E4494 (NCI) Trial
Survival benefits demonstrated in the NCI-sponsored trial
E4494 trial: Elderly DLBCL patients1
Percentages are based on calculations.
*In the E4494 trial, the IPI score, which ranged from 0 to 4, was derived by assigning 1 point for each of the following risk factors: Ann Arbor Stage III or IV, extranodal disease involvement at >1 site, ECOG performance status >2, and elevated LDH.
- In the E4494 trial, a North American Phase III trial, 632 elderly patients were given 6 or 8 twenty-one-day cycles of RITUXAN plus CHOP or CHOP alone1,2
E4494 protocol induction1: R-CHOP x6–8 vs CHOP x6–8
- Patients in the R-CHOP arm received 4 or 5 doses of RITUXAN 375 mg/m2 on Days –7 and –3 (prior to Cycle 1), and 48 to 72 hours pre-Cycle 3, pre-Cycle 5, and pre-Cycle 7 for patients receiving 8 cycles of CHOP induction2
RITUXAN+CHOP prolonged survival in elderly, high-risk DLBCL patients2
E4494 overall survival (N=632)1,2
- At 2 years, RITUXAN+CHOP increased OS from 63% to 74% compared with CHOP alone2
- RITUXAN+CHOP improved median progression-free survival by 94% (3.1 years for R-CHOP vs 1.6 years for CHOP alone)2
- These results reflect a statistical approach, which allows for an evaluation of RITUXAN administered in the induction setting that excludes any potential impact of RITUXAN given after the second randomization2
The authors of the E4494 trial concluded:“After 30 years of CHOP as the treatment of choice for DLBCL, the addition of rituximab to CHOP defines the new standard of care.”3Habermann TM et al. J Clin Oncol. 2006;24:3121-3127.
Grade 3–4 adverse reactions in DLBCL clinical trials
The following Grade 3 or 4 adverse reactions were reported 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%).2
INDICATIONS AND USAGE
Rituxan® (rituximab) is indicated for the treatment of patients with:
- Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
- Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy
- Non-progressing (including stable disease), low-grade, CD20-positive B-cell NHL, as a single agent, after first-line CVP chemotherapy
- Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens
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.
Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusions.
References
- Data on file, Genentech, Inc.
- RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.
- Habermann TM,Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006;24:3121-3127.
