2.03 Protocol Name: Rituximab

Indication  Follicular lymphoma stage III or IV in combination with CVP  Relapsed refractory follicular lymphoma  Second or third line therapy for other indolent B cell non- Hodgkin's lymphoma expressing CD20.  First line therapy in combination with CHOP for aggressive B cell non-Hodgkin's lymphoma expressing CD20.  Multicentric Castleman’s Disease  CLL first line, in combination with chemotherapy (see section 4 for specific dosing etc)  Maintenance in relapsed/refractory follicular lymphoma responding to induction chemotherapy +/- rituximab. Pre-treatment Evaluation  Document histological sub-type of lymphoproliferative disorder according to WHO Classification.  Document FBC (with film), U&E, creatinine, LFTs, LDH, calcium, magnesium, glucose, serum protein electrophoresis, immunoglobulin levels and a direct antiglobulin test (DAT).  Staging should include documentation of B symptoms, CT of chest, abdomen & pelvis and bone marrow aspirate & trephine.  Document WHO performance status of patient.  Document height, weight and body surface area.  Give adequate verbal and written information for patients and relatives concerning patient’s disease, treatment strategy and side effects.  Obtain written consent from patient or guardian.  Consider intravenous hydration in patients with bulk disease and tumour lysis precautions according to local practice.  Rituximab has been associated with potentially serious Hepatitis ‘flare’ in patients with chronic hepatitis B infection. All patients should have hepatitis B serology checked before therapy, and in those who have positive serology lamivudine 100mg daily should be commenced 1-2 weeks prior to rituximab. Currently it is recommended that lamivudine is continued for 6 months after rituximab is discontinued.

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Drug Regimen (OPCS code: X71.2)

D Drugs Dose Route Comments

Paracetamol 1g PO 30-60 minutes before rituximab 1,8,15 and 22 Chlorpheniramine 10mg IV bolus Pre-med OR D1 only Not necessary if receiving oral when in Hydrocortisone 100mg IV bolus steroids, as part of chemotherapy combo regimen with Infusion speed, see below CHOP or 375mg/ IV Rituximab In 250-500mls 0.9% sodium CVP m² infusion chloride

Rituximab infusion speed:

. First infusion: Initiate at 50 mg/h; if tolerated increase rate by 50mg/h increments every 30 minutes to a maximum of 400 mg/h. . Subsequent infusions: Initiate at 100 mg/h; if tolerated increase rate by 100mg/h increments every 30 minutes to a maximum of 400 mg/h. . High tumour burden: Consider reduction of infusion rate in patients with circulating tumour cells of > 50 x 109/l or with high tumour burden. . Fast rate infusion: Many day-care units have implemented this locally as a safe and time efficient method of reducing the infusion time of R-CHOP or R-CVP. Patients MUST have tolerated their first cycle of rituximab (at the standard recommended infusion rates as specified above) before being given the rapid infusion rate. All rituximab doses are prepared in 250mls 0.9% sodium chloride, with 50mls being given over the first 30 minutes and the remaining 200mls given over 1 hour. If a 500ml volume of 0.9% sodium chloride is used, then 100mls is given over the first 30 minutes and the remaining 400mls given over 1 hour.

Cycle Frequency  As single agent- given as weekly intravenous infusion for 4 weeks (i.e. Day 1, 8, 15 and 22). Maximum 2 cycles (8 infusions).

 When used in combination with chemotherapy protocols it is given on Day 1 only (before chemotherapy) for a maximum of 8 cycles.

MAINTENANCE  A single infusion every 3 months for 2 years (licensed indication) OR

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 given as weekly intravenous infusion for 4 weeks (i.e. Day 1, 8, 15 and 22) every 6 months for 2 years.

Dose Modifications - Not necessary based on FBC  Mild to moderate infusion - related reactions respond to a reduction of the rate of infusion.  Circulating tumour cells >50 x 109/l: consider reduction of cell load by other means prior to Rituximab infusion; reduce infusion speed; close monitoring of patient.  Tumour bulk; single lesion >10cm: consider reduction of cell load by other means prior to Rituximab infusion; reduce infusion speed; close monitoring of patient.

Investigations prior to subsequent cycles  FBC should be monitored  LFT, U&E, creatinine, LDH, Immunoglobulins (after last cycle).

Concurrent Medication  Consider allopurinol 300mg od PO prior to therapy and continue for the first two infusions. (100mg daily if creatinine clearance <20mls/min)

Anti-emetics Not required

Adverse Effects:  Infusion related reactions  Severe: Patients should be closely monitored for the onset of cytokine release syndrome. Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or hypoxia should have the infusion interrupted immediately.  The patient should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory tests and, for pulmonary infiltration, with a chest x-ray. The infusion should not be restarted until complete resolution of all symptoms, and normalisation of laboratory values and chest x-ray findings. At this time, the infusion can be initially resumed at not more than one-half the previous rate. If the same severe adverse reactions occur for a second time, the decision to stop the treatment should be seriously considered on a case by case basis.  Mild or moderate infusion-related reactions: Usually responds to a reduction in the rate of infusion. The infusion rate may be increased upon improvement of symptoms.  Cardiac- Angina pectoris or cardiac arrhythmias such as atrial flutter and fibrillation heart failure or myocardial infarction have occurred in patients treated with Rituximab. Therefore patients with a history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely.

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References  Mc Laughlin et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four - dose treatment program. J Clin Oncol 1998,16(8):2825-2833.  Maloney DG et al. IDEC - C2B8 (Rituximab) anti - CD20 monoclonal antibody therapy in patients with relapsed low grade non-Hodgkin’s lymphoma. Blood 1997,90:2188-2195.  Czuczman M et al. Treatment of patients with low grade B - cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. JClinOncol 1999,17(1):268-276.  Howard O et al. Rituxan/CHOP induction therapy in newly diagnosed patients with mantle cell lymphoma. Blood 1999,94,suppl1:2804a.  Sehn L, Donaldson J et al Abstract #1407. ASH meeting Dec 2004

Patient Information http://www.cancerbackup.org.uk/Treatments/Biologicaltherapies/Monoclonalantibodies /Rituximab

Revised by: Dr Ed Kanfer, Dr George Hughes Dr Don McDonald and Pauline McCalla Authorised by: WLCN Haematology TWG Date for review by Haematology TWG:

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