Regimen : Fludarabine Cyclophosphamide Rituximab (FCR-oral)

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1 Regimen : Fludarabine Cyclophosphamide Rituximab (FCR-oral) Indication CLL 1st line as per NICE TAG 174 CLL (relapsed) as per NICE TAG 193 Regimen details Day Drug Dose Route Cycle 1 1 Rituximab 375mg/m 2 IV Cycles 2-6 Administration Frequency 2-6* Cyclophosphamide 150mg/m 2 PO 2-6* Fludarabine 24mg/m 2 PO *Some units give chemotherapy on days 1-5 on Cycle 1-clinical decision 1 Rituximab 500mg/m 2 IV 1-5 Cyclophosphamide 150mg/m 2 PO 1-5 Fludarabine 24mg/m 2 PO Rituximab: Patients with a high tumour burden (>25 x 10 9 /L) circulating malignant cells may be at a higher risk of severe cytokine release syndrome. These patients should be managed with extreme caution and should be very closely monitored throughout the first infusion. Consideration should be given to splitting the first Rituximab infusion over two days e.g. 100mg Rituximab in 100ml Sodium Chloride 0.9% on day 1 with the remainder of the Rituximab dose in 500ml Sodium Chloride 0.9% on day 2. Rituximab infusion rate: First infusion: Initiate at 50 mg/hr; if tolerated increase rate by 50mg/hr increments every 30 minutes to a maximum of 400 mg/hr. Subsequent infusions: Second and subsequent infusions of Rituximab can be given safely over 90 minutes if the first infusion was well tolerated.* *Note: this is not a licensed rate of infusion. In frail patients or patients deemed clinically unsuitable for rapid infusion, the licensed administration recommendations should be adhered to i.e. initiate at 100 mg/hr; if tolerated increase by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. Cyclophosphamide: once daily at breakfast (dose rounded to nearest 50mg tablet) Fludarabine: once daily at lunchtime (dose rounded to nearest 10mg tablet) Note: If the oral regime is not tolerated and/or there are concerns regarding absorption, IV route may be used-see ASWCS10 CLL002 FCR (IV)-CLL Every 28 days for 6 cycles Extravasation Rituxumab is neutral (Group 1) Premedication Emetogenicity Additional recommended Pre-Rituximab: Paracetamol 1g PO Chlorphenamine 10mg IV Hydrocortisone 100mg IV (if clinically appropriate) This regimen has mild emetogenic potential refer to local protocol Allopurinol Co-trimoxazole during treatment and for 6 months after finishing Controlled document Document Number Version Number Page 1 of 5

2 supportive medication Pre-treatment evaluation (i.e. before Cycle 1) Regular investigations (i.e. before Cycle 2 and subsequent cycles) Standard limits for administration to go ahead if blood results not within range, authorisation to administer must be given by prescriber/consultant treatment or count recovery (CD4 count>200), whichever is longer. (In cases of allergy to Cotrimoxazole, consider nebulised Pentamidine 300mg monthly or Dapsone 100mg PO daily). Aciclovir during treatment and for at least 2 months after finishing treatment or count recovery, whichever is longer. All patients who receive Fludarabine should receive irradiated blood products for the duration of chemotherapy treatment and thereafter for life. FBC Baseline results valid for 7 days U+E (incl CrCl) Baseline results valid for 7 days LFT FBC U+E (incl CrCl) LFT Neutrophil count 1 x 10 9 /l Platelet count 75 x 10 9 /l Creatinine clearance Baseline results valid for 7 days Pre D1 results valid for 72 hours Pre D1 results valid for 7 days Pre D1 results valid for 7 days > 70ml/min Controlled document Document Number Version Number Page 2 of 5

