What are the recommended dosing schedules, pre‑medication, monitoring, contraindications, and alternative therapies for rituximab in non‑Hodgkin lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis?

Rituximab: Dosing, Administration, and Management Guidelines

Standard Dosing Schedules

Non-Hodgkin Lymphoma (NHL)

For indolent/follicular NHL, administer rituximab 375 mg/m² intravenously once weekly for 4 weeks as the standard regimen. 1, 2, 3

• Aggressive NHL (diffuse large B-cell lymphoma): Rituximab 375 mg/m² IV once per cycle combined with CHOP chemotherapy for 8 cycles total 1, 2, 3
• Extended schedule for indolent NHL: After initial 4 weekly doses, responsive patients may receive 4 additional weekly infusions during weeks 12-16, extending duration of response from 8-11 months to 16-29 months 1
• Maintenance therapy for high tumor burden: Rituximab 375 mg/m² every 8 weeks for 12 doses (category 1 recommendation) 1, 3

Chronic Lymphocytic Leukemia (CLL)

CLL requires higher dosing at 500 mg/m² due to lower CD20 expression on CLL cells, typically combined with fludarabine and cyclophosphamide (FCR regimen). 2

• First-line therapy options include FCR, PCR (pentostatin, cyclophosphamide, rituximab), or bendamustine plus rituximab 1
• For relapsed/refractory disease with del(11q): Use reduced-dose FCR or bendamustine plus rituximab 1

Rheumatoid Arthritis

Administer rituximab 1000 mg intravenously on days 1 and 15 for patients who have failed disease-modifying antirheumatic drugs including anti-TNF biologics. 2

Pre-Medication Requirements

All patients must receive antipyretic and antihistamine before each infusion to reduce infusion reactions, which occur in up to 77% of patients during first infusion. 2, 4

• Infusion reactions are typically mild-to-moderate flu-like symptoms that decrease with subsequent infusions 5
• Approximately 10% experience severe reactions (bronchospasm, hypotension) requiring intervention 5
• For Grade 1/2 reactions: Slow or temporarily stop infusion and provide symptomatic treatment 4
• For Grade 3/4 reactions: Stop infusion immediately and provide aggressive symptomatic treatment 4

Baseline Monitoring and Screening

Before initiating rituximab, obtain comprehensive baseline assessments including: 2, 4

• Hepatitis B surface antigen (HBsAg), hepatitis B core antibody, and hepatitis C antibody status 2, 4
• Latent tuberculosis screening 2, 4
• Baseline immunoglobulin levels (IgG, IgM, IgA) 2, 4
• Complete blood count with differential 2, 4
• Comprehensive metabolic panel including hepatic and renal function 2, 4

Ongoing Monitoring

• Complete blood count with differential at 2-4 month intervals during treatment 4
• Serum immunoglobulin levels before each rituximab course and in patients with recurrent infections 4
• Monitor for late-onset neutropenia, which can occur even when combined with chemotherapy 1

Critical Safety Considerations and Contraindications

Hepatitis B Reactivation

Patients who are HBsAg-positive require prophylactic antiviral therapy with potent oral anti-HBV agents before starting rituximab. 2

• Fatal hepatitis B reactivation has been reported, particularly in Asian populations where hepatitis B is prevalent 6
• Screen for occult hepatitis B infection (anti-HBc positive, HBsAg negative) as reactivation can occur in these patients 6

Infection Prophylaxis

Provide Pneumocystis jirovecii prophylaxis with trimethoprim-sulfamethoxazole (800 mg/160 mg on alternate days or 400 mg/80 mg daily) for all patients, especially those receiving purine analog-based or alemtuzumab combination therapy. 1, 2, 4

• Alternative agents include dapsone, atovaquone, or inhaled pentamidine for patients intolerant to trimethoprim-sulfamethoxazole 4

Progressive Multifocal Leukoencephalopathy (PML)

Monitor for PML, a rare but fatal complication, particularly in patients receiving multiple immunosuppressive agents. 3, 4

Special Population Warnings

• Transplant patients: Fatal sepsis has been reported in lung transplant patients treated for post-transplant lymphoproliferative disorder 2, 4
• Hypogammaglobulinemia: Repeated treatment increases risk, which may lead to serious infections 6
• Pregnancy: Pregnancy testing required in women of childbearing age before chemotherapy 1

Critical Management Issues

IgM Flare in Waldenström's Macroglobulinemia

In patients with baseline serum IgM ≥4000 mg/dL, perform prophylactic plasmapheresis or avoid rituximab during first 1-2 courses until IgM decreases to safer levels. 1

• IgM flare occurs in approximately 50% of WM patients during first months of treatment 1
• This phenomenon does not indicate treatment failure or progression 1

Hematologic Toxicity Management

Avoid dose reductions for hematological toxicity in patients treated with curative intent; use growth factors (G-CSF) for febrile neutropenia instead. 1, 4

Alternative Therapies

When Rituximab is Contraindicated or Ineffective

• Ofatumumab: Fully human CD20-directed antibody targeting different epitope; dose 300 mg week 1, then 1000-2000 mg/week for weeks 2-4 1
• For rituximab intolerance: Consider therapeutic test dose of ofatumumab with appropriate prophylaxis 1
• CLL with del(17p): Alemtuzumab ± rituximab or ibrutinib-based therapy preferred over standard chemoimmunotherapy 1
• Elderly/infirm patients unable to tolerate combination therapy: Single-agent rituximab 375 mg/m² weekly for 4 doses 3

Combination Regimens by Disease

For indolent NHL: 1, 3

• R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) - Category 1
• R-CVP (rituximab, cyclophosphamide, vincristine, prednisone) - Category 1
• Bendamustine + rituximab - Category 1

For CLL without del(11q) or del(17p): 1

• FCR (fludarabine, cyclophosphamide, rituximab)
• BR (bendamustine, rituximab)
• Chlorambucil + rituximab for elderly/comorbid patients

Dosing Adjustments

For ANCA-associated vasculitis patients receiving rituximab with cyclophosphamide: 4

• 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