Common Pitfalls to Avoid

• Never assume subsequent infusions are safe after a grade 3 reaction—all such patients had recurrent reactions upon rechallenge 5
• Do not overlook hepatitis B screening—reactivation can cause fulminant hepatic failure and death 5
• Never resume infusion at full rate after a reaction—always reduce to 50% rate after symptom resolution 5
• Do not attempt desensitization outside specialized centers for grade 3-4 reactions 5
• Recognize that severe delayed reactions (DRESS, SJS, TEN) require permanent drug avoidance, not desensitization 1, 5