Rafat Faraawi, MD, FRCP(C);1 Mark Brown, PharmD, BCPS;2 Janet Pope, MD, FRCP(C);3 Roy Lee, BSc, PhM, RPh;4 Kelly Roth, RN5

1Division of Rheumatology, McMaster University, Hamilton, Ontario, and St. Mary’s Hospital, K-W Musculoskeletal Research, Kitchener, Ontario; 2Hamilton Health Sciences, Juravinski Hospital and Cancer Centre, Hamilton, Ontario; 3Division of Rheumatology, University of Western Ontario, St. Joseph’s Health Care, London, Ontario; 4Princess Margaret Hospital, University Health Network, Toronto, Ontario; 5K-W Musculoskeletal Research, Kitchener, Ontario

Medical Writer: Anna Christofides, MSc, RD, New Evidence

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Background

Rituximab is a human/murine immunoglobulin G1 chimeric monoclonal antibody that binds to the B-cell CD20 antigen, causing rapid and targeted B-cell depletion.1,2 In Canada, rituximab is approved by Health Canada for the treatment of patients with non-Hodgkin’s lymphoma (NHL) and B-cell chronic lymphocytic leukemia (CLL). Rituximab is also indicated to reduce signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more tumour necrosis factor (TNF) inhibitor therapies. Rituximab in combination with methotrexate (MTX) has been shown to reduce the rate of progression of joint damage as measured by X-ray in the RA setting.3

The addition of rituximab to standard chemotherapy has been shown to improve outcomes in patients with NHL, CLL, and RA. In patients with NHL and untreated CLL, rituximab improves both progression-free survival (PFS) and overall survival (OS); maintenance and second-line rituximab also delays progression in these patients.4–7

Rituximab is a good treatment alternative to patients with RA who have failed TNF inhibitors and has proven to be as or more effective than a second TNF inhibitor in this setting.8,9 Results of clinical trials in RA patients show that a significant number achieve ACR50 and low disease activity levels after treatment with rituximab.10 Ongoing clinical trials are also examining the use of rituximab in vasculitis, multiple sclerosis, refractory thrombotic thrombocytopenic purpura, systemic lupus erythematosus, and epidermolysis bullosa acquisita.

Although generally well tolerated, biologic treatments, including rituximab, are associated with infusion-related reactions. To minimize these reactions, the standard administration of rituximab has a long infusion time, resulting in a significant drain on health resources and patient time. For this reason, shorter infusion protocols have been tested in oncology settings and have proven to be safe and practical. Similarly, routine use of rapid infusion protocols in the RA setting should provide further benefits for these patients and their healthcare providers.

Standard administration protocol

One barrier to effective treatment with rituximab is its lengthy administration protocol, resulting in a timeand labour-intensive process.3,11,12 (Figures 1 and 2) The standard administration protocol for rituximab takes approximately three or four hours for the first infusion and two or three hours for subsequent infusions in the oncology and RA settings, respectively. These long infusion times place a significant strain on health resources.

Patients are expected to arrive at the clinic early and wait afterwards to ensure there are no adverse reactions. A total of around four to six hours of patient time is therefore needed to complete one rituximab infusion, including waiting time.11,12 Because of the long infusion time, patients need to plan for a full day of treatment at the clinic, with a negative impact on their quality of life.

The burden of the standard infusion protocol to the healthcare system is also significant. Long infusion protocols increase required patient chair time, thus decreasing the ability to treat other patients. This results in increased nursing and administration staff workload, longer wait times for treatment, and less efficient delivery of services. The financial cost in terms of healthcare provider time and use of resources is also a concern. Ultimately, the burden of long infusion times may result in a lack of adherence or discontinuation of treatment, potentially reducing treatment efficacy. For these reasons, rapid infusion protocols have been developed in some infusion centres.

