Bendamustine +/- Rituximab (BR) for first line …

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).

6 J Turner 28/11/2012 Anti-emetics: 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.

7 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.. 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.

8 Drug interactions: Bendamustine metabolism involves the CYP P450 1A2 pathway. There is potential for interaction with CYP1A2 inhibitors such as ciprofloxacin, aciclovir and cimetidine. 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.

9 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. 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).

10 J Turner 28/11/2012 transfusion is notified and patient has received a PIL Information for patients needing irradiated blood and Alert Card. 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.