SMILE chemotherapy 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 Extranodal natural killer/t cell lymphoma, nasal type (ENKL) Treatment Intent Radical Anti-Emetics Pre-chemotherapy Akynzeo Post-chemotherapy Frequency & Duration Every 28 days (or upon recovery of bone marrow). 2 cycles followed by assessment of response. Patients may receive further cycles and/or other chemotherapy, with or without autologous/allogeneic HSCT, as appropriate. Day 1 20mmol potassium chloride per litre REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 1 of 10 125ml/m 2 /hr intravenous infusion Day 2 Allopurinol 300mg Oral once daily Phenytoin 300mg Oral once daily at night for 6 days Dapsone 100mg Oral once daily for 28 days Aciclovir 400mg Oral twice daily for 28 days Day 2 (provided urine ph >7.5) concurrently with Akynzeo 300mg/ 0.5mg Orally 1 hour before chemotherapy Dexamethasone 8mg Oral or intravenous prior to Methotrexate 2000mg/m 2 Intravenous infusion in 500ml sodium chloride 0.9% over 6 hours 20mmol potassium chloride per litre Intravenous infusion (combined infusion rate with infusion = 125ml/m 2 /hr) Metoclopramide 10mg Oral four times daily as required
Followed by Day 3 20mmol potassium chloride per litre 20mmol potassium chloride per litre 125ml/m 2 /hr intravenous infusion 125ml/m 2 /hr intravenous infusion Dexamethasone 40mg Orally once daily for 3 days 24 hours after 30 hours after 36 hours after 42 hours after 48 hours after Ifosfamide & Mesna 1500mg/m 2 900mg/m 2 Intravenous infusion in 1000ml sodium chloride 0.9% over 6 hours Etoposide 100mg/m 2 Intravenous infusion in 500ml-1000ml sodium chloride 0.9% over 60 mins (max conc. 0.4mg/ml) REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 2 of 10
Day 4 54 hours after 60 hours after 66 hours after 72 hours after 20mmol potassium chloride per litre Ifosfamide & Mesna 1500mg/m 2 900mg/m 2 125ml/m 2 /hr intravenous infusion Intravenous infusion in 1000ml sodium chloride 0.9% over 6 hours Etoposide 100mg/m 2 Intravenous infusion in 500ml-1000ml sodium chloride 0.9% over 60 mins (max conc. 0.4mg/ml) Day 5 20mmol potassium chloride per litre Ifosfamide & Mesna 1500mg/m 2 900mg/m 2 125ml/m 2 /hr intravenous infusion Intravenous infusion in 1000ml sodium chloride 0.9% over 6 hours Etoposide 100mg/m 2 Intravenous infusion in 500ml-1000ml sodium chloride 0.9% over 60 mins (max conc. 0.4mg/ml) 78 hours after REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 3 of 10
84 hours after 90 hours after 96 hours after Day 7 Filgrastim 300micrograms Subcutaneous injection once daily until neutrophil count>1x10 9 /l **IMPORTANT- READ GUIDANCE ON ASPARAGINASE IN CONJUNCTION** Days 9,11,13,15, 17,19,21 Asparaginase (E.Coli Medac ) 1000units REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 4 of 10 Intradermal test dose Chlorphenamine 10mg Intravenous bolus premedication then as required for hypersensitivity reactions (max 40mg/24 hours) Hydrocortisone 100mg Intravenous bolus premedication then as required for hypersensitivity reactions Paracetamol 1gram Oral premedication then as required for hypersensitivity reactions (max 4g/24 hours) Asparaginase (E.Coli Medac ) 6000units/m 2 Intravenous infusion in 250ml sodium chloride 0.9% over 2 hours Notes: Supportive care 1. Consider allopurinol (300mg) once a day for the prevention of tumour lysis syndrome. Reduce dose to 100mg daily if GFR <30ml/min.