Infusion-related reactions

Rituximab is generally well tolerated in both the oncology and rheumatology settings. However, infusion- related reactions may occur and typically manifest 30 to 120 minutes after rituximab administration. Although the mechanism is poorly understood, symptoms may develop as a result of the binding of rituximab to tumour cells and normal B cells, causing the release of inflammatory cytokines such as TNF-α and interleukin-6 (IL-6) and/or other chemical mediators.1–3,11

Usually, symptoms of infusion reactions are less severe in the RA setting then in the oncology setting. Symptoms are generally mild to moderate in nature and may include fever, rash, and cardiovascular or respiratory insufficiency. Rarely, severe symptoms occur, which may result in urticaria, hypotension, angioedema, hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock.2,3,11

Infusion reactions are more frequent in the oncology than the RA setting due to the higher B-cell burden of these patients. In the oncology setting, older patients and those with increased tumour bulk are at highest risk.2,13,14 Typically, the risk of infusionrelated toxicity is greatest with the first infusion, occurring in 77% and 29% of patients with NHL and RA, respectively.2,10 Infusion reaction rates decrease substantially after the first infusion, with approximately 30% of NHL patients and 12% of RA patients reporting reactions after subsequent infusions.10,11 A similar trend is observed for severe (grade 3/4) reactions, which occur in around 7% of patients with NHL after the first infusion and decrease to 2% after the fourth infusion; severe reactions in RA patients are rare and occur in <1% of patients.2,3,11

The risk for infusion reactions associated with the use of rituximab should be kept in perspective with the risk of reactions associated with other agents. In general, the incidence of infusion reactions associated with rituximab in the oncology setting is similar to that associated with other biologics, taxanes, and platinum agents.14 In the RA setting, the incidence of infusion reactions is similar to that of other biologics and some TNF inhibitors, such as infliximab.15 Discontinuation of rituximab rarely occurs as a result, and the majority of reactions are resolved by slowing or interrupting the infusion and giving supportive care.14 In addition, the clinical benefit of rituximab clearly outweighs the risk, with a favourable risk:benefit profile.

Rapid infusion protocols in clinical trials

Oncology setting

Routine use of rapid infusion protocols can result in significant reductions in healthcare costs and resources. Accelerated infusions of rituximab were first used in the oncology setting in patients diagnosed with NHL or CLL. A preliminary study by O’Brien, et al. (2001) in patients with CLL found that dose escalations of rituximab up to 2,250 mg/m2 given at infusion rates up to 400 mg/hr did not increase the rate of infusion reactions.16 Subsequently, 60- and 90-minute infusion protocols were developed and tested in a number of studies in the oncology setting; these protocols were found to be well tolerated with no increase in the rate of infusion-related reactions. (Appendix A) However, the standard infusion rate was given for the first infusion of all courses in both protocols to assess patient tolerability.

Overall, clinical studies in the oncology setting show that adverse events (AEs) with rapid infusions are rare and manageable, the majority being mild in nature (grade 1/2). The largest study to date included 206 patients receiving the 90-minute protocol and reported no serious infusion reactions and no increase in mild infusion reactions. After follow-up of more than 1,200 patients, only one patient experienced a more serious (grade 3) reaction.11 Based on the results of clinical trials, rapid infusion protocols are now routinely used in the majority of oncology centres across Canada.

RA setting

Due to the success of rapid infusion protocols in the oncology setting, studies are now examining accelerated infusion protocols in patients with RA. (Appendix A) In a recent study by Faraawi and Roth (2010), thirty rapid infusions over two hours were administered to ten patients with RA in a clinical setting. The first infusion was given at the standard infusion rate, with subsequent infusions using the rapid infusion protocol. Premedication for all infusions consisted of oral acetaminophen (1,000 mg), oral diphenhydramine (50 mg), and IV methylprednisolone (100 mg). Only one mild (grade 1) AE was reported, which resolved during the infusion. Overall, the rapid infusion protocol was well tolerated, and patients reported being satisfied with this administration method. Several other studies support the use of accelerated rituximab infusions in RA patients.17,18 Further studies examining rapid infusions in the rheumatology setting should aid in determining its use in clinical practice.

