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Burkitt lymphoma IVAC (iFOSFamide etoposide cytarabine) SUPERSEDED

This protocol has been superseded as a superior alternative is available for use in clinical practice. ID 3725 Burkitt lymphoma R-IVAC is the more commonly used regimen.

Patients with lymphoma should be considered for inclusion into clinical trials. Link to ALLG website, ANZCTR website and Lymphoma Australia website.

This protocol is based on limited evidence; refer to the evidence section of this protocol for more information.

The anticancer drug(s) in this protocol may have been included in the ADDIKD guideline. Dose recommendations in kidney dysfunction have yet to be updated to align with the ADDIKD guideline. Recommendations will be updated once the individual protocol has been evaluated by the reference committee. For further information refer to the ADDIKD guideline. To assist with calculations, use the eviQ Estimated Glomerular Filtration Rate (eGFR) calculator.

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Drug Dose Route Day
Cytarabine (Ara-C) 2,000 mg/m2 TWICE a day (12 hours apart)* IV infusion 1 and 2
Etoposide ** 60 mg/m2 IV infusion 1 to 5
Mesna 360 mg/m2 IV infusion 1
iFOSFamide 1,500 mg/m2 * IV infusion 1 to 5
Mesna 1,500 mg/m2 IV infusion 1 to 5
Methotrexate 12 mg Intrathecal 5
Calcium folinate (Leucovorin) *** 15 mg PO 6
Filgrastim 5 micrograms/kg Subcut 7 and continue daily until neutrophil recovery

* Please see "Dose modifications" for cytarabine and ifosfamide in patients older than 65 years. 

** Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg. Doses in this protocol are expressed as etoposide.

*** Administered 24 hours after intrathecal methotrexate

IVAC to commence on the first day after CODOX-M that ANC is greater than 1.0 x109/L and platelets are greater than 75 x109/L

Link to the International Non-Hodgkin Lymphoma International Prognostic Index (IPI)

Low risk disease THREE cycles of dmCODOX-Mr
High risk disease Alternating dmCODOX-M / IVAC TWICE
(i.e. dmCODOX-M / IVAC / dmCODOX-M / IVAC)r
Proven CNS disease Additional intrathecal cytarabine 70 mg administered on Day 7 and 9 with FIRST cycle of IVAC only.
Note: This is in addition to intrathecal methotrexate given in Day 5 as part of the IVAC protocol

Patients are considered Low Risk if they have at least 3 of the following international prognostic index (IPI) factors:

  • normal LDH
  • Ann Arbor stage I to II
  • WHO performance status 0 to 1
  • number of extra nodal sites less than or equal to 1

All other patients are considered High Risk

Notes:
  • Patients presenting with CNS disease are to receive additional intrathecal therapy with cytarabine on Days 7 and 9 with the first cycle of IVAC only.
  • The dosing schedule of mesna in this protocol differs from the regimen reported in the LY10 trial, and was selected by the Haematology reference committee to reflect clinical practice. 
Drug status:

All drugs in this protocol are on the PBS general schedule

Filgrastim: (PBS authority)

Cost:
~ $3,310 "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Day 1
Cytarabine (Ara-C) 2,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours TWICE a day (12 hours apart) for a total of 4 doses *
Etoposide 60 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
Mesna 360 mg/m2 (IV infusion) in 250 mL sodium chloride 0.9% over 15 minutes as a loading dose 60 minutes before first dose of ifosfamide
iFOSFamide 1,500 mg/m2 (IV infusion) in 500 mL to 1000 mL sodium chloride 0.9% over 2 hours *
Mesna 1,500 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 24 hours
Day 2
Cytarabine (Ara-C) 2,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours TWICE a day (12 hours apart) for a total of 4 doses *
Etoposide 60 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
iFOSFamide 1,500 mg/m2 (IV infusion) in 500 mL to 1000 mL sodium chloride 0.9% over 2 hours *
Mesna 1,500 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 24 hours
Day 3 and 4
Etoposide 60 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
iFOSFamide 1,500 mg/m2 (IV infusion) in 500 mL to 1000 mL sodium chloride 0.9% over 2 hours *
Mesna 1,500 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 24 hours
Day 5
Etoposide 60 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
iFOSFamide 1,500 mg/m2 (IV infusion) in 500 mL to 1000 mL sodium chloride 0.9% over 2 hours *
Mesna 1,500 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 24 hours
Methotrexate 12 mg (Intrathecal)

