Regimen R-HD Methotrexate & Cytarabine

Indication Primary CNS Lymphoma

Therapeutic Intent Curative

Day Medication Dose Route Administration Details As per IELSG 32 trial Add to sodium chloride 0.9%, see local protocol -5 Rituximab 375mg/m2 IV or product SPC for information on rate of infusion. Add to sodium chloride 0.9%, see local protocol 0 Rituximab 375mg/m2 IV or product SPC for information on rate of infusion. 1 Methotrexate 500mg/m2 IV Infuse in 100ml NaCl 0.9% over 15 mins 1 Methotrexate 3000mg/m2 IV Infuse in 1000ml NaCl 0.9% over 3 hrs 2000mg/m2 Infuse in 500ml NaCl 0.9% over 1 hr 2 to 3 Cytarabine IV twice a day Every 12 hours (total of 4 doses)

Cycle Frequency Every 21 days for up to 4 cycles and assess response after 2 cycles

FBC, U&E, LFTs, Cardiac function tests, Pulmonary function tests, Hep B Tests required prior to and viral screening initiation of course GFR calculated using the Wright equation or EDTA testing Tests required prior to FBC, U&E, LFTs individual cycle Antihistamine and paracetamol pre-medication prior to rituximab as per local policy. Allopurinol for first two cycles. Anti-emetics as per local policy. Concurrent Medication Antivirals/Antifungals/Antibacterials as per local policy. GCSF as per local policy from day 7 – primary prophylaxis recommended. PPI as per local policy. Corticosteroid eye drops three times day for 10 days. Suggested hydration and folate rescue schedules – see below.

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Pre-hydration For at least 6 hours prior to commencement of the methotrexate.

Hydration fluid – given pre, during and after methotrexate infusion; • 1 litre Sodium Chloride 0.9% with 20mmol Potassium Chloride add 50mmol Sodium Bicarbonate (= 50ml of 8.4% solution) ALTERNATE WITH • 1 litre Dextrose 5% with 20mmol Potassium Chloride add 50mmol Sodium Bicarbonate (= 50ml of 8.4% solution)

Infusion rate Hydration 125ml/m2/hr (max. 250ml/hr).

Fluid balance Check fluid balance at regular intervals (4-hourly) throughout each day, taking early action if fluid overload occurs by giving furosemide if the urine output falls below 400ml/m2 in any given 4-hour period.

Check urine pH Adjust the sodium bicarbonate concentration to maintain the urinary pH between 7 and 8 (i.e. alkaline). A urinary pH greater than 7 must be achieved before starting the methotrexate infusion.

Serum methotrexate levels should be obtained as follows; • Initially 24 hours after commencement of methotrexate • Then daily until methotrexate level is below 5 x 10-8 M (or 0.05µmol/L) when rescue is stopped

Commence folinic acid rescue at hour 24 from start of methotrexate infusion. Administer intravenously at a dose of 15mg/m2 every 6 hours for 12 doses. Folinic acid rescue & methotrexate levels If high methotrexate levels persist after 48 hours then adjust the folinic acid rescue as follows; • if methotrexate < 0.5µmol/L then folinic acid 15mg/m2 every 6 hours • if methotrexate < 1µmol/L then folinic acid 50mg/m2 every 6 hours • if methotrexate > 1µmol/L then folinic acid 100mg/m2 every 6 hours

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Dose Modifications Hepatic Cytarabine If bilirubin >34µmol/L, give 50% dose. Escalate doses in subsequent cycles in the absence of toxicity. Methotrexate Bilirubin 50-85µmol/l = 75% Methotrexate dose Bilirubin > 85 µmol/l = do not use Methotrexate AST up to 3 x ULN = 75% Methotrexate dose Grade 3 or 4 hepatic toxicity following chemotherapy then reduce both cytarabine and methotrexate by 25% for subsequent cycles. Discuss any grade 3 or 4 toxicity with consultant haematologist. Renal Cytarabine Methotrexate GFR ml/min GFR ml/min >60 = 100% >80 = 100% 46-60 = 60% 60 = 65% 31-45 = 50% 45 = 50% <30 = contraindicated <30 = contraindicated Grade 3 or 4 renal toxicity following chemotherapy then reduce both cytarabine and methotrexate by 25% for subsequent cycles. Discuss any grade 3 or 4 toxicity with consultant haematologist. Haematological Neutrophils (x109/L) Modification <1.5 on day treatment due Delay cycle one week and commence next cycle when neuts > 1.5. Maximum delay is 2 weeks, if no recovery by that time consider referral for Radiotherapy. Platelets (x109/L) Modification <100 on day treatment due Delay cycle one week and commence next cycle when plts > 100. Maximum delay is 2 weeks, if no recovery by that time consider referral for Radiotherapy. Subsequent dose adjustments will depend on neutrophil/platelet nadir following previous cycle; Neutrophils < 0.5 or Platelets< 25 then reduce cytarabine dose by 25% (i.e. omitting the 4th dose)

Additional Information Liaise with BMT team prior to initiation of therapy.

References IELSG 32 protocol. January 2013.

Author Pharmacy CNG

Approved & Checked by Haematology CNG (Review Date = Jan 2019)

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