2. All patients should receive Pneumocystis jirovecii prophylaxis throughout treatment as dapsone 100mg daily. (Note that cotrimoxazole should not be given due to the potential for interaction with ). 3. Aciclovir 400mg twice daily. 4. Hydration (with sodium bicarbonate containing infusions) throughout treatment is essential (at least 3 litres a day). Urinary ph must be maintained between 7 and 8 throughout the period of treatment to ensure excretion. If 100mmol sodium bicarbonate / litre is insufficient to keep the urine ph>7, give 50-100mmol sodium bicarbonate (i.e. 50-100ml of 8.4% sodium bicarbonate) over 30-60 minutes (piggy back onto existing hydration fluids). If repeated extra doses are required, increase the hydration fluids to contain 150mmol sodium bicarbonate / litre. 6. Strict fluid balance chart should be maintained. Prescribe furosemide 20-40mg stat if fluid balance is 2 litres positive. 7. Methotrexate levels every 24 hours, at 48 hours after commencement of the infusion. If the patient is not vomiting folinic acid may be given orally after the first two doses. Folinic acid rescue should continue until the serum level falls to less than 0.1 micromol/l Drug interactions AVOID concurrent use of the following drugs: Aspirin Non-steroidal anti-inflammatories Penicillins (Including Tazocin ) Aminoglycosides Trimethoprim (including co-trimoxazole) Probenacid Sulphonamides Neutropenic sepsis should be managed with Meropenem (discuss with Microbiologist) Pre-treatment tests Prior to day 1: FBC, U&Es, LFTs. Patients require insertion of a double or triple lumen central venous catheter. Prior to cycle 1 and cycle 3: Creatinine clearance measured by 24 hour urine collection or chromium EDTA. REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 5 of 10
Repeat on cycle 2 if there is delayed excretion with the 1 st cycle. Repeat if there is a 20% or greater increase in serum creatinine from the previous cycle. Consider baseline echocardiogram (patients need to be able to tolerate large volumes of fluid). Prior to each asparaginase dose: FBC U&Es & LFTS Blood glucose (daily) Amylase Clotting screen, ATIII, fibrinogen, APTT. 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. If grade 4 thrombocytopenia (platelets <25x10 9 /l) occurs in cycle 1, reduce, ifosfamide and etoposide doses by 33% in cycle 2. Asparaginase: Platelets must be >25x10 9 /l before each asparaginase dose. If the level of fibrinogen is below 0.8 g/ litre and/or the level of ATIII is below 70% and/or the PTT is >70 seconds at any time, then consider replacement therapy with fresh frozen plasma, fibrinogen or antithrombin III concentrate. Discuss with Consultant. REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 6 of 10
2. Non-Haematological toxicity Asparaginase: Discontinue Asparaginase in the presence of: pancreatitis (raised amylase or low serum insulin) thrombosis grade 3 or 4 hypersensitivity reaction any grade 3 non-haematological toxicity Reduce asparaginase dose to 50% if previous grade 1 or 2 hypersensitivity reaction. In this case, consider the use of prednisolone 1mg/kg/day. Discuss with Consultant. 3. Renal impairment GFR ml/min Methotrexate dose > 80 Full dose (2g/m 2 ) 50 80 50% dose (1g/m 2 ) <50 Do not give Consider alternative approaches (e.g. intrathecal) Check serum creatinine levels daily whilst receiving folinic acid rescue. GFR ml/min Ifosfamide Dose Etoposide Dose > 60 Full dose Full dose 40-60 70% of dose 80% of dose < 40 Clinical decision Clinical decision Asparaginase: No dose adjustment required in renal impairment. 4. Hepatic impairment Methotrexate Bilirubin AST/ALT micromol/l Units/L Dose <50 & <180 100% 51-85 or >180 75% >85 omit Etoposide Bilirubin micromol/l AST/ALT IU/L Etoposide Dose REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 7 of 10
26-51 60-180 50% >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. Discuss with Consultant if albumin <35g/l (see Neurotoxicity). Asparaginase: Discontinue if ALT>5xULN or Bil>3xULN 5. Guidance for Administration and Monitoring of Asparaginase Side effects Careful monitoring is required due to the risk of toxicities: Hypersensitivity reactions which can be severe/life threatening Clotting abnormalities, including a reduction in fibrinogen and clotting factors or thrombosis, particularly of the CNS Pancreatitis Hyperglycaemia that may require insulin Hepatotoxicity Myelosuppression Administration of Asparaginase There is a risk of anaphylaxis, therefore ensure an anaphylaxis box containing adrenaline is readily available An intradermal test dose is given before EACH dose. Monitor the patient during and for 1 hour afterwards. A Dr must review the test dose site. If redness/wheals develop, the intravenous dose is NOT to be given. Inform the Consultant. The patient MUST be monitored during the intravenous dose and for 1 hour afterwards for signs of allergic reaction. STOP the infusion if there are any signs of an allergic reaction and administer supportive medicines/notify the Dr. 6. Table for the calculation of folinic acid rescue on the basis of MTX plasma levels. Methotrexate Plasma Concentration (micromol/l) Time after <0.1 0.1-2.0 2.0-20 20-100 >100 REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 8 of 10
48 hours None 15mg/m 2 6hrly 15mg/m 2 6hrly 10mg/ m 2 72 hours None 15mg/m 2 6hrly 10mg/ m 2 100mg/ m 2 96 hours None 15mg/m 2 6hrly 10mg/ m 2 100mg/ m 2 120 hours None 15mg/m 2 6hrly 10mg/ m 2 100mg/ m 2 100mg/ m 2 1000mg/ m 2 1000mg/ m 2 1000mg/ m 2 The dose of folinic acid should also be increased if serum creatinine increases >50% from baseline. 7. 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 24-96 hours after the initiation of ifosfamide and disappears within 48-72 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): REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 9 of 10
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). 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 8. 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. References: 1. Phase II Study of SMILE Chemotherapy for Newly Diagnosed Stage IV, Relapse, or Refractory Extranodal Natural Killer (NK)/T-Cell Lymphoma, Nasal Type: NK-Cell Tumour Study Group. J Clin Oncol. 2011:29:4410-4416. 2. Asparaginase (Medac) Summary of Product Characteristics accessed 26/1/17 at http://www.medicines.org.uk/emc 3. UKALL XII trial protocol Version 4.1 February 2006 4. Asparaginase Monograph BC Cancer Agency accessed 26/1/17 at http://www.bccancer.bc.ca/drug-databasesite/drug%20index/asparaginase_monograph_1june2013_formatted.pdf REVIEWED BY K.GRAHAM AUTHORISED BY: Dr J Addada PAGE 10 of 10