Relapsed or Refractory Hodgkin s and Non-Hodgkin s Lymphoma. 375mg/m 2

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1 Regimen : (R)-GIFOX Indication Relapsed or Refractory Hodgkin s and Non-Hodgkin s Lymphoma Regimen details Age < 65 years This is NOT a NICE-approved indication for rituximab. Please ensure that this regimen is locally funded before prescribing this treatment or discussing with patients. Day Drug Dose Route 0 Rituximab (if appropriate) 375mg/m 2 IV infusion 1 Gemcitabine 1000mg/m 2 IV infusion 2 Oxaliplatin 130mg/m 2 IV infusion 2 MESNA 1g/m 2 (or 20% of calculated Ifosfamide dose) 2 Ifosfamide* 5grams/m 2 MESNA (mixed in same bag as Ifosfamide) 5grams/m 2 IV bolus IV infusion 3 MESNA* 3g/m 2 (or 60% of calculated IV infusion ifosfamide dose) 6-11 GCSF(Lenograstim) If attempting PBSC Subcutaneously mobilisation, 10micrograms/kg Otherwise: 263microgram if patient<85kg; 526microgram if patient >85kg Age > 65 years *As above but administer ifosfamide over days 3, 4 and 5 i.e. 2g/m 2 on days 3 and 4, and 1g/m 2 on day 5. MESNA doses should be split and given with each dose of ifosfamide (20% of calculated ifosfamide dose as IV bolus before each ifosfamide infusion; 100% of calculated ifosfamide dose in the same bag as the ifosfamide infusions on days 3, 4, and 5, and 60% of calculated ifosfamide dose on day 6) Administration Rituximab is administered in 500mL sodium chloride 0.9% as described below. Patients with a high tumour burden (WCC >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 0 with the remainder of the rituximab dose (i.e. 375mg/m 2 100mg) in 500ml sodium chloride 0.9% on day 1. 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 Controlled document Document Number Version Number Page 1 of 6

2 mg/hr; if tolerated increase by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. Gemcitabine is administered in mL sodium chloride 0.9% over 30 minutes. Oxaliplatin is administered in ml glucose 5% over 3 hours. If patients experience laryngo-pharyngeal dysaesthesia (see below), subsequent infusions should be should be given over 4-6 hours. Infusions must be diluted in glucose 5% as oxaliplatin is not compatible with sodium chloride 0.9%. Lines must always be flushed with glucose 5%. Lines must not be piggybacked or flushed with sodium chloride 0.9% immediately after the oxaliplatin infusion. Patients should be observed closely for platinum hypersensitivity reactions, particularly during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of oxaliplatin. Facilities for the treatment of hypotension and bronchospasm must be available. If hypersensitivity reactions occur, minor symptoms such as flushing or localised cutaneous reactions do not require discontinuation of therapy; the infusion may be temporarily interrupted and when symptoms improve restarted at a slower infusion rate. Chlorphenamine 10mg IV may be administered. Severe reactions, such as hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation of oxaliplatin and appropriate therapy. Laryngo-pharyngeal dysaesthesia may be exacerbated by exposure to cold air. If this occurs during infusion, stop infusion immediately and observe patient. Check oxygen saturation: if normal, an anxiolytic agent (e.g.lorazepam 1mg SC/PO/IV) may be given. The infusion can then be restarted at a slower rate (between 4-6 hours) Ifosfamide is administered (with MESNA in the same bag) in 1000mL sodium chloride 0.9% over 24 hours. MESNA on Day 3 (or Day 6 in the case of split-dosing for patients >65 years) is administered in 1000mL sodium chloride 0.9% over 12 hours. Ifosfamide can cause haemorrhagic cystitis - check urine for blood with dipstix every 4 hours. If 3+ administer 1g IV MESNA, if 2+ discuss with consultant, if 1+ observe patient. Encourage patients to drink plenty during treatment. Frequency Every 14 days. Three cycles planned, with reassessment of response by clinical examination, CT scan and bone marrow (if involved at start of therapy). Aim to collect stem cells from the third cycle. Extravasation Rituximab is neutral - group 1 Gemcitabine is neutral - group 1 Oxaliplatin is an exfoliant - group 4 Ifosfamide is neutral group 1 MESNA (diluted) is neutral- group 1 (undiluted MESNA is an irritant- group 3) Premedication 30 minutes prior to the start of each rituximab infusion: Paracetamol 1g PO Controlled document Document Number Version Number Page 2 of 6

