Previously untreated CLL (CLL8)
Proven to drive better outcomes in first-line chronic lymphocytic leukemia (CLL), as shown in a large Phase III trial1
CLL8 TRIAL DESIGN: RITUXAN+FC ×6 cycles vs FC ×6 cycles1–3
- *Binet stage A patients requiring therapy were initially permitted to enter the study but were excluded following the first protocol amendment.2
- FC=fludarabine, dosed at 25 mg/m2/day, and cyclophosphamide, at 250 mg/m2/day, on Days 1 through 3 in both treatment arms. Prior to the first CLL8 protocol amendment, randomization was stratified by site; afterward, randomization was stratified by country and disease stage.3
- NCI-WG=National Cancer Institute-sponsored Working Group; ECOG=Eastern Cooperative Oncology Group; PFS=progression-free survival; R=RITUXAN.
CLL8 Trial of First-Line CLL: Baseline Patient Characteristics2,3†
|Baseline patient characteristics||R-FC (n=408)||FC (n=409)|
|Age range (years)||30-78||36-81|
|Binet stage||A‡ B C||
|ECOG performance status||0 1 2||
- †These patient characteristics are an abbreviated listing of those found in the CLL8 clinical study report.
- ‡Binet stage A patients requiring therapy were initially permitted to enter the study but were excluded following the first protocol amendment.2
The CLL8 trial was not designed or powered to detect a significant difference in PFS by age category. However, exploratory analysis defined by age suggests no observed benefit with the addition of RITUXAN to FC chemotherapy in previously untreated CLL patients 70 years of age or older.
CLL8 Trial—RITUXAN+FC prolonged PFS in first-line CLL1,2
RITUXAN+FC Significantly Improved Median PFS (N=817)1,2
- CI=confidence interval.
- RITUXAN+FC provided a median PFS of 3.3 years in first-line CLL (p<0.01)1
- CR=complete response; ORR=overall response rate.
RITUXAN in combination with FC for previously untreated CLL
- In the CLL8 study of patients with previously untreated CLL, detailed safety data collection was limited to Grade 3 and 4 adverse reactions and serious adverse reactions
- Grade 3 or 4 adverse reactions that occurred more frequently in patients treated with R-FC vs. FC were infusion reactions (9% in the R-FC arm), neutropenia (30% vs. 19%), febrile neutropenia (9% vs. 6%), leukopenia (23% vs. 12%), and pancytopenia (3% vs. 1%)
- The frequency of prolonged neutropenia for patients who received R-FC vs. FC was 8.5% and 5.8% respectively. For patients who did not have prolonged neutropenia, the frequency of late-onset neutropenia for patients who received R-FC vs. FC was 14.8% and 4.3%, respectively
- Grade 3 or 4 adverse reactions that occurred more frequently in R-FC-treated patients ≥70 years of age compared to younger patients were neutropenia (44% vs. 31%), febrile neutropenia (16% vs. 6%), pancytopenia (7% vs. 2%), and anemia (5% vs. 2%)
- RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2013.
- Data on file, Genentech, Inc.
- Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376:1164-1174.
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, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
- 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. Monitor patients closely. Discontinue RITUXAN infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion reactions
- Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving RITUXAN
- Hepatitis B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with RITUXAN, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with RITUXAN. Discontinue RITUXAN and concomitant medications in the event of HBV reactivation
- Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving RITUXAN
Warnings and Precautions
Tumor Lysis Syndrome
- Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, some fatal, can occur within 12−24 hours after the first infusion of RITUXAN in patients with NHL. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden, confers a greater risk of TLS. Administer aggressive intravenous hydration and anti hyperuricemic therapy in patients at high risk for TLS
- Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of RITUXAN-based therapy. Discontinue RITUXAN for serious infections and institute appropriate anti infective therapy
- Discontinue infusions for serious or life threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of RITUXAN for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina
- Severe, including fatal, renal toxicity can occur after RITUXAN administration in patients with NHL. Monitor closely for signs of renal failure and discontinue RITUXAN in patients with a rising serum creatinine or oliguria
Bowel Obstruction and Perforation
- Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving RITUXAN in combination with chemotherapy. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur
- The safety of immunization with live viral vaccines following RITUXAN therapy has not been studied and vaccination with live virus vaccines is not recommended
- Obtain complete blood counts (CBC) prior to each RITUXAN course
Additional Important Safety Information
- The most common Grade 3 or 4 adverse reactions in clinical trials of NHL and CLL were infusion reactions, neutropenia, leukopenia, anemia, thrombocytopenia, and infections. Additionally, lymphopenia and lung disorder were seen in NHL trials; and febrile neutropenia, pancytopenia, hypotension, and hepatitis B were seen in CLL trials
- The most common adverse reactions (incidence ≥25%) in clinical trials of NHL and CLL were infusion reactions. Additionally, fever, lymphopenia, chills, infection, and asthenia were seen in NHL trials; and neutropenia was seen in CLL trials
- Pregnancy: Category C. There are no adequate and well-controlled studies of rituximab in pregnant women
Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.
You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.
You may also report side effects to Genentech at (888) 835-2555.