What is the recommended rituximab dosing, pre‑medication, and monitoring protocol for lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, and ANCA‑associated vasculitis?

Rituximab Protocol: Dosing, Premedication, and Monitoring

Dosing by Indication

Lymphoma

For diffuse large B-cell lymphoma, administer rituximab 375 mg/m² IV once per cycle for 8 cycles in combination with CHOP chemotherapy. 1, 2

• For relapsed or refractory indolent Non-Hodgkin's Lymphoma, use rituximab 375 mg/m² IV once weekly for 4 weeks 1, 2
• For maintenance therapy in indolent NHL with high tumor burden, give 375 mg/m² once every 8 weeks for 12 doses after initial treatment 2

Chronic Lymphocytic Leukemia (CLL)

Rituximab is dosed at 500 mg/m² in CLL (higher than the NHL dose) due to lower CD20 expression on CLL cells, typically administered in combination with fludarabine and cyclophosphamide (FCR regimen). 1

Rheumatoid Arthritis

Administer rituximab 1000 mg IV on days 1 and 15 for patients who have failed disease-modifying antirheumatic drugs including anti-TNF biologics. 1, 3

• Both 2 × 1000 mg and 2 × 500 mg doses have demonstrated efficacy, with the lower dose being safer and more cost-effective 4, 5
• Combination with methotrexate (10-25 mg/week) is recommended for optimal outcomes 4, 6
• Retreatment intervals typically range from 6-12 months based on clinical response 7, 5

ANCA-Associated Vasculitis

For induction therapy in GPA/MPA, administer rituximab 375 mg/m² IV once weekly for 4 weeks. 8, 1, 3

For maintenance therapy, use one of two evidence-based protocols: 1, 2

• MAINRITSAN protocol: 500 mg × 2 at complete remission, then 500 mg at months 6,12, and 18

• RITAZAREM protocol: 1000 mg after induction, then at months 4,8,12, and 16

• Rituximab was non-inferior to cyclophosphamide and appeared more effective for relapsing disease 8

• Optimal duration of remission therapy is 18 months to 4 years after induction 2

Premedication Requirements

All patients must receive premedication with antipyretic and antihistamine before each infusion to reduce infusion reactions. 1, 2

• Infusion reactions occur in up to 77% of patients during the first infusion 1, 2
• Intravenous methylprednisolone premedication reduces the frequency and intensity of first infusion-associated events 4
• For Grade 1/2 infusion reactions: slow or temporarily stop the infusion and provide symptomatic treatment 2
• For Grade 3/4 reactions: stop the infusion and provide aggressive symptomatic treatment 2

Pre-Treatment Screening

Before initiating rituximab, obtain the following baseline assessments: 1, 3, 2

• Hepatitis B testing (HBsAg and anti-HBc) - reactivation can be fatal 1, 3
• Hepatitis C antibody status 1, 3
• Latent tuberculosis screening 1, 3
• Baseline immunoglobulin levels (IgG, IgM, IgA) 1, 3
• Complete blood count with differential 1, 3, 2
• Comprehensive metabolic panel including hepatic and renal function 1, 2

Monitoring During Treatment

Routine Monitoring

Monitor complete blood count with differential at baseline and at 2-4 month intervals during treatment. 3, 2

• Check immunoglobulin levels prior to each course of rituximab and in patients with recurrent infection 8
• In RA patients, 23.3% experienced decreases in IgM below normal, 5.5% in IgG, and 0.5% in IgA after repeated treatment 9
• Peripheral blood CD19 B-cells typically deplete to <10 cells/µL following the first two infusions and remain depleted through month 6 in most patients (84%) 9

Infection Prophylaxis

Pneumocystis jirovecii prophylaxis should be considered in all patients, particularly those receiving combination immunosuppressive therapy. 1

• Use trimethoprim/sulfamethoxazole (800/160 mg on alternate days or 400/80 mg daily) where not contraindicated 8
• Alternatives include dapsone, atovaquone, or inhaled pentamidine 8

For HBsAg-positive patients at high or medium risk, initiate prophylactic antiviral therapy with potent oral anti-HBV agents. 1

Disease-Specific Monitoring

• Vasculitis patients: Urinalysis at each visit to screen for renal relapse; inflammatory markers and renal function every 1-3 months 8
• Patients with prior cyclophosphamide exposure: Investigate persistent unexplained hematuria for bladder cancer risk 8
• All patients: Periodic assessment of cardiovascular risk 8

Special Considerations and Safety

Major Adverse Events to Monitor

Fatal infusion reactions characterized by hypoxia, pulmonary infiltrates, respiratory distress, myocardial infarction, ventricular fibrillation, and cardiogenic shock have been reported, primarily with first infusion. 2

• Progressive multifocal leukoencephalopathy has been reported, especially in patients exposed to multiple immunosuppressants 8, 3
• Fatal sepsis has been reported in lung transplant patients treated for post-transplant lymphoproliferative disorder 1, 2
• Hypogammaglobulinemia develops following treatment, increasing infection risk 2

Vaccination Considerations

Rituximab severely impairs humoral response to vaccinations; administer vaccines prior to treatment whenever possible. 7

• The American College of Rheumatology conditionally recommends continuing other immunosuppressive medications around the time of vaccination 2

Fertility Preservation

Rituximab may be preferable to cyclophosphamide in patients wishing to preserve reproductive potential, as cyclophosphamide is associated with ovarian failure and male infertility. 8

• Long-term effects of rituximab on fertility have not been studied, but no concerns have been reported 8
• Women should avoid rituximab exposure for at least 6 months before conception 5

Dose Adjustments in Special Populations

For elderly patients (≥60 years) with vasculitis receiving rituximab with cyclophosphamide: 2

• Age 60 years: reduce cyclophosphamide to 12.5 mg/kg
• Age 70 years: reduce cyclophosphamide to 10 mg/kg
• GFR <30 mL/min/1.73 m²: reduce cyclophosphamide by 2.5 mg/kg

Avoid dose reductions due to hematological toxicity in patients treated with curative intent; use growth factors for febrile neutropenia instead. 2