3 Chlorphenamine 10mg IV Hydrocortisone 100mg IV (if clinically appropriate) Emetogenicity Additional recommended supportive medication Pre-treatment evaluations Regular investigations Standard limits for administration to go ahead if blood results not within range, authorisation to administer must be given by prescriber/consultant If a patient has previously developed grade 1 or 2 acute hypersensitivity reactions the following premedication is recommended: 30 minutes prior to oxaliplatin: Dexamethasone 20mg IV bolus Chlorphenamine 10mg IV bolus Ranitidine 50 mg IV bolus diluted in at least 20ml sodium chloride 0.9% and given over 2 minutes. This regimen has very high emetogenic potential refer to local protocol Anti-emetics as per ASWCS guidelines G-CSF given with each cycle (as above) Allopurinol 300mg once daily with first two cycles (reduce dose in renal impairment) PPI or H 2 -antagonist if appropriate FBC U+E (incl SrCr) LFT ECG CXR/PFTs FBC U+Es LFTs Neutrophil count 1.0x10 9 /L Platelet count 50x10 9 /L Creatinine clearance Bilirubin Pre-Day 0 results valid for 72 hours. Blood tests on alternate days during chemotherapy and at least twice a week until count recovery. Pre-Day 0 results valid for 72 hours Pre-Day 0 results valid for 7 days >60mL/min <ULN These tests may require performing more frequently depending on results (e.g. to optimise platelet transfusion support) Dose modifications Haematological toxicity Patients 65 years Patients > 65 years No planned dose reductions, delay cycle until above thresholds (discuss with consultant if >5-7days) Neutrophil count (x10 9 /L) Platelet count (x10 9 /L) Dose modification once count recovery Full dose Reduce Gemcitabine to 750mg/m Reduce Gemcitabine to 750mg/m 2 Reduce oxaliplatin to 97.5mg/m 2 Reduce ifosfamide to 3750mg/m 2 (split over 3 days) Renal impairment CrCl (ml/min) Gemcitabine Oxaliplatin Ifosfamide 60 Full dose Full dose Full dose Full dose Full dose 3500mg/m 2 Controlled document Document Number Version Number Page 3 of 6

4 40-49 Full dose 65mg/m mg/m 2 Hepatic impairment NCI Common toxicity criteria Adverse effects the contents of the table indicate the adverse effects that should documented on consent to treatment forms Full dose 65mg/m 2 Clinical decision <30 Consider dose reduction Gemcitabine Oxaliplatin Discuss with consultant Clinical decision There is limited information available on the use of Gemcitabine in patients with hepatic impairment. It should, therefore, be used with caution. AST elevations do not appear to cause dose limiting toxicities. If bilirubin > 1.5 x ULN, start at 800 mg/m 2. Little information available. Probably no dose reduction necessary in mild to moderate impairment. Omit if bilirubin > 5 x ULN Ifosfamide Manufacturers contra-indicate its use in patients with a bilirubin >ULN or serum transaminases or ALP > 2.5 x ULN Toxicity Definition Dose adjustment Neuropathy (Oxaliplatin) All other nonhaematological toxicity (except alopecia) Grade 1 paraesthesia Rare but serious side effects Encephalopathy Grade 2 paraesthesia persisting until next cycle Grade 3 paraesthesia >7 days but resolved before next cycle Grade 3 paraesthesia persisting until next cycle or Grade 4 of any duration Grade 2 (with exception of renal and hepatic impairment- see above) Grade 3 (with exception of alopecia) Grade 4 Platinum hypersensitivity (see table below) Laryngo-pharyngeal dysaesthesia (see table below) Pulmonary fibrosis Serious infection Secondary malignancy Ovarian failure/infertility Teratogenicity Interstitial Pneumonitis, ARDS No dose reduction Reduce dose to 75mg/m 2 and/or increase duration of infusion to 4-6 hours. Reduce dose to 50mg/m 2 Discontinue oxaliplatin No dose reduction Reduce all drug doses by 25%. Stop treatment and discuss with Consultant Frequently occurring side effects Myelosuppression Nausea and vomiting Constipation, diarrhoea Peripheral sensory neuropathy Hot-cold dysaesthesias Fatigue Stomatitis/Mucositis (usually mild) Haematuria Cardiotoxicity Other Headache; anorexia; alopecia (in all patients); transient rise in liver transaminases Controlled document Document Number Version Number Page 4 of 6

