Lymphoma group

R-CODOX-M / R-IVAC INDICATION

Burkitt lymphoma, ‘double hit’ lymphoma or high IPI diffuse large B-cell lymphoma.

TREATMENT INTENT

Curative.

PRE-ASSESSMENT

1. Ensure histology is confirmed prior to administration of chemotherapy and document in notes. 2. Record stage of disease - MRI scan of brain (+/- spinal cord) with Gadolinium enhancement, CT scan (neck, chest, abdomen and pelvis) +/- PET, presence or absence of B symptoms, clinical extent of disease, consider bone marrow aspirate and trephine (with cytogenetics/FISH as indicated). 3. Blood tests - FBC, DAT, U&Es, LDH, ESR, urate, calcium, magnesium, creatinine, LFTs, glucose, Igs, β2 microglobulin, hepatitis B core antibody and hepatitis BsAg, hepatitis C antibody, EBV, CMV, VZV, HIV 1+2 after consent, group and save. 4. 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. Review indications for aspirin and NSAIDs and consider stopping during methotrexate treatment. 5. Patients MUST NOT receive co-trimoxazole, starting from the week before the first methotrexate infusion. Consider pentamidine treatment if considered at risk from Pneumocystis infection. 6. CSF examination • cell count +/- immunophenotype, protein and glucose: can be done as part of 1st intrathecal. 7. Ophthalmic examination - if clinically indicated. 8. Urine pregnancy test • before cycle 1 of each new chemotherapy for women of child-bearing age unless they are post-menopausal, have been sterilised or undergone a hysterectomy. 9. ECG +/- Echo - if clinically indicated. 10. Record performance status (WHO/ECOG), height and weight. 11. 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 given. Obtain written consent on the day of treatment. 12. 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. 13. Hydration - in patients with bulky disease pre-hydrate with sodium chloride 0.9% 1 litre over 4- 6 hours. Patients at high risk of tumour lysis refer to tumour lysis protocol. 14. Consider dental assessment / Advise dental check is carried out by patient's own dental practitioner before treatment starts. 15. Record IPI score. 16. Arrange insertion of double-lumen central venous catheter. 17. Treatment should be agreed in the relevant MDT.

This is a controlled document and therefore must not be changed or photocopied 1 of 9 L.49 Authorised by Lymphoma lead Published: September 2008 Version R-CODOX-M / Dr Graham Collins Reviewed: May 2018 4.4 R-IVAC Date: May 2018 Updated: Aug 2020 Review: May 2022

Lymphoma group

DRUG REGIMEN

For low-risk patients, give 3 courses of CODOX-M. For high-risk patients, give alternate CODOX-M and IVAC for four cycles. Risk groups can be identified as follows:  Patients in the low-risk group must meet at least 3 of the following criteria: o Normal lactate dehydrogenase (LDH) level o WHO performance status 0-1 o Ann Arbor stage I or II o No more than 1 extranodal site (e.g., bone marrow, gastrointestinal tract, or CNS)  Patients in the high-risk group must meet at least 2 of the following criteria: o Raised LDH level o WHO performance status 2-4 o Ann Arbor stage III or IV o More than 1 extranodal site See dose modification for patients over 65 years.

R-CODOX-M Pre-hydration with sodium chloride 0.9% at a rate of 3 L/m2 minimum immediately until day 1. Monitor U&E, calcium, phosphate and urate every 4 hours and urinary pH. Refer to tumour lysis protocol.

