R-ICE Regimen- Rituximab, Etoposide, Ifosfamide (with MESNA), Carboplatin (+ Depocyte if CNS involvement)

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1 R-ICE Regimen- Rituximab, Etoposide, Ifosfamide (with MESNA), Carboplatin (+ Depocyte if CNS involvement) Available for Routine Use in Burton in-patient Derby in-patient Burton day-case Derby day-case Burton community Derby community Burton out-patient Derby out-patient Indication Relapsed DLBCL /DLBCL with CNS involvement Treatment Intent Radical Anti-Emetics Pre-chemotherapy 3 Post-chemotherapy A Frequency & Duration Every 21 days(or upon recovery of bone marrow). For up to 3 cycles after completion of 3 cycles of MATRIX chemotherapy if used in this combination. Day 1 Allopurinol 300mg Oral once daily for 14 days Paracetamol 1g As a single oral dose 30 minutes prior to rituximab Chlorphenamine 10mg As a single intravenous dose 30 minutes prior to rituximab Hydrocortisone 100mg As a single intravenous dose 30 minutes prior to rituximab Rituximab 375mg/m 2 Intravenous infusion in 500ml 0.9% sodium chloride Etoposide 100mg/m 2 Intravenous infusion in 500ml-1000ml sodium chloride 0.9% over 60 mins (max conc. 0.4mg/ml) Phenytoin 300mg Oral once daily at night for 6 days Aciclovir 400mg Oral twice daily until lymphocytes >1 x 10 9 /l Cotrimoxazole 480mg Oral Once daily until lymphocytes >1 x 10 9 /l Metoclopramide 10mg Oral four times daily as required Sodium chloride 1 litre Intravenous infusion over 6 hours 0.9% Sodium chloride 0.9% 1 litre Intravenous infusion over 6 hours Day 2 Dexamethasone 8mg As a single oral or intravenous dose prior to chemotherapy AUTHORISED BY: Dr J Addada PAGE 1 of 6

2 Etoposide 100mg/m 2 Intravenous infusion in 500ml-1000ml sodium chloride 0.9% over 60 mins (max conc. 0.4mg/ml) Carboplatin AUC=5 5x(25+CrCl) (max 800mg) Intravenous infusion in 500ml 5% glucose over 1 hour Mesna 1000mg/m 2 Intravenous infusion in 100ml sodium chloride 0.9% over 15 minutes immediately before Ifosfamide and Mesna infusion Ifosfamide & Mesna 5000mg/m mg/m 2 Intravenous infusion in 2000ml sodium chloride 0.9% (2 x 1000ml infusion bags) over 24 hours Day 3 Etoposide 100mg/m 2 Intravenous infusion in 500ml-1000ml sodium chloride 0.9% over 60 mins (max conc. 0.4mg/ml) Mesna 3000mg/m 2 Intravenous infusion in 1000ml dextrose 4% & sodium chloride 0.18% over 12 hours immediately after the end of Ifosfamide and Mesna infusion Dexamethasone 4mg Oral twice daily for 6 days (if having Depocyte ) or for 2 days otherwise Only if CNS involvement: Day 4 Day 6 Day 6 Liposomal cytarabine (Depocyte ) G-CSF (Filgrastim) (non-mobilising cycles) OR Lenograstim (stem cell mobilising cycles) 50mg 300 micrograms 263 micrograms if BSA <1.8m 2, 368 micrograms if BSA 1.8m 2 Intrathecal injection- prescribe on a separate intrathecal chart Subcutaneous injection ONCE daily until neutrophils > 1.0 x 10 9 /L (supply 8 doses) Subcutaneous injection ONCE daily until adequate stem cell collection (supply 7 doses) AUTHORISED BY: Dr J Addada PAGE 2 of 6

3 Notes: Pre-treatment investigations FBC, U&Es, LFTs, CrCl (ideally by measured Cr-EDTA prior to 1 st cycle) It is recommended that patients receive pre-hydration with 2 litres of sodium chloride 0.9% over 12 hours. Assess response after the 1 st and 3 rd cycle and review treatment plan if stable or progressive disease. Rituximab This section should be read in conjunction with the Guidelines for the administration of Rituximab. 1. Premedication consisting of analgesia and an antihistamine and an intravenous corticosteroid should always be administered 30 minutes before each infusion of rituximab, (e.g. paracetamol 1g oral STAT and chlorphenamine 4mg oral or 10mg IV bolus STAT and hydrocortisone 100mg IV STAT). In addition pethidine 25mg IV should be available in case of a severe infusion reaction 2. Rituximab doses should be rounded to the nearest 100mg Use rituximab rate calculator to assist with rate escalation of rituximab infusion 3. Occurrence of an Infusion Related Event or Hypersensitivity: Stop the infusion and contact a doctor. When symptoms improve, continue the infusion at half the rate prior to the reaction. Accelerate the infusion rate more slowly as tolerated by the patient. Dose modifications and toxicities 1. Haematological toxicity Delay treatment until neutrophils > 1 x10 9 /l and platelets > 100x10 9 /l unless cytopenias are considered to be disease-related. The dose of chemotherapy will be determined according to the nadir neutrophil or platelet counts of the previous course as follows: Nadir neutrophils R-ICE dose (x10 3 /mm 3 ) <0.5 75% dose of ifosfamide if complicated with infection Nadir platelets (x10 3 /mm 3 ) R-ICE dose < 25 75% dose of ifosfamide if complicated with bleeding AUTHORISED BY: Dr J Addada PAGE 3 of 6

