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

Indications

RITUXAN® (Rituximab) is indicated for the treatment of patients with:

  • 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.

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 in combination with FC for previously treated CLL

  • Grade 3 or 4 adverse reactions that occurred more frequently in patients treated with R-FC vs. FC were infusion reactions (7% in R-FC arm), 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 for patients who received R-FC vs. FC was 24.8% and 19.1% respectively. For patients who did not have prolonged neutropenia, the frequency of late-onset neutropenia for patients who received R-FC vs. FC was 38.7% and 13.6%, 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 (56% vs. 39%), infections (30% vs. 14%), anemia (21% vs. 10%), thrombocytopenia (19% vs. 8%), and pancytopenia (7% vs. 2%)
  • Fifty-nine percent of R-FC–treated patients experienced an infusion reaction

References:
  1. Data on file, Genentech, Inc.
  2. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2013.

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

BOXED WARNINGS

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

Infections

  • 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

Cardiovascular

  • 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

Renal

  • 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

Immunization

  • The safety of immunization with live viral vaccines following RITUXAN therapy has not been studied and vaccination with live virus vaccines is not recommended

Laboratory Monitoring

  • 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

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.

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.