adhere to local institution intrathecal policy
Day 6
Calcium folinate (Leucovorin) 15 mg (PO) once only 24 hours after intrathecal methotrexate
Day 7
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously ONCE a day starting on day 7 and continue until ANC greater than 1.0 x 10^9/L

* Please see "Dose modifications" for cytarabine and ifosfamide in patients older than 65 years. 

IVAC to commence on the first day after CODOX-M that ANC is greater than 1.0 x109/L and platelets are greater than 75 x109/L

Link to the International Non-Hodgkin Lymphoma International Prognostic Index (IPI)

Low risk disease THREE cycles of dmCODOX-Mr 
High risk disease Alternating dmCODOX-M / IVAC TWICE
(i.e. dmCODOX-M / IVAC / dmCODOX-M / IVAC)r
Proven CNS disease Additional intrathecal cytarabine 70 mg administered on Day 7 and 9 with FIRST cycle of IVAC only.
Note: This is in addition to intrathecal methotrexate given in Day 5 as part of the IVAC protocol

Drug Dose Route Day
Cytarabine (Ara-C) 2,000 mg/m2 TWICE a day (12 hours apart)* IV infusion 1 and 2
Etoposide ** 60 mg/m2 IV infusion 1 to 5
Mesna 360 mg/m2 IV infusion 1
iFOSFamide 1,500 mg/m2 * IV infusion 1 to 5
Mesna 1,500 mg/m2 IV infusion 1 to 5
Methotrexate 12 mg Intrathecal 5
Calcium folinate (Leucovorin) *** 15 mg PO 6
Filgrastim 5 micrograms/kg Subcut 7 and continue daily until neutrophil recovery

* Please see "Dose modifications" for cytarabine and ifosfamide in patients older than 65 years. 

** Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg. Doses in this protocol are expressed as etoposide.

*** Administered 24 hours after intrathecal methotrexate

IVAC to commence on the first day after CODOX-M that ANC is greater than 1.0 x109/L and platelets are greater than 75 x109/L

Link to the International Non-Hodgkin Lymphoma International Prognostic Index (IPI)

Low risk disease THREE cycles of dmCODOX-Mr
High risk disease Alternating dmCODOX-M / IVAC TWICE
(i.e. dmCODOX-M / IVAC / dmCODOX-M / IVAC)r
Proven CNS disease Additional intrathecal cytarabine 70 mg administered on Day 7 and 9 with FIRST cycle of IVAC only.
Note: This is in addition to intrathecal methotrexate given in Day 5 as part of the IVAC protocol

Patients are considered Low Risk if they have at least 3 of the following international prognostic index (IPI) factors:

  • normal LDH
  • Ann Arbor stage I to II
  • WHO performance status 0 to 1
  • number of extra nodal sites less than or equal to 1

All other patients are considered High Risk

Notes:
  • Patients presenting with CNS disease are to receive additional intrathecal therapy with cytarabine on Days 7 and 9 with the first cycle of IVAC only.
  • The dosing schedule of mesna in this protocol differs from the regimen reported in the LY10 trial, and was selected by the Haematology reference committee to reflect clinical practice. 
Drug status:

All drugs in this protocol are on the PBS general schedule

Filgrastim: (PBS authority)