Rapid infusion protocols in clinical practice

Prevention of infusion-related reactions

Identification of patients at increased risk is of key importance in preventing infusion-related reactions. Prior to rituximab administration, individual patient risk factors for infusion reactions should be assessed. (Table 1) Other factors, such as whether rituximab is to be administered in combination or as a single agent and which (if any) other concomitant therapies will be used may also influence the risk of infusion reactions. Of particular importance is any history of previous allergic reactions. A detailed patient history, including baseline assessments of vital signs and cognition, is therefore an important first step before initiating treatment with rituximab.14

Infusion reactions may be higher in patients with Sjögren’s syndrome than in those with RA. In a small phase II study in patients with primary Sjögren’s syndrome, significant improvements in subjective symptoms and salivary gland function were observed. However, 4/15 patients developed human anti-chimeric antibodies (HACAs), which resulted in serum sickness–like disease in three patients.19

In the oncology setting, pre-medication consisting of an antihistamine and an anti-pyretic should be administered prior to each rituximab infusion. For patients with large tumour burden and therefore higher risk of infusion reactions, IV corticosteroids can be administered in addition to other supportive measures to prevent tumour lysis syndrome.

Stepwise or fractionated dosing, for example administering a 100 mg dose in 1,000 mL of normal saline on day 1 and the remainder on day 2, may also be considered in these high-risk patients.3,14,20 At Princess Margaret Hospital (PMH) in Toronto, Ontario, fractionated dosing is given to CLL patients with high white blood cell (WBC) counts. A similar approach is employed at the Juravinski Hospital and Cancer Centre (JHCC) in Hamilton, Ontario, where physicians may elect to give 50 mg/m2 on day 1 and the remaining 325 mg/m2 on day 2 for the first cycle. For high-risk patients, hospitalization may be necessary when stringent monitoring is required.

Many patients with RA are not given pre-medications, and the use of corticosteroids is not required before rituximab administration. However, in a study by Emery, et al. (2006), use of glucocorticoids reduced infusion reactions and did not alter the response to rituximab in patients with RA.21

Prior to rituximab administration, patients should be educated about the potential for infusion reactions and instructed to report any adverse reactions immediately. Healthcare practitioners should reassure patients that appropriate measures will be taken to prevent infusion reactions. Patients should also be advised that these reactions are generally mild to moderate and are easily managed.

Administration of the rapid infusion protocol

In the oncology setting, it is recommended that rituximab infusions be administered in an environment with full resuscitation facilities and under the close supervision of professionals capable of dealing with severe reactions.3 During infusions, healthcare practitioners should monitor patient vital signs, watching for any sign of infusion reactions. Constant visual observation is important during the first infusion, when patients are at the greatest risk; however, monitoring should continue with every subsequent infusion.14 The first infusion of rituximab should be delivered at the standard infusion rate to assess patient tolerability. If the first infusion is well tolerated, subsequent infusions may be given at an accelerated infusion rate over approximately 90 to 120 minutes in the oncology setting or 120 minutes in the RA setting. (Figure 3)

In the oncology setting, rapid infusion of rituximab has become the standard in the majority of centres across Canada. PMH began using the rapid infusion protocol shortly after data from the Sehn, et al. (2007) study in the NHL setting was released.11 The standard protocol at PMH therefore recommends administering 375 mg/m2 at the 90-minute infusion rate if the patient tolerates the first infusion or has only a mild-to-moderate reaction. If there are significant pulmonary symptoms after the first infusion, the second infusion may be given using the standard infusion rate before moving to the rapid protocol. When patients show more severe reactions (grade 3/4), treatment may be stopped; however, severe reactions rarely occur.

The adoption of a rapid infusion protocol at PMH means that a total of 8 to 10 patients can be seen per day, compared to only 5 patients with the standard protocol. Patients are often able to concurrently book lab and infusion time on the same day, thereby reducing the number of days spent in the clinic. A detailed description of the rapid infusion protocol at PMH is presented in Appendix B.

Recent funding approval in Ontario for the use of rituximab in combination with fludarabine-based treatment for previously untreated CLL has required a slightly different approach to the management of rituximab infusions. First, CLL patients tend to have higher grade 1 and 2 reactions than patients with other lymphocytic subtypes.22 As previously mentioned, this risk is managed by optional fractionated first dosing. Second, the rituximab dose in cycles 2–6 for CLL is 500 mg/m2. Early pharmacokinetic and doseescalation studies observed that rituximab at standard 375 mg/m2 was less effective in CLL than in other lymphoma subtypes. Reasons for this finding include generally lower CD20 expression and a shorter rituximab half-life in CLL, which can be overcome with higher doses.16,22

The current practice at JHCC for rituximab infusions in CLL follows the PMH processes previously described, with cycle 1 at 375 mg/m2 (with optional fractionation) and cycle 2 at 500 mg/m2 at standard infusion rates. Assuming no clinically significant reactions are observed, cycles 3–6 are given at 500 mg/m2 over approximately 90 minutes.

