Fludarabine based chemotherapy [Fludarabine, FC, FCR, FMD]

Approved Haematology Chemotherapy Protocol Fludarabine based chemotherapy [Fludarabine, FC, FCR, FMD] MCCN Ref OPCS Proc OPCS Del CLFLUD X70.5 X72.3 IV CLFC X70.4 X72.2 IV X73.1 O CLFCR X71.5 X72.1 LYFMD X71.2 X72.2 Indications Fludarabine Fludarabine+ Cyclophosphamide (FC) Fludarabine+ Cyclophosphamide + Rituximab (FCR) Fludarabine + Mitoxantrone+ Dexamethasone (FMD) CLL Indolent lymphoproliferative disorders CLL Indolent lymphoproliferative disorders / mantle cell lymphoma CLL Mantle cell lymphoma / low grade lymphomas Follicular and other indolent lymphomas Pre-treatment evaluation 1. Blood tests FBC, U&E, Creatinine Clearance, bone profile, LFTs, LDH, serum immunoglobulins and electrophoresis, DCT, reticulocyte count, serum haptoglobin. Patients undergoing treatment with fludarabine should be monitored for signs of AIHA. Fludarabine can be used in patients with positive DCT without evidence of haemolysis. However they should be monitored carefully for the development of AIHA. FC and FCR (but not single agent fludarabine) can be used in patients with AIHA unrelated to fludarabine. However they should be monitored very carefully for progression of the haemolysis. Fludarabine based regimens are contraindicated in patients with a history of fludarabineinduced haemolysis / PRCA. 2. Undertake relevant staging document B symptoms, BM aspirate, trephine and cytogenetics and CT chest / abdomen / pelvis (if appropriate) 3. FMD regimen :consider echocardiogram (follow local protocol for anthracycline toxicity) 4. Give adequate verbal and written information for patients and relatives concerning disease, treatment strategy and side effects. Obtain written consent from patient. 5. Discuss infertility / early menopause if appropriate. Where pregnancy is possible, advice contraception during therapy and long term after therapy (decision based on individual patient factors). 6. All male patients should be offered sperm banking. 7. All cellular blood components must be irradiated indefinitely. Issue patient with DoH information sheet and card regarding irradiated blood products. Drug Regimen FLUDARABINE (SINGLE AGENT) 1 ORAL REGIMEN: Days Drug Dose Route Comment 1 to 5 Fludarabine 40mg/m 2 PO Same time each day, before or with breakfast See appendix for guide on number of fludarabine tablets to take for 40mg/m 2 PO dose regimen. INTRAVENOUS REGIMEN: Days Drugs Dose Route Comment 1 to 5 Fludarabine 25mg/m 2 I.V. Infuse in 100ml N Saline over 30minutes or bolus in 10ml N Saline. Fludarabine based chemotherapy protocols Page 1 of 6

Cycle frequency and treatment duration: 28 day cycle. Treatment based on a minimum of 3 cycles and a usual maximum of 6 cycles, to achieve optimum response. FLUDARABINE AND CYCLOPHOSPHAMIDE +/- RITUXIMAB (FC+/-R) 1, 2 ORAL FC If Rituximab is required: 1 Rituximab 375 mg /m 2 IV infusion See Rituximab protocol for details regarding pre-medication, infusion speed, and observation during infusion and management of infusion related reactions. FOLLOWED BY: 1 to 5 Cyclophosphamide 150mg /m 2 PO At breakfast 1 to 5 Fludarabine 24mg /m 2 PO At lunchtime IF THE ORAL ROUTE IS NOT TOLERATED DUE TO G.I TOXICITY USE IV FC: INTRAVENOUS FC: If Rituximab is required: 1 Rituximab 375 mg/m 2 IV infusion See Rituximab protocol for details regarding pre-medication, infusion speed, and observation during infusion and management of infusion related reactions. FOLLOWED BY: 1 to 3 Cyclophosphamide 250mg /m 2 IV Bolus Cyclophosphamide should be administered immediately before fludarabine for optimum effect. 