CLL Dosing

CLL dosing

Management strategies

RITUXAN+FC (R-FC) in CLL—Dosing used in 2 Phase III trials, including more than 1,300 patients1

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.

R-FC Dosing in CLL

Chart: R-FC Dosing in CLL
  • *In the REACH trial, patients had received 1 prior therapy. Patients who had previously received RITUXAN or both fludarabine and cyclophosphamide, either sequentially or in combination, were excluded from the trial, as were fludarabine-refractory patients; alkylator-refractory patients were permitted.2
  • CLL=chronic lymphocytic leukemia.

500 mg/m2 dose of RITUXAN in Cycles 2 through 6 of the R-FC regimen is grounded in data from multiple Phase II trials

  • Two Phase II dose escalation trials of single-agent RITUXAN laid the foundation for the R-FC trials in CLL3,4
    • O’Brien et al (N=40) evaluated increasing the dose of RITUXAN
    • Byrd et al (N=33) evaluated RITUXAN monotherapy 3× weekly
  • Two Phase II trials of R-FC, with a 500 mg/m2 dose of RITUXAN, established the regimen for the Phase III trials5,6
    • Keating et al (N=224) evaluated the R-FC regimen in first-line CLL
    • Wierda et al (N=177) evaluated the R-FC regimen in previously treated CLL

RITUXAN is not approved as monotherapy in CLL.

Infusion Reactions

  • RITUXAN can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion, with time to onset of 30 to 120 minutes
  • RITUXAN-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death
  • Premedicate patients with an antihistamine and acetaminophen prior to dosing. Depending on the severity of the infusion reaction and the required interventions, slow the infusion rate, interrupt the infusion, or permanently discontinue RITUXAN
  • Closely monitor patients with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm3)

Management strategies to help patients stay on therapy

THE MAJORITY OF PATIENTS COMPLETED THERAPY1,2

Chart: THE MAJORITY OF PATIENTS COMPLETED THERAPY

Safety for 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. 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%)
  • 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%)

Safety for RITUXAN in combination with FC for previously treated CLL

Grade 3 and 4 adverse reactions

  • Grade 3 or 4 adverse reactions occurred in 80% of R-FC–treated patients vs 74% 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 (49% vs 44%), febrile neutropenia (15% vs 12%), thrombocytopenia (11% vs 9%), hypotension (2% vs 0%), and hepatitis B (2% vs <1%)
  • Grade 3 or 4 infusion-related adverse reactions occurred in 7% of patients treated with R-FC
  • Grade 3 or 4 infections observed during the trial were similar between treatment arms (18% R-FC vs 19% FC)

Most common adverse reactions

  • The most frequent (≥25%) adverse reactions were neutropenia, nausea, and pyrexia. Fifty-nine percent of R-FC–treated patients experienced an infusion reaction

Grade 3 and 4 adverse reactions in previously treated 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 (56% vs 39%), infections (30% vs 14%), anemia (21% vs 10%), thrombocytopenia (19% vs 8%), and pancytopenia (7% vs 2%)

Go here for information on Management Strategies Used in Pivotal CLL Trials.


References:
  1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2011.
  2. Data on file, Genentech, Inc.
  3. O'Brien SM, Kantarjian H, Thomas D, et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol. 2001;19:2165-2170.
  4. 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.
  5. 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.
  6. 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.

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
  • •  Weekly ×4  •  Weekly ×8  •  Bulky disease  •  Retreatment
  • 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 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 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 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.