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  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 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  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  reported that eight patients in the study (13%) had circulating malignant lymphocyte counts greater than 10,000/μl 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 . Study participants received one of two dosage schedules of rituximab (all intravenous): 375 mg/m2once weekly for 8 weeks; and 375 mg/m2 on day 1 followed by 500 mg/m2 on day 8 and once weekly for a further 7 weeks. Rituximab was administered via a peripheral or central intravenous line in an outpatient setting. Infusion was started at an initial rate of 50 mg/hour. If no toxicity was observed during the first hour, then the dosage was escalated by increments of 50 mg/hour every 30 min to a maximum of 300 mg/hour. If the starting dose of rituximab was well tolerated, then the starting flow rate for the administration of the second and subsequent infusions was fixed at 100 mg/hour, with similar increments at 30 min intervals up to 400 mg/hour. The infusion was interrupted if patients experienced severe fever, rigors, edema or mucosal congestion, hypotension, or any other serious AEs. Following resolution of the AEs, the infusion was to be resumed at half the previous rate. The dose was not modified throughout the treatment period. Administration of oral premedication with acetaminophen at 1000 mg and diphenhydramine hydrochloride at 50–100 mg was recommended 30–60 min before each infusion.
Of the 54 patients who were enrolled over a 6-month period, 36 were able to complete the 8-week treatment program. Five patients achieved a complete response and 12 others a partial response. The overall response rate was not statistically significantly different between the two dosage groups.
All patients enrolled in this study received at least one infusion of rituximab. Five patients did not experience any infusion reactions. Altogether, the other 49 patients reported 168 infusion reactions, although nearly 90% of these reactions were termed 'mild to moderate' in severity. In both arms, the majority of AEs occurred during the first infusion and resolved within the same outpatient treatment day. The frequency of AEs and their severity decreased for the subsequent infusions. Grade 3 and grade 4 AEs were seen predominantly during or shortly after the first infusion. Two deaths during the study period were reported, and both were judged secondary to the study disease. Before death, both patients had been withdrawn from the study because of progressive disease.
In another study, Colombat and colleagues  recruited 49 patients with grade 1–3, stage II–IV follicular NHL. Ten patients treated with rituximab achieved a complete response rate and, overall, 39 patients (80% of the patients in the study) achieved objective responses to treatment.
All patients in this trial were able to receive the four weekly infusions at full dose. The most common AEs thought to be related to rituximab infusions were grade 1–2 fever, headache, asthenia, pain, rash, laryngitis, rhinitis, paresthesia, hypotension, and nausea. Two cases of grade 3–4 hypotension and hypertension resolved after appropriate pharmacologic management, given in accordance with the protocol procedures. No hematologic toxicity was observed and only one minor infection was reported during the course of the study.
Davis and coworkers  administered rituximab to 31 patients with follicular NHL, all of whom had previously undergone therapy. All patients received four rituximab doses. The study found that 43% of patients achieved a response to therapy. The time to response was similar to that observed in patients without bulky disease who had been administered rituximab with different treatment protocols.
About 93% of the clinical AEs were considered mild to moderate, or grade 1 or 2. The majority of patients experienced AEs during the first infusion, and incidence declined with subsequent infusions. The most common related events observed during the treatment period included transient fever (61% of patients), chills (36%), leukopenia (23%), nausea (19%), dizziness (19%), and throat irritation (19%). Grade 3 or 4 related nonhematologic clinical events occurred in four patients: two with pulmonary disorders, one with chills, and one with pain and infusion-related hypotension. The AEs resolved in three of these four patients. No grade 3 or 4 infections were reported, and no patients were hospitalized for infection; however, six infections reported in five patients (pneumonia, rhinitis, sinusitis, herpes zoster, and uncategorized infection) were treated subsequently without incident. None of the patients in this study were forced to discontinue treatment because of AEs.
Foran and colleagues  in London treated 131 patients with mantle cell lymphoma, immunocytoma, and small B cell lymphocytic lymphoma; these B cell malignancies express CD20 and historically were incurable with standard therapy. For this study, rituximab 375 mg/m2 was administered for 4 weeks as an intravenous infusion in 1 litre normal saline. Of the 120 evaluable patients (11 could not be included in the treatment response assessment because of treatment-related toxicity, including one who died from splenic rupture), 36 (30%) achieved an objective response to rituximab. Although 10 patients achieved a complete response, most of the enrollees had only a partial response to rituximab. Sixty-one patients had stable disease, and 23 had evidence of progressive disease (confirmed during therapy or at the 1 month restaging analysis).
All 131 patients were evaluated for toxicity. The infusions were generally well tolerated, even though infusion-related side effects such as fever, rigors, and nausea were relatively common. These side effects occurred most frequently with the first treatment, and in most cases they were managed with adjustments to the infusion rate. The researchers noted that the average duration of the first infusion was 5.2 hours compared with 3.4 hours for subsequent infusions, reflecting the requirement for fewer interruptions caused by adverse reactions and a more rapid infusion rate in later weeks.
No evident excess in infusional toxicity was observed in the 10 patients presenting with a marked lymphocytosis (i.e. > 25 × 109/l), although one patient did experience a severe anaphylactic-type reaction with the first infusion, which necessitated its discontinuation. The latter patient was subsequently able to complete treatment without further reaction.
Eight patients did not finish therapy because of AEs, including three who withdrew due to anaphylaxis/severe allergic reactions. Others were withdrawn because of atrial fibrillation, elevated serum liver function tests, syncope, and urticaria. One patient with underlying diabetes mellitus and extensive chemotherapy refractory mantle cell lymphoma died from splenic rupture several hours after completing the first infusion, which had been complicated by fevers, rigors, and hypoglycemia.
The study uncovered 31 episodes of infection, most of which were deemed mild or moderate in nature. Ten patients suffered arrhythmias, which occurred along with or immediately following infusion.