3 Dose modification s Haematologi cal toxicity Renal impairment Hepatic impairment Note: Neutropenia and thrombocytopenia may be due to the disease. Where myelosuppression is deemed treatment-related, the following guidelines apply: If Neutrophils < 1.0 x 10 9 /L or platelets < 75 x 10 9 /L, delay treatment for one week. If counts have not recovered above these levels after two weeks delay, consider proceeding with next course at 50% dose. If Neutrophils < 0.5 x 10 9 /L, delay treatment until count recovery and consider proceeding with next course at 50% dose. CrCl (ml/min) Cyclophosphamide Dose Fludarabine Dose >70 100% 100% % 50% % Omit % Omit <10 50% Omit No dosage adjustment required. NCI Common toxicity criteria For any grade 3 or 4 non-haematological toxicity (except alopecia), clinical judgement should determine whether to discontinue treatment or to continue treatment at a reduced dose (following recovery to grade 2 toxicity) For any grade autoimmune, neurotoxicity, pneumonitis, or > 2 week delay, discontinue treatment. Adverse effects the contents of the table indicate the adverse effects that should be documented on consent to treatment forms Significant drug interactions For full details consult product literature/referenc e texts Comments Rare and/or serious side effects autoimmune haemolytic anaemia (fludarabine) Neutropenia, thrombocytopenia, anaemia (very common) Rash Haemorrhagic cystitis Ovarian failure Infertility Cytokine release syndrome and tumour lysis syndrome (Rituximab) Pulmonary fibrosis, pneumonitis Other No clinically significant interactions. Please refer to product literature for full details. Frequently occurring side effects Infusion related reactions (Rituximab) Fatigue Alopecia Nausea and Vomiting Diarrhoea Opportunistic infections Peripheral neuropathy Cyclophosphamide may irritate the bladder mucosa. Patients should be encouraged to drink a minimum of three litres of fluid per 24 hours whilst Controlled document Document Number Version Number Page 3 of 5

4 Cumulative Doses References receiving cyclophosphamide. Not applicable Boettcher S, Fischer K, Stilgenbauer S, Busch R, Fingerle-Rowson G, Fink A-M et al on Behalf Of GCLLSG. Quantitative MRD Assessments Predict Progression Free Survival in CLL Patients Treated with Fludarabine and Cyclophosphamide with or without Rituximab a Prospective Analysis in 471 Patients from the Randomized GCLLSG CLL8 Trial. American Society of Hematology, Annual Meeting 2008, abstract 326 [internet], viewed 08/10/2010, available at Tam CS, O'Brien S, Wierda W, Kantarjian H, Wen S, Do KA, et al. Longterm results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood (4): Keating MJ, O'Brien S, Albitar M, Lerner S, Plunkett W, Giles F, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol (18): Wierda W, O Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D, et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol (18): National Institute for Health and Clinical Excellence. Rituximab for the firstline treatment of chronic lymphocytic leukaemia, Technology Appraisal Guidance 174, July 2009 [internet], viewed 08/10/2010, available at National Institute for Health and Clinical Excellence. Rituximab for the treatment of relapsed or refractory chronic lymphocytic leukaemia,technology Appraisal Guidance 193, July 2010 [internet], viewed 17/11/2010, available at Summary of Product Characteristics Mabthera (Rituximab) 100mg and 500mg concentrate for solution for infusion (Roche) [internet], accessed 10/09/2010 available from Summary of Product Characteristics Cyclophosphamide Tablets 50mg (Baxter) [internet], accessed 10/09/2010 available from Summary of Product Characteristics Fludara (Fludarabine) oral 10mg film-coated tablets (Genzyme) [internet], accessed 10/09/2010 available from Daniels S. North London Cancer Network. Dose adjustment for cytotoxics in hepatic impairment [internet]. accessed 16/04/2009 available at 0impairment%20-%20Dosage%20adjustment%20for%20cytotoxics.doc Daniels S. North London Cancer Network. Dose adjustment for cytotoxics in renal impairment [internet] accessed 16/04/2009 available at mpairment%20%20-%20dosage%20adjustment%20for%20cytotoxics.doc Baxter K, editor. Stockley s Drug Interactions. Pharmaceutical Press; Accessed online on 06/05/09 available at Trissel LA. Handbook of Injectable Drugs, 15 th ed. American Society for Health-Systems Pharmacists Accessed online on 06/05/09 available Controlled document Document Number Version Number Page 4 of 5

5 at Allwood M, Stanley A, Wright P, editors. The cytotoxics handbook. 4 th ed. Radcliffe Medical Press Document title FCR (Oral)-CLL Document number ASWCS10 CLL001 Approval date 12/05/2011 Written by Jenny Bird, Consultant Haematologist, BHOC Checked by James Carr, Network Pharmacist, ASWCS Authorised by Jenny Bird, Chair, ASWCS Haematology Site Specialist Group Review date 12/05/2012 Document reviewed by Version number 1.1.a Summary of changes Version Controlled document Document Number Version Number Page 5 of 5