In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
Indication
The CD20-directed monoclonal antibody rituximab (Rituxan) was recently approved for single-agent maintenance therapy in patients with previously untreated follicular, CD20-positive, B-cell non-Hodgkin lymphoma (NHL) who achieved a complete or partial response to rituximab in combination with first-line chemotherapy.1,2
Rituximab has prior NHL indications in 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; nonprogressing low-grade CD20-positive B-cell NHL as a single agent after first-line CVP chemotherapy (cyclophosphamide, vincristine, and prednisone); and previously untreated diffuse large B-cell CD20-positive NHL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or other anthracycline-based regimens. Rituximab also has indications in chronic lymphocytic leukemia, as well as in rheumatoid arthritis, Wegener’s granulomatosis, and microscopic polyangiitis.
Approval of rituximab as maintenance therapy was based on an open-label randomized trial (Primary Rituximab and Maintenance [PRIMA] study) comparing rituximab maintenance (n = 505) vs observation (n = 513) for 2 years in 1,018 patients with previously untreated follicular lymphoma with high tumor burden who achieved response to a first-line chemotherapy including rituximab (R).3 Induction therapy consisted of R-CHOP in 75% of patients, R-CVP in 22%, and R-FCM (fludarabine, cyclophosphamide, mitoxantrone) in 3%.
Progression-free survival at a median 36 months of follow-up in the PRIMA study was 75% in the rituximab group vs 58% in the observation group, yielding a 45% reduction in risk for progression (HR = 0.55, P < .0001). At 2 years, 71.5% of rituximab patients and 52% of observation patients were in complete or unconfirmed complete remission (P = .0001). There was no difference between groups in overall survival (HR = 0.87, 95% CI = 0.51–1.47).
How It Works
Rituximab binds specifically to the antigen CD20 (human B lymphocyte–restricted differentiation antigen, Bp35) located on pre-B and mature B lymphocytes.
The CD20 antigen is expressed on greater than 90% of B-cell NHL cells, but is not found on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues. CD20 regulates early steps in the activation process for cell-cycle initiation and differentiation and may also function as a calcium ion channel. CD20 is not shed from the cell surface and does not internalize upon antibody binding, and free CD20 antigen is not found in the circulation.
How It Is Given
The recommended dose of rituximab as single-agent maintenance therapy is 375 mg/m2 given as IV infusion (not bolus or push) starting at 8 weeks following completion of rituximab plus chemotherapy and continuing every 8 weeks for 12 doses. Patients should be premedicated with acetaminophen and an antihistamine. Rituximab is not recommended for use in patients with severe, active infection.
Safety Profile
Rituximab carries a boxed warning for fatal infusion reactions, tumor lysis syndrome, severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy. Fatal reactions within 24 hours of rituximab infusion have been reported, with approximately 80% of these occurring after the first infusion. Severe mucocutaneous reactions and progressive multifocal leukoencephalopathy have resulted in deaths.
In the trial supporting approval of rituximab, safety data collection was limited to grade 2 or higher infections and grade 3 or higher adverse events. Grade 2 to 4 infection occurred in 39% of rituximab recipients and 24% of those in the observation arm (P < .0001). Grade 3 or 4 adverse events occurred in 24% and 17%, respectively (P = .0026). Grade 3 or 4 adverse events occurring at a higher incidence (≥ 2%) in the rituximab group were infections (4% vs 1%) and neutropenia (4% vs < 1%). ■
References
1. RITUXAN® (rituximab) for injection prescribing information. Genentech Inc, April 2011. Available at http://www.gene.com/gene/products/information/pdf/rituxan-prescribing.pdf. Accessed January 18, 2012.
2. U.S. Food and Drug Administration: Rituximab 2011. Available at http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm241928.htm. Accessed January 18, 2012.
3. Salles G, Seymour JF, Offner F, et al: Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): A phase 3, randomised controlled trial. Lancet 377:42-51, 2011.
