Use of rituximab in the treatment of lymphoma: An evidence summary

Questions: 1. In what groups of lymphoma patients has rituximab been studied? 2. What beneficial treatment outcomes are associated with the use of rituximab in patients with lymphoma? 3. What is the toxicity of rituximab? 4. What patients are more-or-less likely to benefit from treatment with rituximab?. Perspective: Evidence was selected and reviewed by 2 people, one of whom is a member of the Cancer Care Ontario Practice Guidelines Initiatives Haematology Disease Site Group (DSG). This evidence summary has been reviewed, discussed, and approved by the DSG, which comprises haematologists, medical oncologists, radiation oncologists, methodologists, and community representatives. Methodology: Sources of Evidence: Relevant evidence was identified by a systematic search of the MEDLINE, CANCERLIT, HealthSTAR, CINAHL, PUBMED databases, and the Cochrane Library (using the text words 'rituxan,' 'rituximab,' 'ritux:,' and 'IDEC C2B8'). Also searched were the American Society of Hematology, the American Society of Clinical Oncology, and the Lugano meeting conference proceedings; the European Organisation for Research and Treatment of Cancer and the Physician Data Query databases; and reference lists from selected articles. Patient Population: Patients with non-Hodgkin's lymphoma. Outcomes of Interest: Survival, quality of life, time-to-progression, response duration, response rate, and toxicity were the primary outcomes of interest. Results: Search Results: Twenty-eight studies were identified: 1 randomised trial of 2 different dosing strategies for rituximab in intermediate-grade lymphoma; 11 reports of single-arm studies of rituximab in follicular, low-grade lymphoma, or mantle-cell lymphoma; 1 abstract of a published paper; 8 abstracts of single-arm studies of rituximab in low- and intermediate-grade lymphoma, Waldenstrom's macroglobulinaemia, and post-transplant lymphoproliferative disorders; 3 abstracts of single-arm studies of rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or interferon alpha in follicular, low- or intermediate-grade lymphoma; 1 paper of a single-arm study of rituximab in combination with CHOP in follicular or low- grade lymphoma; 1 abstract of a single-arm study of rituximab in combination with fludarabine; 1 abstract of rituximab in combination with cyclophosphamide; and 1 abstract of rituximab in combination with carmustine (BCNU), cyclophosphamide and etoposide in low-grade or follicular non- Hodgkin's lymphoma. Benefits: The response rates were highest in patients with follicular lymphoma (60%; 95% Confidence Interval (CI): 52-68%) and lowest for those with small lymphocytic lymphoma (18%; 95% CI: 8-28%). Response rates were higher for patients still sensitive to conventional chemotherapy. Data on 1-year survival for mantle-cell lymphoma patients was 80% with a median duration of response of 14.4 months. Data on quality of life were not available. Harms: Detailed toxicity data were provided in the published phase II study. The majority of patients (84%) treated with rituximab in this study had adverse events. The most common of these were: fever (43%), chills (28%), nausea (18%), headache (14%), and allergic symptoms (43%) including angio-oedema (14%). Severe (grade 3 or 4) toxicity was uncommon. Little haematologic toxicity was noted and there did not appear to be any increase in infections up to 1 year after therapy. The majority of adverse events occurred with the first infusion. A 'Dear Doctor' letter was issued indicating that following approval of the drug in the United States (November 1997) and in Europe (June 1998), there were reports of 8 fatalities resulting from cytokine-release syndrome in an estimated 12 000-14 000 treated patients. These reactions occurred early in the first infusion. This appears more common in patients with high tumour burden or who have more than 50 x 10⁹ circulating malignant cells per litre. Future Steps: Rituximab alone, or in combination with chemotherapy, is being compared with conventional chemotherapy in patients with relapsed, as well as those with newly diagnosed, low-grade or follicular lymphoma. It is also being evaluated as part of initial therapy for intermediate-grade lymphoma. At present, the evidence does not allow a firm clinical recommendation on this topic. Please see the full report for a more detailed discussion of the evidence, an interpretive summary, and a description of the opinions of the Disease Site Group members.