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Lymphoma group This is a controlled document and therefore must not be changed or photocopied L.13 High dose METHOTREXATE (high grade NHL CNS prophylaxis) Authorised by Lymphoma lead Dr. Graham Collins Date: May 2018 Published: September 2010 Update d : Aug 2020 Review: May 20 2 2 Version 1. 7 1 of 6 High dose METHOTREXATE (high grade NHL CNS prophylaxis) INDICATION High grade lymphoma with high risk of CNS involvement Definition of high risk disease for diffuse large B - cell lymphoma is a score 4 or 5 based on the following risk factors:  Age � 60  Raised serum LDH  Stage III or IV  Performance status � 1  Multiple extranodal sites (2 or more)  Renal or adrenal involvement In addition, the following extranodal sites are deemed high risk:  Testes  Epidural  Breast  Renal or adrenal (the following sites are NOT deemed high risk: tonsil, isolated bone marrow involvement, cranio - facial involvement unless erosion through base of skull) Caution in patients over 70 years of age, and/or with significant co - morbidities. . TREATMENT INTENT Used as prophylaxis alongside a curative regimen. Lymphoma group This is a controlled document and therefore must not be changed or photocopied L.13 High dose METHOTREXATE (high grade NHL CNS prophylaxis) Authorised by Lymphoma lead Dr. Graham Collins Date: May 2018 Published: September 2010 Update d : Aug 2020 Review: May 20 2 2 Version 1. 7 2 of 6 PRE - ASSESSMENT 1. Assess creatinine clearance before prescribing. 2. A number of drugs can interfere with tubular secretion of methotrexate. These include penicillins, aspirin and NSAIDs. Tazocin should NOT be used during high dose methotrexate administration or rescue. Consider using meropenem or other alternative. Rev

iew indications for aspirin and NSAI Ds and consider stopping during methotrexate treatment . 3. Patients MUST NOT receive co - trimoxazole in the week before the first methotrexate infusion. Restart co - trimoxazole once methotrexate level is .1 micromol/L and neutrophil count recovery. 4. Blood tests - FBC, creatinine, LFTs, group and save. 5. Record performance status (WHO/ECOG). 6. Record height and weight. 7. Consent - ensure patient has received adequate verbal and written information regarding their disease, treatment and potential side effects. Document in medical notes all information that has been gi ven. Obtain written consent on the day of treatment. 8. Fertility - it is very important the patient understands the potential risk of infertility; all patients should be offered fertility advice by referring to the Oxford Fertility Unit . 9. A fluid space, e.g. pleural effusion or ascites, is potentially very dangerous as methotrexate can accumulate and cause prolonged toxicity. High dose methotrexate should not be given in such cases. 10. Start oral sodium bicarbonate capsules at T = - 12 hours. Administer 1.5 g four times a day + 1.5 g prn for 36 hours, then review. Review reg ular sodium bicarbonate requirements at the end of the methotrexate infusion, and continue as appropriate until methotrexate level 1 micromol/L. 11. Dipstick urine every 2 hours to check pH �7. I f pH give additional bicarbonate as in point 10 . 12. Urine pregnancy test ­ before cycle 1 of each new chemotherapy course for women of child - bearing age unless they are post - menopausal, have been sterilised or undergone a hysterectomy. 13. Treatment should be agreed in the relevant MDT. DRUG REGIMEN Day 0 Hydration / Alkalinisation - Pre methotrexate (starting T= - 12 hours; see below). Day 1 (T=0) METHOTREXATE 3.0 g/m 2 IV infusion Day 1 in exactly

500 mL sodium chloride 0.9% over 3 hrs. Calcium folinate (Folinic acid) post methotrexate (starting 24 hours after start of methotrexate). Continue with fluids and folinic acid rescues until methotrexate level 1 micromol/L. Lymphoma group This is a controlled document and therefore must not be changed or photocopied L.13 High dose METHOTREXATE (high grade NHL CNS prophylaxis) Authorised by Lymphoma lead Dr. Graham Collins Date: May 2018 Published: September 2010 Update d : Aug 2020 Review: May 20 2 2 Version 1. 7 3 of 6 CYCLE FREQUENCY Normally 2 courses of intravenous methotrexate would be administered, after a full course of R - CHOP chemotherapy (typically 6 cycles). R - CHOP chemotherapy should not be interrupted for administration of IV methotrexate. 2 - 4 courses of intrathecal metho trexate also forms part of the CNS prophylaxis regimen, to be administered with the first few courses of R - CHOP (or equivalent chemotherapy). RESTAGING On completion of 2 cycles of HD MTX. INTRAVENOUS HYDRATION Start: T = - 12 hours. Fluid: 1000 mL glucose 2.5%, sodium chloride 0.45% with potassium chloride 20 mmol and sodium bicarbonate 100 mmol added. Following completion of methotrexate infusion, decrease amount of sodium bicarbonate in fluids to 50 mmol/L. Flow rate: 200 mL /ho ur (or 150 mL /hour if less than 1.6 m 2 ). Duration: Continue fluids during methotrexate infusion (run concurrently with methotrexate ). Administer fluids until methotrexate level 1 micromol/L. METHOTREXATE INTRAVENOUS INFUSION Start: T = 0 (aim to start at 10.00 am) Run infusion over 3 hours if possible. May run for longer if technical reasons limit flow rate (maximum 6 hours). Levels: Check 48 hours after the start of the methotrexate infusion , and every 24 hours thereafter until methotrexate level less than 0.1 micromol /L. UR

