Bendamustine +/- Rituximab (BR) for first line Chronic ...

1 Bendamustine +/- Rituximab (BR) for first line Chronic lymphocytic Leukaemia Page 1 of 3 Reason for Update: New protocol Approved by Consultant: S Devereux Indication: first line treatment for B-CLL (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate. Regimen details: Bendamustine 90mg/m2 IV Days 1 and 2 Rituximab 375mg/m2 IV Day 1* Cycle 1 500mg/m2 IV Day 1 Cycles 2 to 6 *Patients with a high tumour burden / lymphocyte count 25 x 109/L are at high risk of severe cytokine release syndrome.

2 Consider a reduced infusion rate for the first infusion and a split dosing over two days during the first cycle, Rituximab 100mg IV Day 1 (cycle 1 only) Rituximab 375mg/m2 minus 100mg IV Day 2 (cycle 1 only) Administration: Bendamustine IV in 500ml sodium chloride over 30 - 60 minutes Rituximab in 100-500ml Sodium Chloride IV Rituximab administration: The first cycle should be administered according to the manufacturer s instruction initial rate 50 mg/hr; after the first 30 minutes, escalated in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.

3 The manufacturer recommends that if the first dose is tolerated, subsequent doses of Rituximab can be infused at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30 minutes intervals, to a maximum of 400 mg/hr. However, if the first cycle was tolerated without any infusion related toxicities, the rapid Rituximab protocol can be followed. Give 100ml of the volume in the bag (20% of the dose) over 30 minutes, and the remainder (80% of the dose) over 60 minutes, total infusion time of 90 minutes.

4 Premedication: 30 to 60 minutes prior to Rituximab administration: Chlorphenamine 10mg IV Paracetamol 1000mg orally Hydrocortisone 100mg IV (if clinically appropriate) If the lymphocyte count is > 25 x 109/L, in addition to a split dosing over two days during the first cycle, administer 100mg prednisolone orally prior to each dose.

5 Frequency: Every 28 days, for up to 6 cycles Extravasation: If there is any possibility that extravasation has occurred, contact a senior member of the medical team and follow local protocol for dealing with cytotoxic extravasation of irritant and non-vesicant drugs. Version: 1 Approved by Chair Haem TWG: M Kazmi Supersedes: All other versions Date: 17/12/2012 Prepared by: Laura Cameron Checked by (Network Pharmacist): J Turner 28/11/2012 Bendamustine +/- Rituximab (BR) for first line Chronic lymphocytic Leukaemia Page 2 of 3 Reason for Update: New protocol Approved by Consultant: S Devereux Version: 1 Approved by Chair Haem TWG: M Kazmi Supersedes: All other versions Date: 17/12/2012 Prepared by: Laura Cameron Checked by (Network Pharmacist): J Turner 28/11/2012 Anti-emetics.

6 Moderate emetogenic potential (30 - 90%) Supportive medication: Allopurinol 100 - 300 mg od (dependent on renal function) for first cycle. Regular investigations: FBC D1 U&E D1 LFTs D1 Dose Modifications Haematological Toxicity due to treatment: Neutrophils (x 109/L) Platelets (x 109/L) Bendamustine dose adjustment x 109/L & 100 x 109/L 100% dose < x 109/L & / or < 100 x 109/L Delay treatment until counts recovered.

7 Renal Impairment Creatinine clearance > 10 ml/min give 100% Bendamustine dose. Creatinine clearance < 10 ml/min; no data available. Hepatic Impairment Bilirubin Bendamustine dose adjustment < 21umol/L 100% dose 21 52umol/L 70% dose > 53umol/L No information available Toxicities: Tumour lysis syndrome, cardiac dysfunction, hypotension, hypertension, diarrhoea, constipation. Drug interactions: Bendamustine metabolism involves the CYP P450 1A2 pathway. There is potential for interaction with CYP1A2 inhibitors such as ciprofloxacin, aciclovir and cimetidine.

8 Comments: Patients with cardiac disorders: Ensure K+ remains > during treatment with Bendamustine . Patients may develop infusion related reactions; symptoms include fever, chills, pruritis and rash. Rarely, anaphylactic reactions can occur. Patients must be asked about symptoms suggestive of infusion reactions after their first cycles of therapy. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids must be considered in subsequent cycles. Patients who have experienced Grade 3 or worse allergic-type reactions should not be re-challenged.

9 Blood and platelet transfusion according to unit guidelines. Products must be irradiated as patients are at risk of transfusion-associated graft versus host disease - ensure blood Bendamustine +/- Rituximab (BR) for first line Chronic lymphocytic Leukaemia Page 3 of 3 Reason for Update: New protocol Approved by Consultant: S Devereux Version: 1 Approved by Chair Haem TWG: M Kazmi Supersedes: All other versions Date: 17/12/2012 Prepared by: Laura Cameron Checked by (Network Pharmacist): J Turner 28/11/2012 transfusion is notified and patient has received a PIL Information for patients needing irradiated blood and Alert Card.

10 References: Phase III Randomised Study of Bendamustine Compared With Chlorambucil in Previously Untreated Patients With Chronic lymphocytic Leukaemia. Knauf WU et al. J Clin Oncol 2009. 4378-4384 NICE TA 216 February 2011 Bendamustine for first - line treatment of Chronic lymphocytic leukaemia Bendamustine in Combination with Rituximab for Previously Untreated Patients With Chronic lymphocytic Leukaemia: A Multicentre Phase II Trial of the German Chronic lymphocytic Leukaemia Study Group. Fisher K et al. J Clin Oncol 2011 29(26):3559-3566