Management Strategies Used in Pivotal CLL Trials

RITUXAN+FC—Management strategies to help CLL patients stay on therapy

CHEMOTHERAPY DOSE MODIFICATIONS AS PER CLINICAL TRIALS1

FC dose modifications for myelosuppression

If a patient experienced a Grade 3 or 4 cytopenia*

  • Neutropenia
  • Anemia
  • Thrombocytopenia

In both the CLL8 and REACH trials:

  • The next cycle of therapy was delayed for up to 2 weeks
  • The dose of FC was reduced by 25% for all subsequent cycles
  • The planned dose of RITUXAN was maintained at 500 mg/m2

If a patient experienced a second Grade 3 or 4 cytopenia*

In both the CLL8 and REACH trials:

  • The next cycle of therapy was delayed for up to 2 weeks
  • The dose of FC was further reduced by 25% for all subsequent cycles
  • The planned dose of RITUXAN was maintained at 500 mg/m2

If a patient continued to experience Grade 3 or 4 cytopenias* at time of next scheduled dose

In the CLL8 trial:

  • The next cycle of therapy was delayed for up to 2 weeks. If cytopenia did not resolve, therapy, including RITUXAN, was discontinued

In the REACH trial:

  • Therapy, including RITUXAN, was discontinued
  • *Blood counts were measured on Day 28 of each dosing cycle.1
  • FC=fludarabine and cyclophosphamide; CLL=chronic lymphocytic leukemia.
  • In the CLL8 and REACH trials, patients 70 years of age or older received a lower dose intensity of fludarabine and cyclophosphamide compared with younger patients, regardless of the addition of RITUXAN2
  • In the CLL8 trial, the dose intensity of RITUXAN was similar in older and younger patients2
  • In the REACH trial, older patients received a lower dose intensity of RITUXAN2

DOSE REDUCTIONS FOR PATIENTS WHO DEVELOPED IMPAIRED RENAL FUNCTION ON STUDY1

In the CLL8 trial of
first-line CLL 		In the REACH trial of previously treated
RITUXAN-naive CLL
  • CrCL 30-70 mL/min: Fludarabine dose was reduced by 20% and cyclophosphamide dose was reduced by 25%
  • CrCL <30 mL/min: Discontinued FC therapy
  • CrCL 31-70 mL/min: Fludarabine dose was reduced by 25% for remainder of study†
  • CrCL ≤30 mL/min: Treatment was delayed for up to 2 weeks
    • If CrCL >30 mL/min, treatment was restarted at 75% of planned dose and patient was closely monitored
    • If CrCl ≤30 mL/min, treatment was permanently discontinued
  • †The dose of fludarabine was not increased if renal function improved.
  • CrCL=creatinine clearance.

Supportive care was administered in both CLL8 and REACH1

In the CLL8 trial of
first-line CLL 		In the REACH trial of previously treated
RITUXAN-naive CLL
G-CSF was administered if a patient experienced Grade 3 or 4 neutropenia with fever or hypothermia G-CSF was administered at the investigator's discretion and also for all patients who experienced Grade 3 or 4 febrile neutropenia
  • G-CSF=granulocyte colony-stimulating factor.

Premedication recommendations from the RITUXAN prescribing information2

  • Patients should be premedicated with an antihistamine and acetaminophen prior to dosing
  • A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden confers a greater risk of tumor lysis syndrome (TLS). Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS
  • Pneumocystis jiroveci pneumonia (PCP) and anti-herpetic viral prophylaxis is recommended for patients with CLL during treatment and for up to 12 months following treatment as appropriate

THE MAJORITY OF PATIENTS COMPLETED THERAPY1,2

Cycle completion by R-FC-treated patients in the Phase III CLL8 and REACH trials
6 CYCLES OF THERAPY WERE ADMINISTERED TO MOST PATIENTS
  • 75% of patients in the CLL8 trial received 6 cycles of therapy
  • 66% of patients in the REACH trial received 6 cycles of therapy

R=RITUXAN.

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%)

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%)
  • The frequency of prolonged neutropenia was 24.8% for patients who received R-FC (n=274) and 19.1% for patients who received FC (n=274). In patients who did not have prolonged neutropenia, the frequency of late-onset neutropenia was 38.7% in 160 patients who received R-FC and 13.6% of 147 patients who received FC
  • 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%)

References:
  1. Data on file, Genentech, Inc.
  2. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2012.

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.