What are the potential side effects of rituximab (a monoclonal antibody) in adults with a history of cancer or autoimmune disease?

Side Effects of Rituximab

Rituximab carries significant risks including fatal infusion reactions, serious infections (particularly progressive multifocal leukoencephalopathy and hepatitis B reactivation), profound B-cell depletion leading to hypogammaglobulinemia, and cardiac complications—all requiring vigilant monitoring and premedication strategies.

Life-Threatening Infusion Reactions

Fatal infusion reactions occur primarily with the first infusion and are characterized by hypoxia, pulmonary infiltrates, respiratory distress, myocardial infarction, ventricular fibrillation, and cardiogenic shock 1. Severe infusion reactions occur in approximately 10% of patients, with an overall incidence of 77% during first administration, decreasing to 3-8% in subsequent infusions 2.

• Premedication with antipyretics, antihistamines (diphenhydramine 25-50 mg), and acetaminophen (650 mg) 30 minutes before each infusion is mandatory 2, 3
• Methylprednisolone 100 mg IV should be strongly considered 30 minutes prior, especially for first infusions 2
• Continuous vital sign monitoring for at least 2 hours during infusion is required, particularly in high-risk patients 2
• Patients with high tumor burden or lymphocyte count >25 × 10⁹/L require reduced infusion rates 2

Infectious Complications

Infections represent the leading cause of death in rituximab-treated patients, accounting for 75% of fatalities in autoimmune blistering diseases and 43.6% in other autoimmune conditions 4.

Critical Infections Requiring Screening and Prophylaxis

• Hepatitis B reactivation can cause fulminant liver failure and death; all patients must be screened for HBV before treatment and receive preemptive antiviral therapy if positive 2, 5
• Progressive multifocal leukoencephalopathy (PML), caused by JC polyomavirus reactivation, has been reported with increasing frequency and is often fatal 1, 2
• Pneumocystis pneumonia risk is elevated, particularly with concomitant immunosuppression; prophylaxis should be considered in all patients 1, 2
• Fatal sepsis has been documented in lung transplant patients, with one case notable for developing hypogammaglobulinemia following treatment 1

Infection Risk Factors

• Prolonged B-cell depletion (median recovery 9 months, range 5.9-14.4 months) dramatically reduces antibody responses to recall antigens 2
• Pre-existing hypogammaglobulinemia significantly increases risk of IgG reduction and serious infections 6
• Concomitant cyclophosphamide or other immunosuppressive therapy increases hypogammaglobulinemia risk 6
• Mortality rate in autoimmune blistering diseases (10.4%) is statistically significantly higher than other autoimmune diseases (2.4%) 4

Hematologic Toxicity

• Neutropenia risk increases with long-term therapy, especially if patients previously or concurrently received cytotoxic chemotherapy 1
• Grade 3-4 neutropenia occurs in 30-49% of patients receiving rituximab with fludarabine/cyclophosphamide 5
• Febrile neutropenia occurs in 9-15% of patients in combination regimens 5
• Thrombocytopenia and pancytopenia occur more frequently with rituximab-containing regimens 5

Cardiovascular Complications

Rituximab may cause chest pain, irregular heartbeats, myocardial infarction, and cardiogenic shock 1, 5. Supraventricular arrhythmias or tachycardia account for most cardiac disorders (4.5% vs. 1.0% without rituximab) 5. Cardiac monitoring during and after treatment is required in patients with symptoms or history of heart problems 5.

Gastrointestinal and Renal Toxicity

• Tumor lysis syndrome (TLS) occurs within 12-24 hours of first infusion, causing kidney failure, abnormal heart rhythm, and electrolyte disturbances 2, 5
• Severe kidney problems leading to death can occur, particularly in non-Hodgkin lymphoma patients 5
• Bowel problems including blockage or tears can occur when rituximab is combined with chemotherapy, sometimes leading to death 5
• Nausea, vomiting, diarrhea, and abdominal pain are common gastrointestinal symptoms during infusion reactions 2, 3

Pulmonary Complications

Interstitial pneumonitis has been reported in several patients with non-Hodgkin lymphoma, with some cases proving fatal 1. Recovery may occur with cessation of rituximab and steroids, but fatal cases have been documented 1. Pulmonary complications include cough, rhinitis, nasal congestion, wheezing, and dyspnea 2.

Immunologic Suppression

• Prolonged B-cell depletion persists even after clinical recovery, with patients remaining at risk for extended periods 4
• Hypogammaglobulinemia develops in some patients for longer than 11 months, with subsequent infection development 5
• Patients fail to mount efficient post-vaccination immune responses against hepatitis B, tetanus, diphtheria, and pneumococcal vaccines 7
• Baseline and periodic monitoring of IgG, IgM, and IgA levels is recommended throughout treatment 6

Severe Cutaneous Reactions

DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms), AGEP (Acute Generalized Exanthematous Pustulosis), Stevens-Johnson syndrome, and toxic epidermal necrolysis are severe reactions requiring permanent drug avoidance 2. These reactions are not amenable to desensitization protocols 3.

Serum Sickness

Serum sickness occurs when rituximab is used for autoimmune diseases, with higher incidence in pediatric patients with idiopathic thrombocytopenic purpura 1. The condition is more common in patients with autoimmune diseases (78-85% of cases) and may respond to systemic glucocorticoids 3.

Pediatric-Specific Considerations

• Mild to moderate infusion reactions are common in children 1
• Serum sickness and hypotension have been reported in pediatric ITP patients 1
• In pediatric DLBCL/BL/BLL/B-AL, serious adverse reactions occur in 55% of patients, with febrile neutropenia (15%), stomatitis (11%), and sepsis (8%) being most common 5
• Fatal adverse reactions occur in 3% of pediatric patients, most often due to sepsis 5

Pregnancy and Lactation

Rituximab is pregnancy category C with no adequate controlled studies in pregnant women 1. High rituximab concentrations and absent B-cells at birth have been documented, though B-cell counts and IgG normalized by 4 months 1. IgG is present in human milk, but rituximab concentrations and infant absorption have not been measured 1.

Essential Monitoring Protocol

• Screen all patients for hepatitis B, hepatitis C, latent tuberculosis, and baseline immunoglobulin levels before initiating therapy 2, 8
• Obtain daily CBC and hepatic/renal function during therapy initiation, then periodically based on clinical response 1, 2
• Monitor B-cell levels until return to normal, even after clinical recovery 4
• Check immunization status and update vaccinations before treatment when possible 8
• Perform blood tests to check for tumor lysis syndrome 5

Common Non-Life-Threatening Side Effects

• Infusion-related reactions including fever, chills, body aches, and tiredness occur in most patients 5
• Upper respiratory tract infections, nasopharyngitis, urinary tract infections, and bronchitis occur in >10% of patients 5
• Aching joints during or within hours of infusion 5
• Fatigue, anemia, peripheral sensory neuropathy, rash/pruritus, arthralgia, and weight gain occur with maintenance therapy 5