Day 1 Pre med - paracetamol 1g PO, chlorphenamine 10 mg IV, hydrocortisone 100 mg IV 30 minutes before rituximab. RITUXIMAB 375 mg/m2 IV infusion daily in 500 mL sodium chloride 0.9%. DOXORUBICIN 40 mg/m2 IV bolus. VINCRISTINE 1.5 mg/m2 (maximum 2 mg) IV infusion in 50 mL sodium chloride 0.9% over 10 minutes. Maximum 1 mg for patients > 70 years. CYCLOPHOSPHAMIDE 800 mg/m2 IV bolus. CYTARABINE 70 mg INTRATHECAL. Days 2 to 5 CYCLOPHOSPHAMIDE 200 mg/m2 IV bolus daily. Day 3 CYTARABINE 70 mg INTRATHECAL. Day 8 VINCRISTINE 1.5 mg/m2 (maximum 2 mg) IV infusion in 50 mL sodium chloride 0.9% over 10 minutes. Maximum 1 mg for patients > 70 years. Hydration /alkalinisation - pre methotrexate (starting T= -12 hours). Refer to sections below. Day 10 METHOTREXATE 300 mg/m2 IV infusion [start at 10.00 hrs] over 1 hour then (T=0) 2700 mg/m2 IV infusion over next 23 hours* (Ordered as 3 g/m2 in exactly 500 mL sodium chloride 0.9%). Calcium folinate (folinic acid) post-methotrexate (starting 36 hours after the start of methotrexate). Refer to sections below Day 13 G-CSF as per local policy. Day 15 METHOTREXATE 12 mg INTRATHECAL. Day 16 Folinic acid (calcium folinate) 15 mg PO 24 hours post IT methotrexate (15 mg tablets). Where a CODOX-M cycle starts on either a Thursday or a Friday, the day 3 IT Cytarabine is due during the weekend, centres should:  Start on a Thursday, but give the day 3 IT cytarabine 2 days late  Start on a Friday, but give the day 3 IT cytarabine a day late This is a controlled document and therefore must not be changed or photocopied 2 of 9 L.49 Authorised by Lymphoma lead Published: September 2008 Version R-CODOX-M / Dr Graham Collins Reviewed: May 2018 4.4 R-IVAC Date: May 2018 Updated: Aug 2020 Review: May 2022

Lymphoma group

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/hour (or 150 mL/hour if less than 1.6 m2). Duration: Continue fluids during methotrexate infusion (run concurrently with methotrexate, through one arm of Y extension). Administer fluids until methotrexate level <0.1 micromol/L.

METHOTREXATE INTRAVENOUS INFUSION

Start: T = 0 (aim to start at 10.00 am) 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.

URINE OUTPUT

Check: Every 4 hours. Aim: 400 mL/m2/4 hours (approx. 700 mL over 4 hours). Furosemide: Administer 20-40 mg to maintain urine output.

FOLINIC ACID RESCUE

Start: 36 hour from 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.

GLUCARPIDASE – reversal agent

NHS England will fund Glucarpidase (unlicensed in UK) for adults receiving high-dose methotrexate chemotherapy (doses >1g/m2) - 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 intravenous injection of 50units/kg

This is a controlled document and therefore must not be changed or photocopied 3 of 9 L.49 Authorised by Lymphoma lead Published: September 2008 Version R-CODOX-M / Dr Graham Collins Reviewed: May 2018 4.4 R-IVAC Date: May 2018 Updated: Aug 2020 Review: May 2022

Lymphoma group

R-IVAC Day 1 Pre med - paracetamol 1g PO, chlorphenamine 10 mg IV and hydrocortisone 100 mg IV 30 minutes before rituximab. RITUXIMAB 375 mg/m2 IV infusion daily in 500 mL sodium chloride 0.9%. (Refer to protocol for titration of dose rate.) Days 1 to 5 ETOPOSIDE 60 mg/m2 IV infusion daily in 500 mL sodium chloride 0.9% over 1 hr. IFOSFAMIDE 1.5 g/m2 together with MESNA 300mg/m2 daily IV infusion daily in 500 mL sodium chloride 0.9% over 1 hour. *MESNA 300 mg/m2 IV infusion 4 & 8 hours post ifosfamide in 50 mL sodium chloride 0.9% over 15 minutes.

