CLL Dosing Rationale

RITUXAN 375 mg/m2 in Cycle 1 and 500 mg/m2 in Cycles 2-6 of R-FC—proven dosing in CLL

TWO LARGE PHASE III STUDIES RESULTED IN THE INDICATED DOSING IN CLL1

FDA-approved dosing of RITUXAN in the R-FC regiment1*
Cycle 1 Cycles 2-6
375 mg/m2 500 mg/m2
given on the day prior to the initiation of the first cycle of FC chemotherapy
 given on Day 1 of subsequent cycles
  • *In the R-FC regimen, fludarabine (25 mg/m2 per day) and cyclophosphamide (250 mg/m2 per day) are given on Days 1-3 of all cycles. Each cycle is 28 days in length.1
  • CLL=chronic lymphocytic leukemia; R=RITUXAN; FC=fludarabine and cyclophosphamide.

From a biologic standpoint, CLL has important differences from NHL

There is lower expression of CD20 on the surface of B cells in CLL than is seen in follicular lymphoma2,3

There is a higher number of circulating malignant cells in CLL than in follicular lymphoma4-6

Increasing evidence led to the RITUXAN 500 mg/m2 dosing in Cycles 2-6 of the R-FC regimen

Early phase II studies of RITUXAN 375 mg/m2 monotherapy in previously treated CLL showed low response rates

  • Winkler et al (N=9), Blood, 19997
  • Nguyen et al (N=15), European Journal of Haematology, 19998
  • Huhn et al (N=28), Blood, 20019
  • Itälä et al (N=23), European Journal of Haematology, 200210

RITUXAN is not approved as monotherapy in CLL.

To determine whether there is a dose-response relationship of RITUXAN in CLL, additional Phase II studies were conducted

  • O’Brien et al dose escalation study (N=40) showed that higher doses of RITUXAN resulted in higher response rates5
  • Byrd et al (N=33) demonstrated that a dose-dense regimen could improve response rates6

Establishment of a RITUXAN dose-response relationship in CLL prompted Phase II studies evaluating RITUXAN at 500 mg/m2 in Cycles 2-6 of the R-FC regimen

  • Keating et al (N=224) evaluated the R-FC regimen in first-line CLL11
  • Wierda et al (N=177) evaluated the R-FC regimen in previously treated CLL12

Based on cumulative evidence from Phase II trials, the Phase III CLL8 and REACH trials of R-FC were designed using the RITUXAN dosing of 500 mg/m2 in Cycles 2-613

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)

NHL=non-Hodgkin's lymphoma

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%)

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


References:
  1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2012.
  2. Almasri NM, Duque RE, Iturraspe J, Everett E, Braylan RC. Reduced expression of CD20 antigen as a characteristic marker for chronic lymphocytic leukemia. Am J Hematol. 1992;40:259-263.
  3. Yee KWL, O’Brien SM. Chronic lymphocytic leukemia: diagnosis and treatment. Mayo Clin Proc. 2006;81:1105-1129.
  4. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute—Working Group 1996 guidelines. Blood. 2008;111:5446-5456.
  5. O’Brien SM, Kantarjian H, Thomas DA, et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol. 2001;19:2165-2170.
  6. 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.
  7. Winkler U, Jensen M, Manzke O, Schulz H, Diehl V, Engert A. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood. 1999;94:2217-2224.
  8. Nguyen DT, Amess JA, Doughty H, Hendry L, Diamond LW. IDEC-C2B8 anti-CD20 (rituximab) immunotherapy in patients with low-grade non-Hodgkin’s lymphoma and lymphoproliferative disorders: evaluation of response on 48 patients. Eur J Haematol. 1999;62:76-82.
  9. Huhn D, von Schilling C, Wilhelm M, et al. Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. Blood. 2001;98:1326-1331.
  10. Itälä M, Geisler CH, Kimby E, et al. Standard-dose anti-CD20 antibody rituximab has efficacy in chronic lymphocytic leukaemia: results from a Nordic multicentre study. Eur J Haematol. 2002;69:129-134.
  11. 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.
  12. 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.
  13. Data on file, Genentech, Inc.

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.