Cost:
~ $3,310 "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Day 1
Cytarabine (Ara-C) 2,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours TWICE a day (12 hours apart) for a total of 4 doses *
Etoposide 60 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
Mesna 360 mg/m2 (IV infusion) in 250 mL sodium chloride 0.9% over 15 minutes as a loading dose 60 minutes before first dose of ifosfamide
iFOSFamide 1,500 mg/m2 (IV infusion) in 500 mL to 1000 mL sodium chloride 0.9% over 2 hours *
Mesna 1,500 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 24 hours
Day 2
Cytarabine (Ara-C) 2,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours TWICE a day (12 hours apart) for a total of 4 doses *
Etoposide 60 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
iFOSFamide 1,500 mg/m2 (IV infusion) in 500 mL to 1000 mL sodium chloride 0.9% over 2 hours *
Mesna 1,500 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 24 hours
Day 3 and 4
Etoposide 60 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
iFOSFamide 1,500 mg/m2 (IV infusion) in 500 mL to 1000 mL sodium chloride 0.9% over 2 hours *
Mesna 1,500 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 24 hours
Day 5
Etoposide 60 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
iFOSFamide 1,500 mg/m2 (IV infusion) in 500 mL to 1000 mL sodium chloride 0.9% over 2 hours *
Mesna 1,500 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 24 hours
Methotrexate 12 mg (Intrathecal)

adhere to local institution intrathecal policy
Day 6
Calcium folinate (Leucovorin) 15 mg (PO) once only 24 hours after intrathecal methotrexate
Day 7
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously ONCE a day starting on day 7 and continue until ANC greater than 1.0 x 10^9/L

* Please see "Dose modifications" for cytarabine and ifosfamide in patients older than 65 years. 

IVAC to commence on the first day after CODOX-M that ANC is greater than 1.0 x109/L and platelets are greater than 75 x109/L

Link to the International Non-Hodgkin Lymphoma International Prognostic Index (IPI)

Low risk disease THREE cycles of dmCODOX-Mr 
High risk disease Alternating dmCODOX-M / IVAC TWICE
(i.e. dmCODOX-M / IVAC / dmCODOX-M / IVAC)r
Proven CNS disease Additional intrathecal cytarabine 70 mg administered on Day 7 and 9 with FIRST cycle of IVAC only.
Note: This is in addition to intrathecal methotrexate given in Day 5 as part of the IVAC protocol

  • Burkitt lymphoma in adults 65 years of age or younger
    • Patients older than 65 years require specific dose reductions (refer to 'Dose modifications')
Venous access

Central venous access device (CVAD) is required to administer this treatment.

Read more about central venous access device line selection
Hypersensitivity/infusion related reaction

High risk with etoposide.
Antiemetics for multi-day protocols

Antiemetic therapy should be administered throughout the duration of the chemotherapy protocol and to cover delayed nausea. The acute and delayed emetic risk of multi-day chemotherapy protocols will overlap depending on the individual drugs and their sequence of administration. More or less antiemetic cover may be required. 

Ensure that patients also have sufficient antiemetics for breakthrough emesis:

Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR

Prochlorperazine 10 mg PO every 6 hours when necessary.

Read more about preventing anti-cancer therapy induced nausea and vomiting
Ifosfamide induced encephalopathy

May occur in patients treated with high dose ifosfamide (~ 5 to 8 g/m2). Assess neurological function prior to each ifosfamide dose.

Read more about ifosfamide induced encephalopathy

Link to ifosfamide encephalopathy assessment chart
Haemorrhagic cystitis associated with high dose chemotherapy

Hydration regimen pre high dose cyclophosphamide or ifosfamide (as per local guidelines).
There is limited evidence and no consensus regarding hydration regimens and mesna dose, route or timing of administration.

Read more about haemorrhagic cystitis
Cytarabine induced neurotoxicity

This may occur in patients treated with high dose cytarabine. Assess cerebellar function prior to each cytarabine dose.

Read more about neurotoxicity associated with high dose cytarabine and access the cytarabine cerebellar neurotoxicity assessment chart  
Ocular toxicities

Administer corticosteroid eye drops to minimise corneal toxicity from high dose cytarabine. Commence on the day of first dose of cytarabine and continue for at least 72 hours after completion of final cytarabine dose.

