What are the toxicities of rituximab and the recommended monitoring and management?

Toxicity of Rituximab: Monitoring and Management

Life-Threatening Infusion Reactions

Fatal infusion reactions occur primarily with the first rituximab infusion and are characterized by hypoxia, pulmonary infiltrates, respiratory distress, myocardial infarction, ventricular fibrillation, and cardiogenic shock. 1, 2

• Infusion-related reactions occur in approximately 77% of patients during the first administration, decreasing to 3-8% in subsequent infusions 2
• Severe reactions (grade 3-4) occur in approximately 10% of patients 1, 3
• Mild-to-moderate reactions include fever, rigors, chills, myalgias, headache, rash, urticaria, and transient hypertension in 20-32% of patients 2, 4

Mandatory Premedication Protocol

• Administer acetaminophen 650-1000 mg and diphenhydramine 25-50 mg 30 minutes before each infusion 2, 5
• Add methylprednisolone 100 mg IV 30 minutes prior, especially for the first infusion 2
• Corticosteroid premedication reduces severe reactions from 4.7% to 1% 2

Infusion Rate Management

• Start the first infusion at 50 mg/hour for 30 minutes, then increase by 50 mg/hour every 30 minutes to a maximum of 400 mg/hour 2
• For grade 1 reactions (cutaneous symptoms only): stop or slow to 50%, treat symptoms, resume at 50% of previous rate 2
• For grade 2 reactions (urticaria, nausea, dyspnea): stop immediately, give methylprednisolone 40 mg IV if not already given, resume at 50% after complete resolution 2
• For grade 3 reactions (symptomatic bronchospasm, hypoxia): stop immediately and permanently discontinue for that session 2
• For grade 4 reactions (anaphylaxis, shock): permanently discontinue rituximab and never rechallenge 2, 5

Infectious Complications

Hepatitis B Reactivation

All patients must be screened for hepatitis B before initiating rituximab, as reactivation can cause fulminant liver failure and death. 1, 2, 5

• Patients who are HBsAg-positive or anti-HBc-positive require preemptive antiviral therapy before starting rituximab 2
• Monitor HBV DNA levels during and for at least 12 months after completing rituximab 2

Progressive Multifocal Leukoencephalopathy (PML)

• PML is a rare but lethal encephalitis caused by JC polyomavirus reactivation 1, 2
• Risk increases with concomitant immunosuppressive medications 1
• Maintain high clinical suspicion for new neurological symptoms (confusion, vision changes, weakness, speech difficulties) 2

Pneumocystis Pneumonia

• Prophylaxis with trimethoprim-sulfamethoxazole should be considered in all patients, particularly those receiving concomitant immunosuppression 1, 2, 6
• Continue prophylaxis for at least 6 months after the last rituximab dose regardless of B-cell recovery 6, 7

Other Infections

• Fatal sepsis has been reported in lung transplant patients treated with rituximab for PTLD 1
• Antibody responses to recall antigens are dramatically reduced, with median B-cell recovery time of 9 months (range 5.9-14.4 months) 2
• Vaccination with live virus vaccines is contraindicated before or during rituximab therapy 5
• Administer non-live vaccines at least 4 weeks prior to rituximab when possible 5

Hematologic Toxicity

• Grade 3-4 neutropenia occurs in 13-29% of patients receiving rituximab with bendamustine 1, 7
• When combined with chemotherapy, rituximab increases neutropenia rates but does not translate to higher infection rates 4, 3
• Rituximab itself does not require dose reduction for neutropenia; adjust chemotherapy doses instead 7
• Monitor CBC weekly for the first 4-6 weeks after each cycle, then every 2 weeks until the third cycle 7

Immunologic Effects

Hypogammaglobulinemia

• Risk of hypogammaglobulinemia increases only after several cycles of therapy 1
• One case of fatal sepsis following hypogammaglobulinemia development has been reported 1
• Monitor serum immunoglobulin levels before and periodically after rituximab 2
• IgM levels may decrease while IgG and IgA typically remain stable 4, 8

B-Cell Depletion

• Rituximab causes rapid depletion of CD20-positive B-cells in peripheral blood 4, 8
• B-cells remain low or undetectable for 2-6 months, generally returning to pretreatment levels within 12 months 4, 8
• T-cells are unaffected, which explains the rarity of opportunistic infections compared to other immunosuppressants 4

Cardiovascular Complications

• Myocardial infarction, ventricular fibrillation, and cardiogenic shock have been documented 1, 2, 5
• Monitor vital signs continuously for at least 2 hours during infusion, particularly for high-risk patients 2
• Chest pain, irregular heartbeats, and hypotension require immediate evaluation 2

Pulmonary Toxicity

• Interstitial pneumonitis has been reported in patients with non-Hodgkin's lymphoma, with some fatal cases 1, 2
• Severe infusion reactions may present with hypoxia and pulmonary infiltrates 2
• Patients with high tumor burden or lymphocyte count >25 × 10⁹/L require reduced infusion rates 2

Gastrointestinal Toxicity

• Abdominal pain, bowel obstruction, and perforation can occur, in some cases leading to death 5
• Mean time to gastrointestinal perforation is 6 days (range 1-77 days) in NHL patients 5
• Evaluate immediately if abdominal pain or repeated vomiting occurs 5
• Grade 3 diarrhea occurs in approximately 15% of patients 2

Severe Mucocutaneous Reactions

• DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms), AGEP (Acute Generalized Exanthematous Pustulosis), Stevens-Johnson syndrome, and toxic epidermal necrolysis require permanent drug avoidance 2, 5
• Serum sickness has been reported, with higher incidence in pediatric patients with ITP 1, 2

Renal Toxicity

• Severe, including fatal, renal toxicity can occur, particularly in patients experiencing tumor lysis syndrome 5
• Monitor closely for rising serum creatinine or oliguria 5
• Discontinue rituximab in patients with signs of renal failure 5

Critical Monitoring Algorithm

Before Each Infusion

• Screen for active infections, fever, or new symptoms 2
• Verify hepatitis B status is documented 2, 5
• Obtain CBC if not done within the past week 7
• Administer premedication 30 minutes before infusion 2

During Infusion

• Monitor vital signs continuously for at least 2 hours 2
• Have resuscitation equipment immediately available 2
• Stop infusion immediately for any grade 2 or higher reaction 2

After Treatment

• Monitor for delayed infections, particularly PML symptoms 2
• Check CBC and hepatic/renal function periodically 2
• Continue PJP prophylaxis for 6 months after last dose 6, 7
• Monitor for B-cell recovery at 6-12 months 4, 8

Special Populations

Pregnancy

• Rituximab is pregnancy category C with documented B-cell lymphocytopenia in infants exposed in utero 2, 5
• High rituximab concentrations and absent B-cells at birth have been documented, though B-cell counts normalized by 4 months 2
• Advise females of reproductive potential to use effective contraception during treatment and for 12 months after the last dose 5

Elderly Patients

• Elderly patients (>65 years) may require more aggressive supportive care due to increased infection risk 7
• Consider reduced infusion rates and enhanced monitoring 2