1 to 3 Fludarabine 25mg/m 2 IV Infuse in 100ml N Saline over 30minutes or bolus in 10ml N Saline. Cycle frequency and treatment duration: 28 day cycle. Treatment based on a minimum of 3 cycles and a usual maximum of 6 cycles, to achieve optimum response. STAGE C CLL i.e. Hb <10 g/dl and platelets <100 x 10 9 /l not due to autoimmune phenomena should receive prednisolone 30mg/m 2 for 3 weeks, plus 1 week tailing off, followed 1 or 2 weeks later by the chemotherapy. 1 FLUDARABINE, MITOXANTRONE, DEXAMETHASONE (FMD) 3 1 to 3 Fludarabine 40mg/m 2 PO 10mg tablets see dosing chart in appendix 1 for number of tablets to take. OR 25mg/m 2 IV Intravenous bolus in 10ml 0.9% NaCl or infuse over 30min in 100ml 0.9% NaCl 1 Mitoxantrone 12mg/m 2 IV Slow IV bolus injection (diluted in 50ml 0.9% NaCl) over >3 minutes into the sidearm of a fast running NaCl 0.9% infusion or infuse in 100ml 0.9% NaCl over 15 minutes 1 to 5 Dexamethasone 20mg PO / IV Take in the morning Cycle frequency and treatment duration: Every 28 days, usual minimum of 4 cycles and a maximum of 8 cycles (a maximum of 6 cycles should be considered for patients experiencing repeated delayed myelosuppression with fludarabine). Fludarabine based chemotherapy protocols Page 2 of 6

Dose modifications Haematological: FC +/- R Neutropenia and thrombocytopenia may be due to the disease. However, if the treating haematologist considers that the fall in counts is due to the treatment, the following guidelines should be followed for the next treatment course 1. If neutrophils <1 x 10 9 /L and/or platelet <75 x 10 9 /L on day of treatment delay treatment for 1-2 weeks 2. If after 2 weeks delay the values are unchanged, treatment may proceed at 50% of the dose 3. If neutrophils <0.5 x 10 9 /L or platelets <50 x 10 9 /L when a new cycle is due delay treatment until the counts rise to at least these levels, with dose modifications as above if necessary. 4. Consider the use of GCSF to maintain treatment schedule. 5. For patients starting with thrombocytopenia, delay treatment if counts had not returned to baseline values by 4 weeks. FMD 1. Counts for the start of the second and subsequent cycles must be neutrophils >1.0 x 10 9 /L and platelets > 100 x 10 9 /L 2. If both criteria above are not met defer treatment for up to 2 weeks (Day 42) until criteria are met and reduce dose to level 1. 3. If delayed beyond this ensure G-CSF support initiated. 4. If criteria above reached before 4 weeks delay (Day 56) proceed with a minimum dose level with G- CSF support. 5. If delayed beyond 4 weeks (Day 56) despite G-CSF support consider discontinuation. 6. If neutrophils <0.5 x 10 9 /L for > 5 days or platelets <20 x 10 9 /L or second episode of neutropenic sepsis requiring admission reduce dose by one level for next cycle. If after this dose reduction the subsequent cycle has no associated haematological toxicity (neutrophil nadir > 1 x 10 9 /L and platelet nadir > 100 x10 9 /L) increase doses by one level Minimum Level 1 Standard level Fludarabine 15mg/m 2 25mg/m 2 25mg/m 2 Mitoxantrone 6mg/m 2 10mg/m 2 12mg/m 2 Dexamethasone 20mg 20mg 20mg RITUXIMAB 4 Patients with high numbers of circulating malignant cells (>25 x 10 9 /l) avoid rituximab until cell count reduced by other measures. Renal impairment: Fludarabine: 4 CrCl (ml/min) Dose >70 100% 30-70 50% <30 OMIT Cyclophosphamide: 10 CrCl (ml/min) Dose >50 100% 10-50 75% < 10 50% Hepatic impairment: Mitoxantrone: 5 Serum bilirubin Dose Fludarabine based chemotherapy protocols Page 3 of 6