5 Refer to the table below to differentiate between platinum hypersensitivity and laryngopharyngeal dysaesthesia during or following oxaliplatin infusion. Clinical Symptoms Laryngo-pharyngeal Dysaesthesia Platinum Hypersensitivity Dyspnoea Present Present Bronchospasm Absent Present Laryngospasm Absent Present Anxiety Present Present O 2 saturation Normal Decreased Difficulty swallowing Present (loss of sensation) Absent Pruritus Absent Present Cold-induced symptoms Yes No Blood Pressure Normal or increased Normal or decreased Treatment Significant drug interactions For full details consult product literature/reference texts Anxiolytics; observation in a controlled clinical setting until symptoms abate or at physician s discretion. Oxygen, steroids, adrenaline, bronchodilators; Fluids and vasopressors if appropriate Warfarin/coumarin anticoagulants Avoid if possible as use often causes an elevation or fluctuation in the INR in the first instance consider switching patient to a low molecular weight heparin during treatment or if the patient continues taking an oral anticoagulant monitor the INR at least once a week and adjust dose accordingly. Aminoglycosides: increased risk of nephrotoxicity and possibly of ototoxicityavoid concomitant use with ifosfamide and oxaliplatin. Avoid all nephrotoxic drugs where possible. Comments Cumulative Doses References Clozapine: increased risk of agranulocytosis, avoid concomitant use. Diuretics: increased risk of nephrotoxicity and ototoxicity when platinum compounds given with diuretics Sulfonylureas: ifosfamide may enhance the hypoglycaemic effects of these drugs None Not applicable Corazzelli G,Russo F,Capobianco G, Marcacci G, Della Cioppa P, and Pinto A Gemcitabine, ifosfamide, oxaliplatin and rituximab (R-GIFOX), a new effective cytoreductive/mobilizing salvage regimen for relapsed and refractory aggressive non-hodgkin s Lymphoma: results of a pilot study. Ann Oncol 2006; 17 (Supplement 4):iv18-1v24. Corazzelli G.,Frigeri F., Marcacci G. et al. Rituximab plus gemcitabine, ifosfamide, oxaliplatin (R-GIFOX) as salvage therapy for recurrent Hodgkin Lymphoma. J Clin Oncol 2009; 27: 15s, (suppl; abstr 8579) Daniels S. North London Cancer Network, Dose adjustment for cytotoxics in hepatic impairment [internet]. accessed 18/11/2011 available at %20Dosage%20adjustment%20for%20cytotoxics.doc Daniels S. North London Cancer Network, Dose adjustment for cytotoxics in renal impairment [internet]. accessed 18/11/2011 available at 20-%20Dosage%20adjustment%20for%20cytotoxics.doc Baxter K, editor. Stockley s Drug Interactions. Pharmaceutical Press; Accessed online on 03/01/11 available at Allwood M, Stanley A, Wright P, editors. The cytotoxics handbook. 4 th ed. Radcliffe Medical Press, Controlled document Document Number Version Number Page 5 of 6

6 Summary of Product Characteristics Oxaliplatin Hospira 5mg/ml concentration for solution for infusion (Hospira) [internet]. accessed 14/01/2011 available from Summary of Product Characteristics Ifosfamide Injection 2g (Baxter) [internet]. accessed 18/11/2011 available from Summary of Product Characteristics Gemcitabine 200mg powder for solution for infusion, Gemcitabine 1g powder for solution for infusion, Gemcitabine 2g powder for solution for infusion (Hospira) [internet]. accessed 18/11/2011 available from Summary of Product Characteristics MESNA Injection 1000mg/10mL (Baxter) [internet]. accessed 18/11/2011 available from North of England Cancer Network. Cetuximab+FOLFOX (Oxaliplatin DeGramont) Protocol [internet]. Accessed 18/11/2011 available from rectal Document title R-GIFOX for Relapsed or Refractory Hodgkin s and Non-Hodgkin s Lymphoma Document number ASWCS11 LYM002 Approval date 27/01/2012 Written by Phil Robson, Consultant Haematologist, BHOC Checked by James Carr, Network Pharmacist, ASWCS Authorised by Jenny Bird, Chair, ASWCS Haematology Site Specialist Group Review date January 2013 Document reviewed by Version number 1.1.a Summary of changes Version Controlled document Document Number Version Number Page 6 of 6