Read more about ocular toxicities associated with high dose cytarabine
Cytarabine syndrome

Treatment with cytarabine may cause a "cytarabine syndrome" characterised by flu-like symptoms, skin rash and occasionally chest pain.
Etoposide conversion factor

Note: Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg.
Doses in this protocol are expressed as etoposide.
Central nervous system (CNS) prophylaxis

Consider CNS relapse assessment in patients with high grade lymphoma. 

Read more about CNS prophylaxis in diffuse large cell lymphoma
Tumour lysis risk

Patients are at high risk of developing tumour lysis syndrome, prophylaxis is recommended.

Read more about the prevention and management of tumour lysis syndrome.
Mesna dosing and administration

There is evidence for several mesna doses as well as differing administration timings (e.g. 2, 4, 6, or 8 hours post initiation or completion of the ifosfamide/cyclophosphamide dose) with no clear evidence that one particular regimen is superior over another. The eviQ mesna recommendations may be based upon the individual trial/study or reference committee consensus and provide guidance on one safe way to administer the protocol. Individual institutional policy may vary and should be evidence based.
Pneumocystis jirovecii pneumonia (PJP) prophylaxis

PJP prophylaxis is recommended.

Myelosuppression may be exacerbated if trimethoprim/sulfamethoxazole is used in combination with methotrexate.

Read about prophylaxis of pneumocystis jirovecii (carinii) in cancer patients
Antiviral prophylaxis

Antiviral prophylaxis is recommended.

Read more about antiviral prophylaxis drugs and doses
Antifungal prophylaxis

Antifungal prophylaxis is recommended.

Read more about antifungal prophylaxis drugs and doses.
Biosimilar drug

Read more about biosimilar drugs on the Biosimilar Awareness Initiative page
Growth factor support

G-CSF (short or long-acting) is available on the PBS for chemotherapy induced neutropenia depending on clinical indication and/or febrile neutropenia risk.  

Access the PBS website
Blood tests

FBC, EUC, LFTs and LDH at baseline, and prior to each cycle and as clinically indicated.
Hepatitis B screening and prophylaxis

Routine screening for HBsAg and anti-HBc is recommended prior to initiation of treatment. Prophylaxis should be determined according to individual institutional policy.

Read more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy
Vaccinations

Live vaccines are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease.

Refer to the recommended schedule of vaccination for immunocompromised patients, as outlined in the Australian Immunisation Handbook.

Read more about COVID-19 vaccines and cancer.
Fertility, pregnancy and lactation

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive potential prior to commencing treatment. There is a risk of foetal harm in pregnant women. A pregnancy test should be considered prior to initiating treatment in females of reproductive potential if sexually active. It is important that all patients of reproductive potential use effective contraception whilst on therapy and after treatment finishes. Effective contraception methods and adequate contraception timeframe should be discussed with all patients of reproductive potential. Possibility of infant risk should be discussed with breastfeeding patients.

Read more about the effect of cancer treatment on fertility
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.
The dose recommendations in kidney dysfunction (i.e.renal impairment) displayed may not reflect those in the ADDIKD guideline and have been included for historical reference only. Recommendations will be updated once the individual protocol has been evaluated by the reference committee, with this version of the protocol then being archived. Clinicians are expected to refer to the ADDIKD guideline prior to prescribing in kidney dysfunction.
International Consensus Guideline for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).

Note: All dose reductions are calculated as a percentage of the starting dose

Haematological toxicity
Next cycle to be given when ANC is 1.0 x 109/L or greater and platelets are greater than 75 x 109/L
Renal impairment
Creatinine clearance (mL/min)
less than 30 Reduce ifosfamide by 25%
No dose modifications required for cytarabine. However, increased risk of neurotoxicity has been associated with high dose cytarabine when creatinine clearance is less than 60 mL/min.
Hepatic impairment
Bilirubin (micromol/ L)
greater than 34 Reduce cytarabine by 50%
Age older than 65 years
Patients older than 65 years of age are to receive reduced doses of cytarabine, ifosfamide and mesna as below:r
Drug Dose Route Days
Cytarabine 1000 mg/m2 IV infusion 1 and 2
Ifosfamide 1000 mg/m2 IV infusion 1 to 5
Mesna 1000 mg/m2 * IV infusion 1 to 5

* Loading dose of mesna on day 1 remains unchanged.