4 2. Non-haematological toxicity For CTCAE grade 2 or less non-hematological toxicity, no dose reductions will be required. For CTC (version 4.03) grade 3-4 non-hematological toxicity, the total dose of etoposide, carboplatin and ifosfamide to be administered for the next course will be reduced as follows: Toxicity Grade 3 Grade 4 Cardiovascular Interruption Interruption Coagulation Unchanged 75% dose of ifosfamide Gastrointestinal Unchanged 75% dose of all drugs Renal 75% dose of all drugs 75% dose of all drugs Hepatic 75% dose of all drugs 75% dose of all drugs Pulmonary Unchanged 75% dose of all drugs 3. Renal impairment GFR ml/min Ifosfamide Dose Etoposide Dose > 60 Full dose Full dose % of dose 80% of dose < 40 Clinical decision Clinical decision Carboplatin: Contraindicated if CrCl<20ml/min 3. Hepatic impairment Etoposide Bilirubin AST/ALT micromol/l IU/L Etoposide Dose % >51 >180 omit Ifosfamide No standard dose modification therefore clinical decision. Consider dose reduction of ifosfamide in patients with significant hepatic dysfunction. The manufacturer states that ifosfamide is not recommended if bilirubin>17umol/l or serum transaminases or ALP>2.5xULN. Clinical decision. Carboplatin: No dose reduction necessary. AUTHORISED BY: Dr J Addada PAGE 4 of 6

5 4. Neurotoxicity Ifosfamide may cause a reversible encephalopathy at high doses. This usually manifests as decreased rousability and disorientation often leading to somnolence. In severe cases this can progress to irreversible encephalopathy and death. Patients should be monitored regularly for signs/symptoms of neurotoxicity. Symptoms may develop within 2 hours of initiation or up to 28 days after treatment; the usual onset is within hours after the initiation of ifosfamide and disappears within hours of discontinuing ifosfamide. Risk factors include: Elevated serum creatinine Previous exposure to cisplatin (cumulative dose >300mg/m 2 ) Low serum albumin. Discuss with Consultant if albumin <35g/l. Previous exposure to ifosfamide Abdominal lymphoma Short ifosfamide infusions (<6hrs) Prior cranial irradiation Other CNS-active drugs If a patient is at risk of developing encephalopathy, consideration should be given to the use of an alternative (non-ifosfamide containing) regimen. Management of ifosfamide-induced encephalopathy 1. Discontinue ifosfamide. 2. Consider use of methylthioninium chloride (methylene blue) (Unlicensed indication): 50mg slow intravenous bolus over 5 minutes. This may need to repeated up to 6 times/day. Methylthioninium chloride is available as a 0.5% solution; 10ml of 0.5% solution is equivalent to 50mg. The 0.5% solution does not require filtering, and is incompatible with sodium chloride 0.9% so will need to be diluted in 5% dextrose if dilution is necessary. 3. In patients who have had a history of ifosfamide-induced encephalopathy and require further doses of ifosfamide, methylthioninium chloride has been used prophylactically (50mg slow intravenous bolus over 5 minutes 4 times daily). AUTHORISED BY: Dr J Addada PAGE 5 of 6

6 4. Haloperidol & lorazepam have been reported to help with hallucinations and agitation. Use with caution, -no controlled trials exist and these agents may mask the evolution or severity of neurotoxicity. Methylthioninium chloride frequently colours secretions blue, patients should be made aware of this effect 4. Haemorrhagic Cystitis Urine should be dipstick tested for signs of haematuria. If microscopic haematuria is present, an increase in hydration can be used to facilitate the elimination of ifosfamide and its metabolites. Additional mesna appears to have little benefit as its role is in prevention rather than treatment. However, owing to its low toxicity consideration should be given to increasing the dose of mesna (although arbitrary, local practice is to double the dose). In the case of frank haematuria, a urological opinion should be sought. Mesna is of little value at this point as it s role is to prevent haemorrhagic cystitis and not for its treatment. Supportive care 1. Consider allopurinol (300mg) once a day if bulky disease. Reduce dose to 100mg daily if GFR <10mls/min. 2. All patients should receive Pneumocystis jiroveci prophylaxis throughout treatment:: Co-trimoxazole 480mg ONCE daily. In cases of allergy to co-trimoxazole, consider dapsone 100mg daily. 3. Aciclovir 400mg twice daily. 4. All patients receive primary prophylaxis with GCSF. GCSF is mandatory for stem cell collection. Typically this is performed after the 2 nd or 3 rd MATRIX cycle or the 1 st R-ICE cycle in selected patients with extensive or bulky disease. References 1. Kewalramani et al. Rituximab and ICE as second line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B cell lymphoma. Blood 2004; 103: IELSG 42 Protocol- version 3.0- Fenruary 08, 2016 AUTHORISED BY: Dr J Addada PAGE 6 of 6