*for patients with good oral intake, consider replacing the second and third MESNA intravenous infusion of each day with oral MESNA 600mg/m2 PO at 2 hours and 6 hours after the START of ifosfamide infusion. Days 1 to 2 CYTARABINE 2 g/m2 IV infusion twice a day (4 doses) in 500 mL sodium chloride 0.9% over 3 hours. Day 5 METHOTREXATE 12 mg INTRATHECAL. Day 6 CALCIUM FOLINATE 15 mg PO 24 hours post IT methotrexate (15 mg tablets) Day 7 G-CSF as per local policy (continue until neutrophils >1.0 x 109/L for 3 consecutive days). Where IVAC starts on a Tuesday or a Wednesday, the day 5 IT Methotrexate is due during the weekend, centres should:  Start on a Tuesday but give the day 5 IT methotrexate 2 days late  Start on a Wednesday but give the day 5 IT methotrexate a day late Hydration - ensure patient has a fluid input of >3 litres, supplement intravenously as necessary.

CNS DISEASE

For patients with CNS disease, intensified intrathecal treatment is given to all patients for THE FIRST TWO CYCLES ONLY, regardless of age. Cycle Day Drug INTRATHECAL dose 1, 3, 5 Cytarabine 70 mg 1 15, 17 Methotrexate 12.5 mg CODOX-M 16, 18 Calcium Folinate 15 mg PO 24 hours after each lumbar puncture 5 Methotrexate 12.5 mg 2 6 Calcium Folinate 15 mg PO 24 hours after each lumbar puncture IVAC 7, 9 Cytarabine 70 mg

IFOSFAMIDE-INDUCED ENCEPHALOPATHY

Refer to nomogram to assess risk.

This is a controlled document and therefore must not be changed or photocopied 4 of 9 L.49 Authorised by Lymphoma lead Published: September 2008 Version R-CODOX-M / Dr Graham Collins Reviewed: May 2018 4.4 R-IVAC Date: May 2018 Updated: Aug 2020 Review: May 2022

Lymphoma group

CYCLE FREQUENCY

The next cycle may be given once there is bone marrow recovery. If neutrophil count is 1.0 x 109/L and platelets >75 x 109/L, stop the G-CSF, if counts are maintained after 24 hours, commence next cycle of chemotherapy. If neutrophil count is >1.0 x 109/L but platelets are <75 x 109/L, stop G-CSF and await platelet recovery.

RESTAGING

At completion of the protocol, for low-risk patients after 3 cycles and for high-risk patients after 4 cycles.

DOSE MODIFICATIONS (Discuss with consultant)

Haematological toxicity There are no dose modifications for haematological toxicity.

Doxorubicin: Renal impairment Hepatic impairment Discuss with consultant if renal Bilirubin micromol/L Dose impairment severe 20-51 50% 51-85 25% >85 omit If AST 2-3 x normal, give 75% dose If AST >3 x ULN, give 50% dose Doxorubicin maximum cumulative dose (additive to other anthracyclines): 450-550 mg/m2 (in normal cardiac function) 400 mg/m2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation). Consider dose reduction in the event of cardiac impairment. Vincristine: Renal impairment Hepatic impairment No dose reduction necessary Bilirubin 26-51 micromol/L or ALT/AST 60-180 u/L: 50% dose Bilirubin >51 micromol/L & normal ALT/AST: 50% dose Bilirubin >51 micromol/L & ALT/ AST >180 u/L: omit Clinical decision Vincristine In the presence of motor weakness or severe sensory symptoms, discuss reducing or withholding vincristine with a consultant.

Cyclophosphamide: Renal impairment Hepatic impairment GFR (mL/min) Dose Clinical decision. Exposure to active metabolites may not >20 100% be increased, suggesting dose reduction may not be 10-20 75% necessary. <10 50%

This is a controlled document and therefore must not be changed or photocopied 5 of 9 L.49 Authorised by Lymphoma lead Published: September 2008 Version R-CODOX-M / Dr Graham Collins Reviewed: May 2018 4.4 R-IVAC Date: May 2018 Updated: Aug 2020 Review: May 2022

Lymphoma group

Methotrexate - clinical judgment discuss with consultant.

