In this study, our step-by-step procedure allowed the safe administration of rituximab, providing comfort for both patients and oncology practitioners. Remarkably, only 1% of the patients in this study experienced IRRs in the second rituximab cycle, and no patient experienced IRRs in the third rituximab cycle; however, 33% and 54% of the patients received short infusions in the second and third cycles, respectively. Although approximately one-third of the patients in the low-risk group experienced IRRs in the first rituximab cycle, the conversion rate to short infusion in the third cycle was over 80%, and no patient experienced IRRs. Moreover, the overall incidence of IRRs to rituximab in the study participants was lower than those recorded in previous studies, where incidences of IRR to rituximab of up to 80% have been reported [2, 8]. Hence, the present findings suggest that rituximab may be administered efficiently with a low incidence and severity of IRRs in patients with various B-NHL subtypes, provided a suitable protocol is used.
The incidences of IRRs were similar among the low-, moderate-, and high-risk groups. This may be due to a lower-than-expected incidence of IRRs in the moderate-risk group. In this group, we administered hydrocortisone phosphate, which may have reduced the incidence of IRRs. Nevertheless, the incidence of IRRs in the high-risk group was as high as we had anticipated. It is important to note, however, that the small number of patients in this group could have reduced the statistical power of the analysis.
In general, the incidence and severity of IRRs are highest after the initial rituximab cycle; hence, the first infusion takes approximately 4 to 6 h. In contrast, IRRs to rituximab in subsequent cycles are infrequent and mostly manageable. For this reason, unless patients experience severe IRRs during the first rituximab administration, the second and subsequent doses are often administered by rapid infusion, requiring only 60 to 90 minutes in total . Nevertheless, despite over a decade of clinical experience, no standardized method has yet been developed to determine which patients may safely receive rituximab by rapid infusion after completing conventional infusion procedures [9–11].
A pivotal phase III study evaluated the safety of a 90 min rituximab infusion in patients with previously untreated diffuse large B-cell and follicular lymphomas . A total of 425 patients received the first rituximab cycle per the standard procedure, with a median infusion duration of 4 h. The 363 patients who did not experience grade ≥ 3 IRRs received subsequent infusions over 90 minutes. During cycle 2 (i.e., the first 90 min rituximab infusion), 135 (37%) and 4 (1%) patients experienced grade 1/2 and 3 IRRs, respectively . The present study did not evaluate the incidence of IRRs to rapid infusion of rituximab. However, it was assumed that our patients who received short infusions could safely receive rapid rituximab infusions because the maximum infusion rate of 400 mg/h in the short infusion cycle was not substantially different from that of the rapid infusion cycle. Therefore, our protocol may be applied to select patients for whom rapid infusion is considered safe.
Severe or life-threatening IRRs to rituximab, i.e., grade ≥ 3, occur in approximately 10% of patients with B-NHL [2, 5, 8]. However, in the present study, none of the patients experienced IRRs to rituximab of grade 3 or higher. There are several possible reasons for the absence of severe IRRs. First, we avoided administering rituximab before the initial cytotoxic chemotherapy in 83% of the patients. This procedure may help reduce the tumor burden, which is the leading cause of IRR occurrence. Second, we limited the maximum infusion rate for the initial administration of rituximab to 100 mg/h in high-risk patients. Although this resulted in the total administration of rituximab requiring greater than 6 h in most patients, it helped prevent serious adverse reactions. Finally, we carefully chose patients who received rituximab by short infusion in the second cycle onwards, and this yielded a protocol compliance rate of 94%. As a result, this study successfully minimized the severity of IRRs in B-NHL patients with various risk factors.
One of the major limitations of this study is the lack of safety data on the rapid infusion of rituximab. This is partly because most patients in the study received biosimilar rituximab. While the incidence of IRRs is similar between biosimilar rituximab and reference rituximab , the package insert of biosimilar rituximab available in Japan does not support infusions within 60 to 90 min. Furthermore, the number of patients in the high-risk group was small, resulting in statistically underpowered results. Therefore, the present findings should be validated in further multicenter studies.