Breakout 1 Optimising resources: efficient use of rituximab

3. Background Indications for rituximab use continue to expand monotherapy for relapsed or refractory low grade or follicular NHL combination with CHOP chemotherapy for DLBCL combination with CVP chemotherapy for untreated follicular NHL maintenance treatment of follicular NHL following response to R-CHOP Commonly used in practice in a variety of additional settings

4. Rituximab use in British Columbia

5. Impact on health resources Physical burden of rituximab administration lengthy infusion times require expanded infusional services difficulty coordinating rituximab and chemotherapy administration waiting lists and delays in treatment may negatively impact clinical outcomes

6. Standard administration schedule Premedications: diphenhydramine/acetaminophen optional steroids First infusion: rituximab 375 mg/m2 iv administered at an initial rate of 50 mg/h escalate the infusion rate in 50 mg/h increments as tolerated every 30 minutes, to a maximum of 400 mg/h Subsequent infusions: rituximab 375 mg/m2 iv administered at an initial rate of 100 mg/h escalate the infusion rate in 100 mg/h increments as tolerated every 30 minutes, to a maximum of 400 mg/h

7. Standard administration in practical terms First infusion: 4–6 hour infusion nurses must check vitals and adjust rate every 30 minutes minimum 7–8 adjustments per infusion Subsequent infusions: 3–4 hour infusion nurses must check vitals and adjust rate every 30 minutes minimum 4–5 adjustments per infusion

8. Common toxicities of rituximab infusion

9. Biologic mechanism of infusion reaction Not well understood May involve a cytokine release syndrome Elevations of TNF-a and IL-6 have been documented Risk is increased with elevated levels of circulating lymphocytes (> 50 x 109/l) Symptom complex is usually self-limited, rarely fatal

10. Risk of grade 3 and 4 toxicities Risk of reaction greatest with the first infusion Rate of grade 3–4 infusion reactions: 7% with first infusion 2% with fourth infusion 0% with eighth infusion

11. BC rapid rituximab infusion protocol:Study rationale Rituximab infusion guidelines were largely empirically derived Risk of rituximab infusion reaction may be lower in combination with steroid-containing chemotherapy regimens Lengthy infusion may be unnecessary

12. Methods In March 2004, a pilot study was initiated investigating the safety of a rapid infusion rituximab schedule for all successive patients with NHL receiving rituximab with a steroid-containing chemotherapy regimen Schedule of administration for cycle 1 unaltered Remaining cycles administered same day as chemotherapy, over a total infusion time of 90 minutes Safety information was collected prospectively using an infusion monitoring record

13. Administration schedule for rapid rituximab infusion Premedications: diphenhydramine 50 mg po acetaminophen 375 mg po daily prednisone dose according to chemotherapy protocol Cycle 1: rituximab 375 mg/m2 iv infused according to product monograph Cycles 2–8: rituximab 375 mg/m2 iv in 250 ml NS 20% of dose infused over 30 minutes remaining 80% of dose infused over 60 minutes total infusion time of 90 minutes

14. Results 150 patients treated 473 rapid infusions administered Median infusions per patient = 3

15. Patient characteristics

16. Rapid infusion rituximab schedule extremely well tolerated No grade 3 or 4 infusion reactions observed Rate of grade 3–4 infusion reactions: 0% (95% CI: 0–0.019) No increased incidence of minor reactions noted Safety

17. Safety Ten patients experienced an adverse reaction with first cycle (standard rate), and subsequently tolerated rapid infusion without an event Eight patients not receiving steroids due to contraindication tolerated rapid infusion without an event No patients had an elevated circulating lymphocyte count, thus safety in this setting remains unknown

18. Additional studies of accelerated administration of rituximab Byrd et al. J Clin Oncol, 2001: Rituximab using a thrice weekly dosing schedule in CLL and SLL Aurran-Schleinitz et al. ASH 2005: “One hour” rituximab infusion is safe and improves patient care and outpatient unit management Middleton et al. ASH 2005: Accelerated delivery of rituximab is safe on an outpatient basis Ghielmini et al. ASH 2005: Infusion speed-escalation trial to give rituximab in 1 hour without steroid pre-medication Salar et al. Eur J Haematol 2006: Rapid infusion of rituximab with or without steroid-containing chemotherapy: 1-year experience in a single institution Provencio et al. Ann Oncol 2006: Rapid infusion rituximab in lymphoma treatment

19. Single institution experience of rapid infusion of rituximab: Salar et al. Eur J Haematol 2006 Inclusion criteria: previous infusion of rituximab without grade 3 or 4 toxicity lymphoid cells < 5 x 109/l 70 patients received 319 infusions of the 90-minute protocol 40% with steroids, 60% without steroids No grade 3 or 4 reactions seen Three patients experienced grade 1 symptoms Resource utilisation and patient satisfaction were dramatically improved

20. Ongoing experience in BC In June 2004, the rapid infusion schedule was adopted as routine policy in the province of British Columbia Approximately 1200 additional patients have been safely treated across the province This rapid infusion schedule has been adopted at many sites across Canada and internationally

21. Preliminary results of rapid infusion rituximab in maintenance therapy In March 2006, a rituximab maintenance protocol was adopted in BC for patients with indolent NHL who responded to induction therapy Rituximab 375 mg/m2 every 3 months for 2 years Rituximab was routinely administered according to the 90-minute infusion protocol Patients treated at BC Cancer Agency sites were monitored prospectively for toxicity 50 patients have received 81 infusions (median 2) 2 patients experienced grade 1 toxicity

22. Impact on resources Rituximab administration times have been cut by half Ease of administration has lessened nursing workload More patients can be conveniently treated with rituximab on the same day as chemotherapy Rituximab waiting times have been eliminated bb

23. Conclusions Rapid infusion rituximab schedule in combination with a steroid-containing chemotherapy regimen is safe and well tolerated when administered from the second infusion onward Increasing evidence suggests that accelerated infusion may be safe when rituximab is administered without steroids and as maintenance therapy Accelerated infusion rate results in a substantial reduction in resource utilisation