In patients over 65 years, consider alternate regime or reduce methotrexate dose to 100 mg/m2 over 1 hour and 900 mg/m2 infusion over 23 hours (Order as 1 g/m2 in exactly 500 mL sodium chloride 0.9%).

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.

Renal impairment Hepatic impairment CrCl (mL/min) Dose Bilirubin AST Dose >80 100% micromol/L 60 65% <50 and <180 100% 45 50% 51-85 or >180 75% <30 Contra-indicated >85 CI (CI) It is expected that patients receiving high dose methotrexate will develop hypertransaminasemia and occasionally hyperbilirubinemia. These elevations can last up to 2 weeks following the methotrexate infusion and are not considered toxicity requiring discontinuation of repeated administration of methotrexate. Persistant hyperbilirubinemia 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

IVAC: In patients over 65 years, reduce ifosfamide dose to 1 g/m2, mesna to 200 mg/m2, cytarabine infusion to 1 g/m2. Discuss with consultant: Etoposide: Renal impairment Hepatic impairment CrCl (mL/min) Dose Consider >50 100% Bilirubin 26-51 micromol/L or AST 60-180 u/L: 50% dose 15-50 75% Bilirubin >51 micromol/L or AST >180 u/L: clinical <15 50% decision Subsequent doses should be based on clinical response.

Ifosfamide: Renal impairment Hepatic impairment - discuss with consultant GFR >60 mL/min 100% dose SPC recommendations: not recommended in patients GFR 40-59 mL/min 70% dose with a raised bilirubin or serum transaminases or ALP GFR <40 mL/min clinical decision. >2.5 x ULN. Clinical decision. This is a controlled document and therefore must not be changed or photocopied 6 of 9 L.49 Authorised by Lymphoma lead Published: September 2008 Version R-CODOX-M / Dr Graham Collins Reviewed: May 2018 4.4 R-IVAC Date: May 2018 Updated: Aug 2020 Review: May 2022

Lymphoma group

Cytarabine: Renal impairment - dose reduction Hepatic impairment may not be necessary High dose 1-3 g/m2 consider Bilirubin >34 micromol/L give 50% dose. Escalate doses in subsequent cycles in the absence of GFR (mL/min) Dose toxicity. >60 100% 46-60 60% 31-45 50% <30 Contra-indicated

INVESTIGATIONS

 First cycle - FBC, U&Es, calcium, magnesium, LFTs, urate  Subsequent cycles - FBC, U&Es, calcium, magnesium, LFTs, urate, (creatinine clearance if serum creatinine is increased by 20% of previous value)

CONCURRENT MEDICATION

Tumour Lysis Prophylaxis Consider rasburicase – refer to tumour lysis guideline Aciclovir 200 mg three times a day PO for duration of chemotherapy and for 3 months after completion. Fluconazole 50 mg daily PO for duration of chemotherapy. Proton pump inhibitor (PPI) Daily for the duration of treatment MESNA See “Drug Regimen” section for IVAC cycles 600mg/m2 PO at 2 hours and 6 hours after the START of each ifosfamide infusion. Norethisterone 5 mg three times a day PO as appropriate. Prednisolone 0.5-1% eye drops For IVAC cycles only. Starting from Day 1, one drop to each Or eye QDS. Continue for 5 days after cytarabine (due to risk of Dexamethasone 0.1% eye drops cytarabine-induced conjunctivitis). In the event of (depending on local formulary) conjunctivitis, consider increasing the frequency to 2 hourly until resolution of symptoms. Liaison with ophthalmologists may be necessary in this situation. Pentamidine 4 mg/kg (max 300mg) IV monthly before each CODOX-M. Co-trimoxazole 480 mg daily Mon, Wed, Fri after final cycle of chemotherapy, methotrexate level is < 0.1 micromol/L and when neutrophils >2x109/L. Continue for 3 months. A number of drugs can interfere with tubular secretion of methotrexate. These include penicillins, aspirin 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 aspirin and NSAIDs and consider stopping during methotrexate treatment.