<1.5 x ULN 100% 1.5 3.0 x ULN 50% >3.0 x ULN 25% GI toxicity: Fludarabine and cyclophosphamide: Patients receiving oral therapy who experience gastrointestinal symptoms, such as nausea and/or vomiting and/or diarrhoea may have their administration switched to the IV route in accordance with IV protocol. Cardiac toxicity: Mitoxantrone: 6 The maximum cumulative dose in adults is 140mg/m 2 if no prior anthracycline and normal cardiac function. It is 120mg/m 2 if previous anthracycline, thoracic radiation and cyclophosphamide. This is reduced to 100mg/m2 if previous maximum dose anthracycline and normal cardiac assessment. However close monitoring of cardiac function is advisable e.g. echocardiogram every 2 cycles. Investigations prior to each subsequent treatment cycle 1. Blood tests FBC, U&Es, LFTs, LDH, DAT, reticulocyte count, DCT, serum haptoglobin 2. Restage after cycle 3 and after cycle 6 (if indicated). 3. Blood pressure and blood glucose monitoring as indicated for each patient if on FMD. Support therapy Suggested regimen only, follow local protocols The following is a possible schedule, follow local protocols. 1. Allopurinol 300mg daily during the first cycle (100mg daily if creatinine clearance <20 ml/min). 2. Anti-emetics regular 5HT 3 during chemotherapy and when needed post chemotherapy. 3. Co-trimoxazole 480mg bd PO on Mon, Wed, Fri during therapy and for at least 6 months after therapy 4. Aciclovir 400mg bd during therapy. 5. Fluconazole 50mg od or nystatin susp 1ml qds during therapy. 6. Chlorhexidine 0.2% MW 10ml qds during therapy. 7. PPI if on FMD. Anticipated toxicity Anticipated toxicity Fludarabine single agent Neutropenia 27% grade 3 or 4 7 (40% in CLL4?grades) Thrombocytopenia 13% grade 3 or 4 7 FC +/ - R (toxicities reported are those of FCR) In relapsed/ refractory CLL patients, 15% and 66% patients had 1 or more episodes of grade 3 or 4 respectively (grade 3 in 21% & grade 4 in 41% of 529 assessable courses 9 Grade 3 & 4 neutropenia occurred in 24% & 28% of 927 courses respectively as initial therapy of CLL 2 In relapsed/ refractory CLL patients, 16% & 18% patients had one or more episodes grade 3 or 4 respectively ( grade 3 in 10% & grade 4 in 7% of courses) 9 Grade 3 or 4 occurred in 4% and < 1% of courses respectively as initial therapy of CLL 2 Infections 16% grade 3 or 4 7 Major infections (sepsis, pneumonia, or infections Fludarabine based chemotherapy protocols Page 4 of 6 FMD Grade 4 in 26% of courses 11 Grade 3/4 in 8% of courses 11 30 infectious episodes (12% of courses) in 22

requiring hospitalisations) occurred in 16% of relapsed/ refractory patients. PUO in 31% of relapsed/refractory patients & minor infections in 18% of relapsed/refractory patients 9.As a first line therapy, major infections (e.g. pneumonia, sepsis) in only 2.6% of the courses 2. Minor infections (including PUO, UTIs, URTI, sinusitis) in 10% of courses. Opportunistic infections also reported in a few patients patients (out of 51 patients). 5 were minor and 12 more severe and were presumed to be bacterial infections including 10 in the setting of neutropenia. 13 episodes were proven or suspected opportunistic infections (6 shingles, 2 PCP, 4 suspected PCP and MAI, the latter proved fatal) Rate not reported 11 Anaemia 11.6% grade 3 or 4 8 5% Patients had grade 3 or 4 anaemia 9 AIHA 3.8% 8, 10% in CLL4 Rare Not reported 11 Anticipated toxicity Fludarabine single agent GI side-effects up to 40-50% (nausea, vomiting, diarrhoea, ulcers) Treatment-related deaths All grades 3/4 toxicities Tumour lysis/ hyperuricaemia Rituximabassociated toxicities-see also Rituximab Protocol Haemorrhagic cystitis Other side effects Extravasation - See also the latest version of the MCCN Cytotoxic Extravasation Guidelines FC +/ - R (toxicities reported are those of FCR) Nausea in 23% courses & vomiting in 7% courses newly treated patients 2 Fludarabine based chemotherapy protocols Page 5 of 6 FMD 21.6% nausea (mild in all but one), 5.9% vomiting, 11.8% mild stomatitis, 3.9% mild diarrhoea 11 FM 10 regime-nil treatmentrelated Not given 11 1% 7, 1.7% 8 Not given in FCR studies 2, 9. 