INE OUTPUT Check: Every 4 hours. Aim: 400 m L /m 2 /4 hours (approx. 700 mL over 4 hours). Furosemide: Administer 20 - 40 mg to maintain urine output. Lymphoma group This is a controlled document and therefore must not be changed or photocopied L.13 High dose METHOTREXATE (high grade NHL CNS prophylaxis) Authorised by Lymphoma lead Dr. Graham Collins Date: May 2018 Published: September 2010 Update d : Aug 2020 Review: May 20 2 2 Version 1. 7 4 of 6 FOLINIC ACID RESCUE Start: 24 hours after the start of methotrexate infusion. Dose: 30 mg every 3 hours for 5 doses, then every 6 hours until methotrexate level is less than 0.1 micromol/L. Administration: Give intravenous boluses for at least the first 4 doses, then change to oral if the patient is compliant and not vomiting. GLUCARPI DASE – reversal agent NHS England will fund Glucarpidase as a reversal agent for methotrexate (unlicensed in UK) for adults receiving high - dose methotrexate chemotherapy (doses �1g/m 2 ) - Who develop significant deterioration in renal function (�1.5x ULN and rising, or the presence of oliguria) OR - Have toxic plasma methotrexate level AND - Have been treated with all standard rescue and supportive measures AND - At risk of life - threatening methotrexate - induced toxicities The recommended dose is one single int ravenous injection of 50units/kg DOSE MODIFICATIONS Renal impairment Hepatic impairment CrCl (mL /min) �80 60 - 80 45 - 59 30 - 44 Dose 100% 65% 50% Discuss with Consultant Contra - indicated Bilirubin micromol/L 51 - 85 �85 AST a nd o r �180 Dose 100% 75% Contra - indicated It is expected that patients receiving high dose methotrexate will develop hypertransaminasemia and occasionally hyperbilirubinemia. These elevati

ons can last up to 2 weeks following the methotrexate infusion and are not considered toxicity requiring discontinuation of repeated administration of methotrexate. Persistant hyperbilirubine mia and/or grade 3 - 4 hypertransaminasemia for longer than 3 weeks should result in discontinuation of the drug. Dose - reduce, particularly in patients with concomitantly impaired renal function. Severe hepatic impairment – Contra - indicated Lymphoma group This is a controlled document and therefore must not be changed or photocopied L.13 High dose METHOTREXATE (high grade NHL CNS prophylaxis) Authorised by Lymphoma lead Dr. Graham Collins Date: May 2018 Published: September 2010 Update d : Aug 2020 Review: May 20 2 2 Version 1. 7 5 of 6 INVESTIGATIONS  FBC, creatinine, LFTs,  CXR CONCURRENT MEDICATION Proton pump inhibitor Daily for the duration of treatment Aciclovir 200 mg three times a day for duration of treatment and for 3 months after completion A number of drugs can interfere with t ubular secretion of methotrexate. These include penicillins, aspirin , co - trimoxazole and NSAIDs. Tazocin (piperacillin with tazobactam) should NOT be used during high dose methotrexate administration or rescue. Consider using meropenem or other alternative. Review indications for aspiri n and NSAI Ds and consider stopping during methotrexate treatment. EMETIC RISK Moderate. ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS  Renal damage  Hepatotoxic  Interstitial pneumonitis (cough, dyspnoea, fever)  Stomatitis, diarrhoea  Skin changes and increased skin sensitivity to sun  Gritty eyes  Hair loss  Neurotoxicty including headache, dizziness, blurred vision and loss of balance EXTRAVASATION RISK Meth otrexate: i nflammatory agent Lymphoma group

This is a controlled document and therefore must not be changed or photocopied L.13 High dose METHOTREXATE (high grade NHL CNS prophylaxis) Authorised by Lymphoma lead Dr. Graham Collins Date: May 2018 Published: September 2010 Update d : Aug 2020 Review: May 20 2 2 Version 1. 7 6 of 6 TREATMENT RELATED MORTALITY 1% REFERENCES 1. Cheah CY and Seymour JF. Central nervous system propohylaxis in non - Hodgkin Lymphoma: Who, What and When? Curr oncol rep (2015) [Epub ahead of print] 2. McMillan A, Areshna K et al . Guidelines on the prevention of secondary CNS lymphoma: British Committee for Standards in Haematology. Brit J Haematol 163 (2013): 168 - 181 3. Eyre, Toby & Martinez Calle et al (2018). CNS Relapse Risk in Consecutive R - CHOP/R - Mini - CHOP - Treated Elderly DLBCL Is Low, with High Risk Particularly Apparent in Those with CNS IPI 5 - 6 and/or Renal/Adrenal Involvement. Blood. 132. 169 4 - 1694. 10.1182/blood - 2018 - 99 - 111010. 4. Eyre TA, Djebbari F, Kirkwood AA, Collins GP. Efficacy of central nervous system prophylaxis with stand - alone intrathecal chemotherapy in diffuse large B - cell lymphoma patients treated with anthracycline - based chemothe rapy in the rituximab era: a systematic review. Haematologica. 2020;105(7):1914 - 1924. doi:10.3324/haematol.2019.229948 5. MRC LY10 Protocol Version 1.1 February 2002. 6. MRC UKALL XII 2003 and 2011. 7. UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009). 8. UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009). Review Name Revision Date Version Review date Cheuk - kie Jackie Cheung Haematology Pharmacist Removal of fluconazole in line with other first line DLBCL regimen Dec 2019 1.6 May 2020 NSSG Lymphoma Group Annual protocol review Aug 2020 1.7 May