Drug interactions in eviQ protocols are under review and being updated to align with current literature. Further site-wide updates and changes will occur in due course. References & Disclaimer

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources:  

Cytarabine
No specific clinically significant drug-drug interactions
Etoposide and Etoposide Phosphate
  Interaction Clinical management
CYP3A4 and P-gp inhibitors (e.g. amiodarone, aprepitant, azole-antifungals, ritonavir, lapatinib, nilotinib, sorafenib, macrolides, ciclosporin etc.) Increased toxicity of etoposide possible due to reduced clearance Avoid combination or monitor for etoposide toxicity
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of etoposide possible due to increased clearance Avoid combination or monitor for decreased clinical response to etoposide
Glucosamine Reduced efficacy of etoposide (due to induction of glucose-regulated stress proteins resulting in decreased expression of topoisomerase II) Avoid combination or monitor for decreased clinical response to etoposide
Grapefruit juice Reduced efficacy of oral etoposide possible due to possible alteration of P-gp mediated intestinal transport of etoposide Avoid combination or monitor for decreased clinical response to etoposide
Ifosfamide
  Interaction Clinical management
Aprepitant Increased risk of ifosfamide-induced neurotoxicity due to increased levels of active metabolites Avoid combination or monitor closely for neurotoxicity; consider alternate antiemetic regimens
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Increased toxicity of ifosfamide possible due to increased conversion to active and toxic metabolites Avoid combination or monitor for ifosfamide toxicity
CYP3A4 inhibitors (e.g. azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Reduced efficacy of ifosfamide possible due to decreased conversion to active metabolites Avoid combination or monitor for decreased clinical response to ifosfamide
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor renal function closely
Suxamethonium Potentiation of muscle relaxant effect possible Alert the anaesthetist if a patient has been treated with ifosfamide within ten days of planned general anaesthesia
CNS depressants (including opiates, opioids, phenothiazines) Increased risk of ifosfamide-induced neurotoxicity due to additive CNS effects Avoid combination or monitor for excessive CNS depression/encephalopathy
Mesna 
No specific or clinically significant drug interactions 
General
  Interaction Clinical management
Warfarin Anti-cancer drugs may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

Interaction with both CYP3A4 and P-gp inhibitors /inducers.

DOAC and anti-cancer drug levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).

Apixaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. If treating VTE, avoid use with strong CYP3A4 and P‑gp inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 and P‑gp  inhibitors.

Dabigatran: avoid combination with strong P‑gp inducers and inhibitors.

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin Anti-cancer drugs can damage the lining of the intestine; affecting the absorption of digoxin. Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics Both altered antiepileptic and anti-cancer drug levels may occur, possibly leading to loss of efficacy or toxicity. Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the anti-cancer therapy.
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia. Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update
Vaccines Diminished response to vaccines and increased risk of infection with live vaccines. Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

eviQ provides safe and effective instructions on how to administer cancer treatments. However, eviQ does not provide every treatment delivery option, and is unable to provide a comprehensive list of cancer treatment agents and their required IV line giving set/filter. There may be alternative methods of treatment administration, and alternative supportive treatments that are also appropriate. Please refer to the individual product information monographs via the TGA website for further information.

Days 1 and 2

General patient assessment prior to each treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

Prime IV line(s).

Access CVAD.

Note: A large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

  • daily weight
  • dip stick all urine for haematuria
  • strict fluid balance input and output

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Cytarabine 

Prior to administration:

Ensure corticosteroid eye drops have been administered before starting cytarabine.

