Risk reduction demonstrated in NCI*-sponsored trial using up to 16 doses of RITUXAN following CVP†
ECOG 1496: Previously untreated patients1
Percentages are based on calculations.
*NCI: National Cancer Institute.
†CVP: Cyclophosphamide, vincristine, and prednisone.
‡ECOG: Eastern Cooperative Oncology Group.
§CALGB: Cancer and Leukemia Group B.
||The IPI score, which ranged from 0 to 5, was derived by assigning 1 point for each of the following risk factors: age >60 years, Ann Arbor Stage III or IV, extranodal disease involvement at >1 site, ECOG performance status >2, and elevated LDH.
- 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 induction1,2
Study schema from “Results of E1496: A phase III trial of CVP with or without maintenance rituximab in advanced indolent lymphoma (NHL)”¶
E1496 protocol: 16 doses of RITUXAN vs observation following CVP1
¶Hochster HS,Weller E, Ryan T, et al. Results of E1496: A phase III trial of CVP with or without maintenance rituximab in advanced indolent lymphoma (NHL) [abstract]. J Clin Oncol. 2004;22(suppl).Abstract 6502.
¤IWF: International Working Formulation.
**Patients who had progressive disease were not randomized.
- Patients had a tissue diagnosis of low-grade NHL (IWF type A, B, or C). Patients who did not progress after 6–8 cycles of CVP received either 4 weekly doses of RITUXAN every 6 months for up to 2 years (n=162) or observation (n=160)1,2
RITUXAN following CVP reduced risk of progression, relapse, or death by 51%2
Clinical benefit was consistent across diverse patient subgroups1
E1496: subgroup analysis1
- Primary study endpoint: progression-free survival (PFS), defined as time from randomization to progression, relapse, or death2
- Doubled reduction in risk related to PFS was achieved with RITUXAN vs observation (median 28-months follow-up)1
- Risk reduction was observed in a diverse set of patient subgroups studied, including those characteristics associated with a poorer prognosis: baseline age >60 years, and gross residual disease post-CVP therapy1
E1496 dosing strategy based on proven B-cell depletion and recovery2
B-cell§§ recovery began at 6 months and returned to baseline
levels by 12 months after a 4-week course of RITUXAN monotherapy3
††The reduction in risk was derived from the upper limit of the hazard ratio range.
‡‡Hazard ratio 0.49; p<0.05 vs observation.1,2
§§CD19+ is usually coexpressed on B cells expressing CD20+.4
- E1496 dosing (375 mg/m2 weekly x4 every 6 months for up to 2 years)1,2 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)3
- B cells were depleted rapidly3
Most frequent adverse reactions in low-grade NHL patients
RITUXAN following CVP vs observation: 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%).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.
- 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.
- 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.