Given the success of rapid infusion protocols in the oncology setting and the growing evidence of their safety in patients with RA, the accelerated protocol should become the standard of care in the RA setting across Canada.

Conclusion

Rituximab has proven to be an invaluable treatment option, dramatically improving the outcome of patients with non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis. Despite the clear benefits of rituximab in the oncology and rheumatology settings, its standard administration is time consuming, resulting in a significant burden for patients and healthcare providers.

Studies using accelerated infusion protocols for rituximab in both oncology and RA settings have shown rapid administration to be safe and practical. Rapid infusion of rituximab can reduce healthcare costs, improve resource utilisation, and increase patient satisfaction and quality of life. Based on the positive results of studies in the oncology and RA settings, rapid infusion of rituximab should be recommended in all infusion clinics across Canada.

References:
1.
Provencio M, Cerdeira S, Bonilla F, et al. Rapid-infusion rituximab in lymphoma treatment. Ann Oncol 2006;17:1027–1028. 2. Atmar J. Review of the safety and feasibility of rapid infusion of rituximab. J Oncol Pract 2010;6:91–93. 3. Hoffmann-La Roche Ltd. RITUXAN® Product Monograph, 2010.4. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376:1164–1174. 5. Robak T, Dmoszynska A, Solal-Celigny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010;28:1756–1765. 6. 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 2011;377:42–51. 7. van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: longterm outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 2010;28:2853–2858. 8. Finckh A, Dudler J, Moeller B. Effectiveness of riutximab versus alternative TNF antagonists in preventing radiographic joint damage in rheumatoid arthritis patients with inadequate response to TNF antagonists. Ann Rheum Dis 2010;69(Suppl 3):383. 9. Chatzidionysiou K, Carli C, Van Vollenhoven R. Rituximab versus anti-TNF in patients who previously failed one or more anti-TNFs in an observational cohort: the SARASTRA study. Ann Rheum Dis 2009;68(Suppl 3):445. 10. Volkmann E, Agrawal H, Maranian P, Furst D. Rituximab for rheumatoid arthritis: a meta-analysis and systematic review. Clin Med Insights 2010;2:749–760. 11. Sehn LH, Donaldson J, Filewich A, et al. Rapid infusion rituximab in combination with corticosteroid-containing chemotherapy or as maintenance therapy is well tolerated and can safely be delivered in the community setting. Blood 2007;109:4171–4173. 12. Faraawi R, Roth K. Experience with accelerated rituximab infusion for rheumatoid arthritis in a single community practice. Ann Rheum Dis 2010;69(Suppl 3):383. 13. Byrd JC, Murphy T, Howard RS, et al. Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol 2001;19:2153–2164. 14. Vogel WH. Infusion reactions: diagnosis, assessment, and management. Clin J Oncol Nurs 2010;14:E10–21. 15. Schering-Plough Inc. REMICADE® Product Monograph, 2010. 16. O’Brien SM, Kantarjian H, Thomas DA, et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 2001;19:2165–2170. 17. Bukh G, Larsen S, Rasmussen S. Accelerated infusion-rate of rituximab for rheumatoid arthritis is well tolerated and safe. Program and abstracts of the 2008 American College of Rheumatology Annual Scientific Meeting, October 24–29, 2008; San Francisco, CA: Abstract 1885. 18. Schoeffel D, Henn SM, Goedde A. Simplified treatment protocol of rituximab in rheumatoid arthritis. Ann Rheum Dis 2008;67(Suppl II):337. 19. Pijpe J, van Imhoff GW, Spijkervet FK, et al. Rituximab treatment in patients with primary Sjögren’s syndrome: an open-label phase II study. Arthritis Rheum 2005;52:2740–2750. 20. Byrd JC, Waselenko JK, Maneatis TJ, et al. Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance. J Clin Oncol 1999;17:791–795. 21. Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006;54:1390–1400. 22. Keating MJ, O’Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 2005;23:4079–4088.

Appendix A. Rapid infusion protocols used in clinical trials

Appendix B. Rituximab infusion protocol at Princess Margaret Hospital