Verify that cytarabine neurological assessment has been performed prior to administration of cytarabine:

  • if the patient scores 0 then administer cytarabine as charted
  • if the patient scores 1 or above, do not administer the cytarabine and immediately notify medical officer.
Administer cytarabine:
  • via IV infusion over 2 to 3 hours:
  • flush with ~50 mL of sodium chloride 0.9%.
Administer second dose of cytarabine 12 hours after first dose.

Etoposide

Administer etoposide (irritant):
  • via IV infusion over 30 to 60 minutes
  • rapid infusion may cause hypotension
  • observe for hypersensitivity
  • flush with ~ 100 mL sodium chloride 0.9%
  • if using etoposide phosphate administer in ~ 50 mL sodium chloride 0.9% or glucose 5% over ~15 minutes.
Stop infusion at first sign of reaction:
  • if symptoms are mild and resolve when infusion is stopped, consider recommencing infusion after review by medical officer at a slower rate.
  • for severe reactions seek medical assistance immediately and do not restart infusion.

Mesna 

First dose of mesna (loading dose):
  • administer via IV infusion over 15 minutes
  • start 60 minutes prior to the commencement of ifosfamide (Day 1 only)
Second dose of mesna:
  • via IV infusion
  • over 24 hours (to commence immediately after loading dose)
  • the administration of mesna causes a false positive ketonuria​.

Ifosfamide infusion

Prior to administration:
  • assess neurological function at baseline and prior to each ifosfamide dose
    • inpatients: 4 hourly assessments until 24 hours after ifosfamide infusion is completed
    • outpatients: advise patient/carer of the potential for neurotoxicity
  • perform baseline urinalysis and monitor for haematuria prior to each ifosfamide dose
    • note the administration of mesna will cause a false positive for ketonuria
  • ensure patient receives at least 3 L of IV or oral fluids per day
Administer ifosfamide (irritant):
  • via IV infusion over 2 hours
  • flush with ~100 mL of sodium chloride 0.9%

Continue safe handling precautions until 7 days after completion of drug(s)

Days 3 and 4

General patient assessment prior to each treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

Note: A large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

  • continue daily weight
  • dip stick all urine for haematuria
  • strict fluid balance input and output 

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Continue corticosteroid eye drops for 72 hours after completion of the last dose of cytarabine.

Etoposide

Administer etoposide (irritant):
  • via IV infusion over 30 to 60 minutes
  • rapid infusion may cause hypotension
  • observe for hypersensitivity
  • flush with ~ 100 mL sodium chloride 0.9%
  • if using etoposide phosphate administer in ~ 50 mL sodium chloride 0.9% or glucose 5% over ~15 minutes.
Stop infusion at first sign of reaction:
  • if symptoms are mild and resolve when infusion is stopped, consider recommencing infusion after review by medical officer at a slower rate.
  • for severe reactions seek medical assistance immediately and do not restart infusion.

Ifosfamide infusion

Prior to administration:
  • assess neurological function at baseline and prior to each ifosfamide dose
    • inpatients: 4 hourly assessments until 24 hours after ifosfamide infusion is completed
    • outpatients: advise patient/carer of the potential for neurotoxicity
  • perform baseline urinalysis and monitor for haematuria prior to each ifosfamide dose
    • note the administration of mesna will cause a false positive for ketonuria
  • ensure patient receives at least 3 L of IV or oral fluids per day
Administer ifosfamide (irritant):
  • via IV infusion over 2 hours
  • flush with ~100 mL of sodium chloride 0.9%

Mesna 

  • administer via IV infusion over 24 hours
  • the administration of mesna causes a false positive ketonuria​.

Continue safe handling precautions until 7 days after completion of drug(s)

Day 5

General patient assessment prior to each treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

Note: A large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

  • continue daily weight
  • dip stick all urine for haematuria
  • strict fluid balance input and output 

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Continue corticosteroid eye drops for 72 hours after completion of the last dose of cytarabine.