This is a controlled document and therefore must not be changed or photocopied 7 of 9 L.49 Authorised by Lymphoma lead Published: September 2008 Version R-CODOX-M / Dr Graham Collins Reviewed: May 2018 4.4 R-IVAC Date: May 2018 Updated: Aug 2020 Review: May 2022

Lymphoma group

EMETIC RISK

CODOX-M: IVAC: Day 1: High Days 1 - 2: High Days 2 - 5: Moderate Days 3 - 5: Moderate Day 8: Minimal Days 10 and 11: Moderate

POTENTIALLY HAZARDOUS INTERACTIONS WITH OTHER DRUGS

Ifosfamide possibly enhances effect of warfarin.

METHYLENE BLUE

If patient develops neurotoxicity, STOP ifosfamide and administer: Methylthioninium chloride (methylene blue) can be given as prophylaxis against, or treatment of, ifosfamide-induced encephalopathy. This should be started on the day of ifosfamide administration and continued for 24 hours after administration or until neurotoxic symptoms subside. Dose: 50 mg TDS IV or orally. NB: 50 mg = 5 mL of 1% solution. IV: Administer 50 mg in 50 to 100 mL sodium chloride 0.9% or glucose 5%, over 15 to 30 minutes. Orally: Use injection for oral administration. Dilute one ampoule in 100 mL water before taking orally to minimise GI effects. Drink through a straw to avoid staining teeth. 53-97% oral absorption.

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS  Cyclophosphamide / ifosfamide may irritate bladder mucosa. Patients should be encouraged to drink a minimum of three litres of fluid per 24 hours.  Vincristine may cause neurotoxicity.  Cardiotoxicity - monitor cardiac function. Doxorubicin may be stopped in future cycles if signs of cardiotoxicity, e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue.  Methotrexate induced mucositis - folinic acid (calcium folinate) rescue

EXTRAVASATION RISK

Cyclophohsphamide: neutral Cytarabine: neutral Doxrubicin: vesicant Etoposide: irritant Ifosfamide: neutral Methotrexate: inflammatory agent Vincristine: vesicant Rituximab: neutral

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Lymphoma group

TREATMENT RELATED MORTALITY

5%

REFERENCES

1. Cancer Research UK.1 LY10 A Clinicopathological Study in Burkitt's and Burkitt's like non- Hodgkin's lymphoma September 2002 Version 2.0 (Simon Clawson Clinical Trials Manager Tel: 020 7670 4801). 2. Küpfer A, Aeschlimann C, Wermuth B, Cerny T. Prophylaxis and reversal of ifosfamide encephalopathy with methylene-blue. Lancet. 1994 Mar 26;343(8900):763-4. 3. Ifosfamide Chemotherapy Management. Professor Bass Hassan and Bharti Tailor. Final version approved by BHOC Chemotherapy Group 16/09/05. 4. Mead, G.M., Sydes, M.R., Walewski, J., Grigg, A., Hatton, C.S., Pescosta, N., Guarnaccia, C., Lewis, M.S., McKendrick, J., Stenning, S.P., Wright, D., and Norbert, P., An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol, 2002. 13(8): p. 1264-74 5. UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009). 6. UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January 2009).

Review Name Revision Date Version Review date Cheuk-kie Cheung Addition of oral as alternatives to Sep 2018 4.3 May 2020 (Pharmacist) IV MESNA during IVAC cycles.

NSSG Lymphoma Group Annual protocol review Aug 2020 4.4 May 2021

This is a controlled document and therefore must not be changed or photocopied 9 of 9 L.49 Authorised by Lymphoma lead Published: September 2008 Version R-CODOX-M / Dr Graham Collins Reviewed: May 2018 4.4 R-IVAC Date: May 2018 Updated: Aug 2020 Review: May 2022