Efficacy in Non-progressing Low-grade
Non-Hodgkin's Lymphoma after CVP

"Results of E1496: A phase III trial of CVP* with or without maintenance rituximab in advanced indolent lymphoma (NHL)"[2]

E1496 was a Phase III, multicenter trial sponsored by NCI† and conducted by ECOG‡ with participation from CALGB,§ designed to evaluate the efficacy and safety of RITUXAN following CVP in low-grade, B-cell NHL patients who did not progress after CVP induction[1,3]

*CVP: Cyclophosphamide, vincristine, and prednisone.
† NCI: National Cancer Institute.
‡ ECOG: Eastern Cooperative Oncology Group.
§ CALGB: Cancer and Leukemia Group B.

Study Schema for Extended Therapy

E1496 protocol

Patients who did not progress after 6-8 cycles of CVP received either RITUXAN 375 mg/m2 weekly x4 every 6 months for up to 2 years (n=162) or observation (n=160)[1,3]

Reduction in Risk of Progression, Relapse, or Death with up to 16 Doses of RITUXAN

51 percent decrease in the risk of disease progression

  • Progression-free survival (PFS), defined as time from randomization to progression, relapse, or death, was the primary endpoint for E1496[3]
  • Double reduction in risk related to PFS was achieved with RITUXAN following CVP vs observation (median 28-month follow-up)[1]
  • Grade 3-4 adverse reactions observed in E1496: Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the RITUXAN arm compared with those who received no further therapy (4% vs 1%).[3]

Dosing Strategy Based on Proven B-Cell Depletion and Recovery

E1496 dosing (CVP followed by Rituxan 375 mg/m2 weekly x4 every 6 months for up to 2 years)[3] was based on findings from the original single-agent multicenter pivotal study of RITUXAN 375 mg/m2 weekly x4 in relapsed or refractory, low-grade or follicular NHL (McLaughlin study N=166).[4]

  • B cells were depleted rapidly[4]
  • B cells began recovery at 6 months and returned to baseline levels by 12 months after a 4-week course of RITUXAN monotherapy[4]
  • The most common Grade 3 or 4 adverse reactions that occurred in patients receiving single-agent RITUXAN were lymphopenia (40%), neutropenia (6%), leukopenia (4%), and infection (4%)[3]

B-cell recovery began at 6 moths and returned to baseline levels by 12 months after a 40-week course of RITUXAN monotherapy

|| CD19+ is usually coexpressed on B cells expressing CD20+.[5]

Efficacy in Previously Untreated Follicular NHL in Combination with CVP

INDICATIONS AND USAGE

Rituxan® (rituximab) is indicated for the treatment of patients with:

BOXED WARNINGS and Additional Important Safety Information

WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

Infusion Reactions
Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions.

Tumor Lysis Syndrome (TLS)
Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin's lymphoma (NHL) patients with Rituxan.

Severe Mucocutaneous Reactions
Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan.

Progressive Multifocal Leukoencephalopathy (PML)
JC virus infection resulting in PML and death can occur in patients receiving Rituxan.

Rituxan has also been associated with fatal hepatitis B reactivation with fulminant hepatitis, other serious viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation.

The most common adverse reactions of Rituxan (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. These infusion reactions generally have resolved with slowing or interruption of the infusion and with supportive care.

Indication-Specific Safety

Single Agent Rituxan for Relapsed or Refractory, Low-Grade or Follicular NHL
The most common adverse reactions of Rituxan (incidence ≥ 25%) observed in patients with relapsed or refractory, low-grade or follicular NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. Respiratory system events were reported in 38% of patients, and 31% reported infectious events. Grade 3 and 4 cytopenias were reported in 48% of patients and included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%).

Rituxan in Combination with CVP for Previously Untreated, Follicular NHL
Patients in the R-CVP arm had higher incidences of infusional toxicity and of neutropenia as compared to those in the CVP arm. The following adverse reactions occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs 5%), cough (15% vs 6%), flushing (14% vs 3%), rigors (10% vs 2%), pruritus (10% vs 1%), neutropenia (8% vs 3%), and chest tightness (7% vs 1%).

Single Agent Rituxan for Low-Grade NHL, after First-Line CVP Chemotherapy
The following common adverse reactions were reported more frequently (≥5%) in patients receiving Rituxan following CVP compared with those who received no further therapy: fatigue (39% vs 14%), anemia (35% vs 20%), peripheral sensory neuropathy (30% vs 18%), infections (19% vs 9%), pulmonary toxicity (18% vs 10%), hepatobiliary toxicity (17% vs 7%), rash and/or pruritus (17% vs 5%), arthralgia (12% vs 3%), and weight gain (11% vs 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the Rituxan arm compared with those who received no further therapy (4% vs 1%).

Rituxan in Combination with CHOP Chemotherapy for DLBCL
The following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs 46%), lung disorder (31% vs 24%), cardiac disorder (29% vs 21%), and chills (13% vs 4%). In the GELA LNH 98-5 study, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP).

The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs 7%) and lung disorder (6% vs 3%). Other Grade 3 or 4 adverse reactions reported more frequently among patients receiving R-CHOP were viral infection (GELA LNH 98-5 study), neutropenia (GELA LNH 98-5 and MInT studies), and anemia (MInT study).

For additional safety information, please see the full prescribing information, including BOXED WARNINGS and Medication Guide.

References

1. Data on file, Genentech, Inc.

2. Hochster HS, Weller E, Ryan T, et al. Results of E1496: A phase III trial of CVP with or without rituximab in advanced in advanced indolent lymphoma (NHL) [abstract]. J Clin Oncol. 2004;22(suppl).Abstract 6502.

3. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.

4. McLaughlin P, Grillo-López AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16:2825-2833.

5. Fisher RI, Mauch PM, Harris NL, Friedberg JW. Non-Hodgkin's lymphomas. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2005:1957-1997.