1.2% with FC 8 deaths 55% 7, 54% 8 Not given in FCR studies 2, 9. 72.6% with FC 8 Rare Rare Rare Extravasation (Fludarabine is neutral in terms of extravasation & wouldn t be expected to cause inflammation/ tissue damage 12), loss of appetite, fever, chills, joint pains, tiredness, sore mouth and ulcers, taste changes, rash, headache, confusion, agitation, pulmonary (pneumonitis, fibrosis), infertility 63% with the first infusion (all grade 1 or 2 except 1 patient with grade 3 breathlessness) 9 Rare - Extravasation (Fludarabine & Cyclophosphamide and Rituximab are classed as neutral in terms of extravasation & wouldn t be expected to cause inflammation/tissue damage 12 ), sore mouth and ulcers, taste changes, poor appetite, diarrhoea, tiredness, skin changes (rash), alopecia, infertility, early menopause, fever, joint pains, temporary abnormal LFTs, confusion, headache, agitation, pneumonitis, pulmonary fibrosis, secondary malignancies, - Extravasation (Fludarabine is neutral in terms of extravasation & wouldn t be expected to cause inflammation/tissue damage. Mitoxantrone is an exfoliant and can cause inflammation & shedding of the skin 12 ), alopecia, cardiac failure (5.9%) in patients with previous anthracycline 11 ), ovarian failure, infertility, SEs of dex (insomnia, gastric irritation, fluid retention, hypertension, high glucose, behavioural changes), bluegreen urine, sore mouth and ulcers, temporary abnormal LFTs, taste

changes, anorexia, tiredness, secondary malignancies. References 1. CLL4 Trial Protocol. LRF. Feb 2001 2. Keating MJ et al. Early Results of a Chemoimmunotherapy Regimen of Fludarabine, Cyclophosphamide, and Rituximab As Initial Therapy for Chronic Lymphocytic Leukemia. J Clin Oncol. 2005;23:4079-4088. 3. A Randomised Trial of MCD v FMD in untreated advanced stage follicular lymphoma. CSLG and BNLI. Fen 2000. 4. http://emc.medicines.org.uk. SPC for rituximab and fludarabine 5. ASWCS Haematology chemotherapy protocols. FMD. May 2007. http://www.aswcs.nhs.uk/pharmacy/chemohandbook/hcp/part1/fmd.pdf. Last checked Feb 2008. 6. Cancer Drug Manual. www.bccancer.bc.ca/hpi/drugdatabase 7. Rai K et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukaemia. NEJM. 2000; 343:1750-1757 8. Eichhorst BF et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukaemia. Blood. 2006;107:885-891 9. Wierda W et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukaemia. J Clin Oncol. 2005;23:4070-4078 10. Dose adjustments for cytotoxics in renal impairment North London Cancer Network. S Daniels. 2003 11. McLaughlin P et al. Fludarabine, Mitoxantrone and Dexamethasone: An effective new regimen for indolent lymphomas. J Clin Oncol. 1996; 14: 1262-1268. 12. The Cytotoxics Handbook 4 th Edition. Allwood M; Stanley A; Wright P. Appendix 1 40mg m 2 oral dosing table Guide to how many tablets of Fludarabine to be taken daily for a 40mg/m 2 PO dose based on BSA Body Surface Area (BSA Calculated total daily dose based on BSA (mg No of tablets per day m 2 ) /day) 1.14-1.38 46-55 5 (50mg) 1.39-1.63 56-65 6 (60mg) 1.64-1.88 66-75 7 (70mg) 1.89-2.13 76-85 8 (80mg) Written by: Approved by: Review Date: Cathy Rimmer, Ian Hincks, R Salim Fludarabine based chemotherapy protocols Page 6 of 6