B cell non-Hodgkin's lymphoma: rituximab safety experience

0 Division of Hematology, Keck School of Medicine, University of Southern California , Los Angeles, California , USA A substantial body of data supports use of rituximab as first-line and maintenance therapy for the treatment of indolent nonHodgkin's lymphoma. With 7 years of postmarketing surveillance experience and more than 370,000 patient exposures, the safety profile of rituximab is well defined. Several multicenter trials suggest that infusion reactions associated with rituximab administration are well characterized and generally associated with the first infusion; toxicity is reduced with subsequent doses. Since some adverse events are related to circulating tumor loads of nonHodgkin's lymphoma, fewer events are anticipated in rheumatoid arthritis. Low infection rates in oncology would indicate similar safety in patients with rheumatoid arthritis. - Introduction The US Food and Drug Administration (FDA) approved the chimeric anti-CD20 monoclonal antibody rituximab in 1997 as a single-agent treatment for relapsed or refractory, low grade or follicular CD20+, B cell non-Hodgkins lymphoma (NHL). In as many as 85% patients, NHL is of B cell origin, and a majority has high affinity expression for CD20. For that reason, rituximab is now widely used in hematologic oncology. Almost half a million patients have been treated with rituximab, either alone or in combination, from phase II and III of development through postmarketing approval. Although not formally approved for use in combination protocols by the FDA, rituximab is now included in a standard-of-care, in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy, for treatment of aggressive lymphomas of B cell origin. In the original clinical studies, patients received four weekly doses of 375 mg/m2; this dosage schedule increased to eight weekly infusions of 375 mg/m2 in subsequent trials. The choice of cumulative dosage was somewhat arbitrarily based on biologic factors. Doctors frequently give extended courses of rituximab (four to eight courses instead of the standard Arthritis Research & Therapy 2005, 7(Suppl 3):S19-S25 (DOI 10.1186/ar1739) single 4-week course) to those patients who have not reached dose limiting toxicity. Overall, rituximab has exhibited very strong and consistent efficacy alone and in combination with virtually all of the chemotherapeutic agents used to treat B cell lymphomas. This has resulted in a very large safety database, permitting accurate assessment of the nature of the specific side effects and risks involved in using this drug. Safety of rituximab A substantial and growing body of data illustrates the safety of rituximab when used as first-line treatment and maintenance therapy for NHL. Although responses in a rheumatoid arthritis (RA) population are different from those in NHL patients, knowledge gained in the oncology setting may be of significant relevance to treatment of RA patients. McLaughlin and coworkers [1] described the safety profile of rituximab monotherapy in a pivotal phase III study conducted in relapsed and refractory indolent NHL. In that trial patients with relapsing low grade or follicular lymphoma received, on an outpatient basis, intravenous rituximab 375 mg/m2 weekly for 4 weeks. A total of 166 patients were enrolled in the trial, with an approximately 48% response rate. With a median follow up of 11.8 months, the authors observed that among responders the projected time to progression was 13.0 months. The majority of adverse events (AEs), which were grade 1 and 2 in severity, occurred during the first infusion period, with fever and chills being the most common symptoms. Only 12% of patients had grade 3 toxicities, and 3% had grade 4 toxicities. A human antichimeric antibody was detected in only one patient. The researchers suggested that the toxicity was mild. The risk factors for severe AEs associated with use of rituximab are well defined. Moreover, because some of the AE = adverse event; CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone; CLL = chronic lymphocytic leukemia; NHL = nonHodgkins lymphoma; RA = rheumatoid arthritis; SLL = small lymphocytic lymphoma. rare AEs of rituximab are related to circulating tumor loads in NHL, it can be anticipated that they will be less likely to occur in the RA population. The AE profile for rituximab has been consistent throughout numerous subsequent studies in both indolent and aggressive NHL. Hainsworth and coworkers [2] enrolled 62 patients with indolent follicular or small lymphocytic subtypes of NHL. These patients, who were previously untreated with systemic therapy, received intravenous rituximab 375 mg/m2 weekly for 4 weeks. Patients were restaged at week 6 to assess the response; those with an objective response or stable disease received maintenance rituximab courses (identical dose and schedule) at 6-month intervals. The minimum follow-up period was 24 months. Median actuarial progression-free survival was 34 months. The study reported that treatment with rituximab was well tolerated. Of the 62 patients who received 245 rituximab doses (four doses per patient), only two developed grade 3 or grade 4 AEs. One patient, the only patient in whom therapy was discontinued because of treatment-related toxicity, had flushing, dyspnea, and ischemic chest pain. One additional patient had severe chills and rigors with the first dose of rituximab but was able to continue treatment without further episodes. The most common grade 1 or 2 toxicities were fever (18%), chills/rigors (26%), and nausea (21%). Almost all AEs occurred during the first rituximab infusion. The infusion reaction also appeared to be related to the tumor load, suggesting that such reactions might be less likely or severe in patients with RA. Hainsworth and coworkers [2] reported that eight patients in the study (13%) had circulating malignant lymphocyte counts greater than 10,000/ l upon initiation of treatment. Four of these eight patients experienced grade 1 or 2 infusion related toxicity during the first dose of rituximab, but none developed grade 3 or 4 toxicity. The incidence of toxicity in patients older than 70 years was comparable to that in younger patients. The other grade 1 or grade 2 AEs related to infusions included flushing (five patients), hypotension (three patients), headache (three patients), and chest pain, angioedema and bronchospasm (one case each). Overall, 18 patients reported fatigue, four had anemia and two developed leukopenia, all grade 1 or 2 AEs. No cumulative or additional toxicities were seen with maintenance courses. French researchers conducted an open label, randomized, phase II trial to evaluate the clinical efficacy and safety of rituximab in patients with progressive intermediate or high grade NHL [3]. Study participants received one of two dosage schedules of rituximab (all intravenous): 375 mg/m2 once weekly for 8 weeks; and 375 mg/m2 o (...truncated)