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

Chart: CLL8 TRIAL DESIGN R-FC x6 cycles vs FC x6 cycles
  • *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.

The 500 mg/m2 dose of RITUXAN in Cycles 2 through 6 of the R-FC regimen was established in multiple Phase II trials.4–7

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
Median age 61 61
Binet stage A‡ B C 4%
64%
31% 		5%
63%
31%
ECOG performance status 0 1 2 57%
43%
- 		58%
41%
<1%
B symptoms 41% 48%
  • †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

Treatment considerations

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.1

CLL8 Trial—RITUXAN+FC prolonged PFS and improved CR rates in first-line CLL1,2

8.3 month improvement in median PFS

RITUXAN+FC Significantly Improved Median PFS (N=817)1,2

Chart: CLL8 Protocol: R-FC x6 cycles vs FC x6 cycles
  • CI=confidence interval.
  • RITUXAN+FC provided a median PFS of 3.3 years in first-line CLL (p<0.01)1
  • RITUXAN+FC more than doubled complete response rates and significantly improved overall response rates vs FC alone (CR=36% vs 17%, p<0.0001; ORR=86% vs 73%, p<0.0001)1,2
  • In responders, RITUXAN+FC provided more durable responses (median duration of response 40.2 months vs 34.7 months with FC alone, p=0.004)2
  • CR=complete response; ORR=overall response rate.

Safety for RITUXAN in combination with FC for previously untreated CLL

Grade 3 and 4 adverse reactions

  • 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. In this study, Grade 3 and 4 adverse reactions occurred in 77% of R-FC–treated patients vs 62% of FC-treated patients
  • Grade 3 or 4 adverse reactions that occurred more frequently (≥2%) in patients treated with R-FC vs FC were neutropenia (30% vs 19%), febrile neutropenia (9% vs 6%), leukopenia (23% vs 12%), and pancytopenia (3% vs 1%)
  • The frequency of prolonged neutropenia was 8.5% for patients who received R-FC (n=402) and 5.8% for patients who received FC (n=398). In patients who did not have prolonged neutropenia, the frequency of late-onset neutropenia was 14.8% of 209 patients who received R-FC and 4.3% of 230 patients who received FC
  • Grade 3 or 4 infusion-related adverse reactions occurred in 9% of patients treated with R-FC
  • Grade 3 or 4 infections observed during the trial were similar between treatment arms (18% R-FC vs 17% FC)

Grade 3 and 4 adverse reactions in previously untreated patients ≥70 years of age

  • Grade 3 or 4 adverse reactions that occurred more frequently in R-FC–treated patients ≥70 years of age compared with R-FC–treated patients <70 years of age were neutropenia (44% vs 31%), febrile neutropenia (16% vs 6%), pancytopenia (7% vs 2%), and anemia (5% vs 2%)

References:
  1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2012.
  2. Data on file, Genentech, Inc.
  3. 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.
  4. Keating MJ, O’Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23:4079-4088.
  5. Wierda W, O’Brien S, Wen S, et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005;23:4070-4078.
  6. O’Brien SM, Kantarjian H, Thomas D, et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol. 2001;19:2165-2170.
  7. Byrd JC, Murphy T, Howard RS, et al. Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol. 2001;19:2153-2164.

Indications

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

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 infusion.