Etoposide

Administer etoposide (irritant):
  • via IV infusion over 30 to 60 minutes
  • rapid infusion may cause hypotension
  • observe for hypersensitivity
  • flush with ~ 100 mL sodium chloride 0.9%
  • if using etoposide phosphate administer in ~ 50 mL sodium chloride 0.9% or glucose 5% over ~15 minutes.
Stop infusion at first sign of reaction:
  • if symptoms are mild and resolve when infusion is stopped, consider recommencing infusion after review by medical officer at a slower rate.
  • for severe reactions seek medical assistance immediately and do not restart infusion.

Ifosfamide infusion

Prior to administration:
  • assess neurological function at baseline and prior to each ifosfamide dose
    • inpatients: 4 hourly assessments until 24 hours after ifosfamide infusion is completed
    • outpatients: advise patient/carer of the potential for neurotoxicity
  • perform baseline urinalysis and monitor for haematuria prior to each ifosfamide dose
    • note the administration of mesna will cause a false positive for ketonuria
  • ensure patient receives at least 3 L of IV or oral fluids per day
Administer ifosfamide (irritant):
  • via IV infusion over 2 hours
  • flush with ~100 mL of sodium chloride 0.9%

Mesna 

  • administer via IV infusion over 24 hours
  • the administration of mesna causes a false positive ketonuria​.

Intrathecal methotrexate

Intrathecal methotrexate is to be administered today. The intrathecal procedure is to be done separately to the IV administration of all other cytotoxic drugs

Read more about the procedure for intrathecal methotrexate administration.

Post intrathecal care:

Local policies and guidelines regarding bed rest post dural puncture should be adhered to. At a minimum:

  • the patient should have at least 1 set of observations including:
    • vital signs and GCS
    • any abnormal neurological signs such as nausea, vomiting, chills, fever, confusion, headache or other changes in neurological status
  • educate the patient to recognise and immediately report any adverse reactions including blurred vision, dizziness, pain and or headache
  • observe the lumbar puncture site for any leakage or bleeding post procedure
  • document the procedure including outcomes in the patients notes

Continue safe handling precautions until 7 days after completion of drug(s)

Day 6

Note: A large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

  • continue daily weight
  • dip stick all urine for haematuria
  • strict fluid balance input and output 

Hydration if prescribed

Calcium Folinate (Leucovorin)

  • administer ONCE orally 24 hours after intrathecal methotrexate 

Deaccess CVAD.

Day 7

Filgrastim

  • administer filgrastim subcutaneous starting on day 7 and continuing until ANC is greater than 1 x 109/L

Discharge information

Calcium folinate (leucovorin) 
  • Calcium folinate (leucovorin) tablets with instructions to take 24 hours after intrathecal methotrexate.
Antiemetics
  • Antiemetics as prescribed.
Corticosteroid eye drops
  • Continue corticosteroid eye drops for at least 72 hours after completion of final cytarabine dose.
Growth factor support
  • Arrangements for administration if prescribed.
Prophylaxis medications
  • Prophylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antifungals, antivirals.
Patient information
  • Ensure patient receives patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Bone pain

Bone pain, usually in the lower back or pelvis, associated with G-CSF.
Encephalopathy

Ifosfamide induced encephalopathy has been reported in 10 to 30% of patients receiving high dose ifosfamide. Common symptoms include confusion, ataxia, weakness, seizures, somnolence and hallucinations. Onset may be 2 to 48 hours after commencing treatment. When reversible, symptoms usually resolve within 1 to 3 days.

Read more about ifosfamide-induced encephalopathy
Haemorrhagic cystitis

An inflammatory process, characterised by diffuse mucosal inflammation with haemorrhage involving the entire bladder. Patients are at risk following treatment with cyclophosphamide, ifosfamide and radiation therapy. 

Read more about haemorrhagic cystitis
Neurotoxicity

High dose cytarabine has been associated with acute cerebellar syndrome and diffuse cerebral dysfunction.

Read more about neurotoxicity associated with high dose cytarabine
Ocular toxicities

Reversible corneal toxicity (keratitis), haemorrhagic conjunctivitis, vision loss and other ocular side effects can occur with high dose cytarabine.  Corticosteroid eye drops must be administered concurrently with treatment. 

