ECOG 1496 Trial
RITUXAN after first-line CVP induction—a proven strategy for low-grade NHL
ECOG 1496 TRIAL DESIGN1
- *CVP=cyclophosphamide 1 g/m2 on Day 1; vincristine 1.4 mg/m2 on Day 1; prednisone 100 mg/m2 on Days 1–5. After the completion of 6 to 8 twenty-one–day cycles of CVP, patients achieving a CR, PR, or SD were randomized to receive no further treatment or to receive post-induction therapy with RITUXAN. Beginning 4 weeks after completion of induction therapy, patients randomized to RITUXAN received 1 cycle of 4 weekly treatments with 375 mg/m2 RITUXAN, every 6 months for up to 4 cycles.1
- ECOG=Eastern Cooperative Oncology Group; NHL=non-Hodgkin's lymphoma; IWF=International Working Formulation; CR=complete response; PR=partial response; SD=stable disease; PFS=progression-free survival.
ECOG 1496 dosing strategy based on proven B-cell depletion and recovery
B-CELL DEPLETION AFTER RITUXAN MONOTHERAPY IN THE McLAUGHLIN TRIAL2
- McLaughlin P et al. J Clin Oncol. 1998;16:2825-2833.
- In the McLaughlin monotherapy trial in relapsed or refractory, low-grade or follicular NHL2:
- RITUXAN 375 mg/m2 was administered once weekly for 4 weeks
- B cells were rapidly depleted after 4 doses of RITUXAN
- Recovery began at 6 months and returned to baseline levels by 12 months after completion of a 4-week course of RITUXAN monotherapy
- B-cell depletion observed in the McLaughlin trial formed the basis for the ECOG 1496 dosing strategy following first-line CVP induction in low-grade NHL2
The ECOG 1496 trial included both low- and high-risk patients
|Age range (years)||26-84||26-85|
|Elevated LDH (>1×ULN)||24%||21%|
|Ann Arbor Stage||I/II III/IV||
|ECOG performance status||01||
|Bulky disease (>10cm)||19%||24%|
|Number of extranodal sites||01≥2||
|CRF-derived IPI score†||0-1 2 3-4||
- †The IPI score, which ranged from 0 to 5, was derived by assigning 1 point for each of the following risk factors: >60 years of age, Ann Arbor Stage III or IV, extranodal disease involvement at >1 site, ECOG performance status ≥2, and elevated LDH.
- R=RITUXAN; Obs=observation; LDH=lactate dehydrogenase; ULN=upper limit of normal; CRF=case report form; IPI=International Prognostic Index.
- The ECOG 1496 trial's diverse patient population included3:
- Patients across a broad spectrum of age groups (range: 26 to 85 years of age)
- Higher-risk patients with elevated LDH levels and bulky disease
- Lower-risk patients with ECOG performance status of 0-1
RITUXAN after first-line CVP induction more than doubled the likelihood of remaining progression-free at 2.3-year follow-up
- CVP→R provided a 51% reduction in the risk of relapse, progression, or death vs CVP→observation, at 2.3-year median follow-up (p≤0.05)3,4
- Patients with advanced low-grade NHL were randomized to receive either RITUXAN or no further therapy if they achieved a CR, PR, or SD with CVP induction therapy
Safety for 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%)
- Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG 1496 study. J Clin Oncol. 2009;27:1607-1614.
- 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.
- Data on file, Genentech, Inc.
- RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2012.
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 first-line chemotherapy and, in patients achieving a complete or partial response to RITUXAN in combination with chemotherapy, as single-agent maintenance therapy
- 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
- Previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC)
RITUXAN is not recommended for use in patients with severe, active infections.
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) with RITUXAN monotherapy.
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.
Warnings and Precautions
RITUXAN has also been associated with other serious and/or fatal adverse reactions. These include
- hepatitis B reactivation with fulminant hepatitis; hepatic failure resulting in death
- serious, including fatal, bacterial, fungal, and new or reactivated viral infections
- cardiovascular events, including serious or life-threatening cardiac arrhythmias
- severe, including fatal, renal toxicity
- abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving RITUXAN in combination with chemotherapy
Additional Important Safety Information
- The most frequent Grade 3 or 4 adverse reactions observed in NHL were cytopenias, including lymphopenia. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia. The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. These infusion reactions typically resolved with slowing or interruption of the infusion and with supportive care
- The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with CLL were infusion reactions and neutropenia. Infusion-related adverse reactions occurring during or within 24 hours of the start of infusion included nausea, pyrexia, chills, hypotension, vomiting, and dyspnea
- Most CLL patients treated with R-FC experienced at least one Grade 3 or 4 adverse reaction. The Grade 3 or 4 adverse reactions observed more frequently with R-FC compared with FC alone were neutropenia, leukopenia, febrile neutropenia, thrombocytopenia, infusion reactions, pancytopenia, hypotension, and hepatitis B
- In clinical trials, CLL patients 70 years of age or older who received R-FC had more Grade 3 and 4 adverse reactions compared with younger CLL patients who received the same treatment
Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.