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Brand name(s): Rituxan®

• Approved for low-grade or follicular B-cell, CD20-positive non-Hodgkin's lymphoma
• Approved for diffuse large B-cell, CD20-positive non-Hodgkin's lymphoma

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

Low-grade or follicular B-cell, CD20-positive NHL

The first indication was based on a 322 patient study. Patients had an advanced-stage, follicular, CD20+ NHL and were previously untreated with chemotherapy. Patients were randomized (1:1) to receive either a maximum of eight three-week cycles of CVP chemotherapy alone or CVP chemotherapy in combination with rituximab (375 mg/m2 on day 1 of each 21-day cycle).

Patients receiving rituximab plus CVP showed a statistically significant improvement in progression-free survival (PFS) compared to those receiving CVP alone (median PFS 2.4 vs. 1.4 years; hazard ratio 0.44, p<0.0001 two-sided stratified log rank test).

The second indication was based on a 322 patient trial enrolling previously untreated low-grade, B-cell NHL (IWF Grades A, B or C) patients with stable disease or partial or complete responses following six to eight CVP chemotherapy cycles. Patients were randomized (1:1) to receive either no additional therapy or rituximab (375 mg/m2 once weekly for four doses) every six months for up to 16 doses.

A statistically significant reduction in PFS was observed; the hazard ratio for reduction in the risk of progression, relapse, or death ranged from 0.36 to 0.49 for rituximab versus those who received no additional treatment.

The safety profile observed in these trials was consistent with the previously described safety profile provided in the product label.

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Diffuse large B-cell, CD20-positive NHL

Safety and efficacy were demonstrated in three randomized, active-controlled, open-label, multicenter studies with a collective enrollment of 1,854 patients. These trials enrolled primarily patients with diffuse large B-cell lymphoma who had not received prior therapy.

Two of the three studies (E4494 and LNH 98-5/GELA) were restricted to patients 60 years of age or greater, while the third (M39045/MiNT) enrolled patients between ages 18 and 60 years. In E4494 and LNH98-5, the majority of patients had stage III-IV disease, while the majority had stage I-II disease in M39045. Patients received rituximab 375 mg/m2 by differing schedules in combination with CHOP or other anthracycline-based chemotherapy regimens (R-CHEMO).

Each study utilized composite time-to-event endpoints, incorporating disease progression events as the main outcome measure and included overall survival among secondary analyses. Determination of the primary endpoint was based upon investigator-assessment.

In each study, hazard ratios for the main outcome measures favored the rituximab-containing arms. In addition, each study showed an overall survival benefit among patients receiving rituximab. With two years of follow-up, more patients were alive by Kaplan-Meier estimates in the rituximab-containing versus control arms for each study as follows: 74 percent vs. 63 percent, 69 percent vs. 58 percent, and 95 percent vs. 86 percent.

In one of the studies, five-year data were available and demonstrated that the survival advantage persisted with estimated five-year survival rates of 58 percent vs. 46 percent for R-CHOP and CHOP, respectively. Results were generally consistent across subgroups, including age, gender and disease prognostic variables.

There was neither additional improvement in progression-free survival nor overall survival for patients in E4494 receiving R-CHOP who were subsequently randomized to additional rituximab after achieving a complete or partial response as compared to those who received R-CHOP alone.

In all three studies, the dose intensity for rituximab in the R-CHOP and R-CHEMO induction arms was high and rituximab treatment was not associated with a reduction in the dose intensities of individual chemotherapy components.

Adverse events associated with rituximab were generally consistent with the labeled adverse reactions described for single-agent rituximab. Grade 3/ 4 adverse events occurring with ≥ 2 percent excess in the rituximab arm in at least one study included infection, thrombocytopenia, and lung toxicity/dyspnea.

The following serious adverse reactions, some with fatal outcomes, have been reported in patients receiving rituximab: severe or fatal infusion reactions, tumor lysis syndrome, severe mucocutaneous reactions, hepatitis B reactivation with fulminant hepatitis, other viral infections, hypersensitivity reactions, cardiac arrhythmias, renal (kidney) toxicity, and bowel obstruction and perforation.

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