Regimen : Fludarabine Cyclophosphamide Rituximab (FCR-oral)

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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

1 Rituximab 375mg/m2 _IV

2-6* Cyclophosphamide 150mg/m2 _PO

2-6* Fludarabine 24mg/m2 _PO

Cycle 1

*Some units give chemotherapy on days 1-5 on Cycle 1-clinical decision

1 Rituximab 500mg/m2 _IV

1-5 Cyclophosphamide 150mg/m2 _PO

Cycles 2-6

1-5 Fludarabine 24mg/m2 _PO

Administration Rituximab: Patients with a high tumour burden (>25 x 109/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

Frequency Every 28 days for 6 cycles Extravasation Rituxumab is neutral (Group 1) Premedication Pre-Rituximab:

Paracetamol 1g PO Chlorphenamine 10mg IV

Hydrocortisone 100mg IV (if clinically appropriate)

Emetogenicity This regimen has mild emetogenic potential – refer to local protocol Additional

recommended

Allopurinol

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supportive medication 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 Pre-treatment

evaluation (i.e. before Cycle 1)

LFT Baseline – results valid for 7 days

FBC Pre D1 – results valid for 72 hours

U+E (incl CrCl) Pre D1 – results valid for 7 days

Regular investigations (i.e. before Cycle 2 and subsequent cycles)

LFT Pre D1 – results valid for 7 days

Neutrophil count ≥ 1 x 109_/l

Platelet count ≥75 x 109_/l

Creatinine clearance > 70ml/min

Standard limits for administration to go ahead – if blood results not within range, authorisation to administer must be given by prescriber/consultant

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Dose

modification s

Haematologi cal toxicity

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 109/L or platelets < 75 x 109/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 109/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% 30-70 100% 50% 21-29 100% Omit 10-20 75% Omit Renal impairment <10 50% Omit Hepatic impairment

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.

Rare and/or serious side effects Frequently occurring side effects

autoimmune haemolytic anaemia (fludarabine) Infusion related reactions (Rituximab)

Neutropenia, thrombocytopenia, anaemia (very

common) Fatigue

Rash Alopecia

Haemorrhagic cystitis Nausea and Vomiting

Ovarian failure Diarrhoea

Infertility Opportunistic infections

Cytokine release syndrome and tumour lysis syndrome

(Rituximab) Peripheral neuropathy

Pulmonary fibrosis, pneumonitis Adverse

effects – the contents of the table indicate the adverse effects that should be documented on consent to treatment forms Other Significant drug interactions – For full details consult product literature/referenc e texts

No clinically significant interactions.

Please refer to product literature for full details.

Comments Cyclophosphamide may irritate the bladder mucosa. Patients should be

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receiving cyclophosphamide.

Cumulative Doses

Not applicable References

• Boettcher S, Fischer K, Stilgenbauer S, BuschR, 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

http://ash.confex.com/ash/2008/webprogram/Paper13658.html

• Tam CS, O'Brien S, Wierda W, Kantarjian H, Wen S, Do KA, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008 112(4):975-80.

• 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. 2005 23 (18):4079-88.

• 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 2005 23 (18):4070-4078.

• National Institute for Health and Clinical Excellence. Rituximab for the first-line treatment of chronic lymphocytic leukaemia, Technology Appraisal Guidance 174, July 2009 [internet], viewed 08/10/2010, available at

http://www.nice.org.uk/nicemedia/live/11907/44906/44906.pdf • 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

http://guidance.nice.org.uk/TA193/Guidance/doc/English

• Summary of Product Characteristics Mabthera® (Rituximab) 100mg and 500mg concentrate for solution for infusion (Roche) [internet], accessed 10/09/2010 available from

http://www.medicines.org.uk/EMC/medicine/2570/SPC

• Summary of Product Characteristics Cyclophosphamide Tablets 50mg (Baxter) [internet], accessed 10/09/2010 available from

http://www.ecomm.baxter.com/ecatalog/loadResource.do?bid=33781 • Summary of Product Characteristics Fludara® (Fludarabine) oral 10mg

film-coated tablets (Genzyme) [internet], accessed 10/09/2010 available from http://www.medicines.org.uk/EMC/medicine/4240/SPC

• Daniels S. North London Cancer Network. Dose adjustment for cytotoxics in hepatic impairment [internet]. accessed 16/04/2009 available at

http://www.nlcn.nhs.uk/sites/default/files/pro_board_gu/2008/07/Hepatic%2 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

http://www.nlcn.nhs.uk/sites/default/files/pro_board_gu/2008/07/Renal%20i mpairment%20%20-%20Dosage%20adjustment%20for%20cytotoxics.doc

• Baxter K, editor. Stockley’s Drug Interactions. Pharmaceutical Press; 2009. Accessed online on 06/05/09 available at

https://www.medicinescomplete.com/mc/

• Trissel LA. Handbook of Injectable Drugs, 15th ed. American Society for Health-Systems Pharmacists 2009. Accessed online on 06/05/09 available

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at http://www.medicinescomplete.com/mc/hid/current/

• Allwood M, Stanley A, Wright P, editors. The cytotoxics handbook. 4th_ed.

Radcliffe Medical Press 2002.

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

Jenny Bird

Digitally signed by Jenny Bird DN: cn=Jenny Bird, o, ou, email=james.carr@aswcs.nhs.uk, c=GB Date: 2011.05.12 17:48:58 +01'00'

Jenny Bird

Digitally signed by Jenny Bird DN: cn=Jenny Bird, o, ou, email=james. carr@aswcs.nhs.uk, c=GB Date: 2011.05.12 17:49:19 +01'00'

James Carr

Digitally signed by James Carr

DN: cn=James Carr, o=ASWCS, ou=Network Pharmacist, email=james.carr@aswcs.nhs.uk, c=GB Date: 2011.05.12 17:49:44 +01'00'