Read more about ocular toxicities associated with cytarabine
Taste and smell alteration

Read more about taste and smell changes

Early (onset days to weeks)
Neutropenia

Abnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. 

Read more about immediate management of neutropenic fever
Thrombocytopenia

A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding.  

Read more about thrombocytopenia
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Cytarabine (Ara-C) syndrome

Flu-like symptoms including fever, myalgia and malaise can occur 6 to 12 hours after cytarabine administration. Symptoms generally resolve within 24 hours of completing therapy.
Fatigue

Read more about fatigue
Nephrotoxicity

Renal dysfunction resulting from damage to the glomeruli, tubules or renal vasculature.
Oral mucositis

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following chemotherapy, radiation therapy to the head, neck or oesophagus, and high dose chemotherapy followed by a blood and marrow transplant (BMT).

Read more about oral mucositis
Skin rash

Anti-cancer drugs can cause a number of changes in the skin with maculo-papular rash the most common type of drug-induced skin reaction. 

Read more about skin rash

Late (onset weeks to months)
Alopecia

Hair loss may occur from all parts of the body. Patients can also experience mild to moderate discomfort of the hair follicles, and rarely pain as the hair is falling out.

Read more about alopecia
Anaemia

Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. 

Read more about anaemia
Cognitive changes (chemo fog)

Changes in cognition characterised by memory loss, forgetfulness and feeling vague. This is also referred to as 'chemo brain' or 'chemo fog'.

Read more about cognitive changes (chemo fog) 

Delayed (onset months to years)
Pulmonary toxicity

Pulmonary toxicity may include damage to the lungs, airways, pleura and pulmonary circulation. 

Read more about pulmonary toxicity associated with anti-cancer drugs

The dose modified (dm) CODOX-M/IVAC protocol for Burkitt Lymphoma (BL) is an iteration of the original treatment regimen described by Magrath et al in 1996.r The intention was to provide a dose intensive, compact, non cross-resistant regimen with effective CNS targeting. The promising results of this study were confirmed in the LY06 study which was a larger, multicentre, international phase 2 trial.r This regimen was refined in the LY10 trial, whereby methotrexate was dose modified to 3 g/m2 (from 6.7 g/m2) in order to reduce toxicity.r LY10 forms the basis of the current eviQ dmCODOX-M/IVAC protocol.

LY10 was a prospective, international, non­-randomised phase 2 study that included 53 patients (median age 37 years; range 17 to 76 years) with newly diagnosed BL. Patients with documented CNS involvement received additional intrathecal therapy. The LY10 trial included 11 low risk and 42 high risk patients.r

Patients were considered 'Low Risk' if they had at least 3 of the 4 following international prognostic index (IPI) factors: normal LDH, Ann Arbor stage I to II, WHO performance status 0 to 1 and number of extra nodal sites less than or equal to 1. These patients were treated with three cycles of dmCODOX-­M.r

All other patients were considered 'High Risk' and received alternating cycles of dmCODOX­-M/IVAC twice. Seventy-­six percent of the patients were able to complete the planned therapy. Severe (grade 3/4) toxicities included neutropenia (99%), neutropenic fever (80%), thrombocytopenia (86%), mucositis (47%), and neuropathy (8%). The treatment ­related death rate was 8%. Two­ year progression ­free survival (PFS) and overall survival (OS) rates were 64% and 67%, respectively.r

In recent years it has been common practise for rituximab to be added to the dmCODOX­-M/IVAC regimen, though there has been no prospective randomised evaluation of the efficacy of this addition. The largest prospective studyr utilised rituximab 375 mg/m2 on day 1 of each dmCODOX-M and IVAC cycle. 15 patients with BL and 15 with unclassifiable lymphomas intermediate between BL and diffuse large B cell lymphoma were evaluated. This regimen was associated with acceptable toxicity and outcomes commensurate with historical dmCODOX-M/IVAC patients who were not exposed to rituximab. Several other groups have reported retrospective data on CODOX-M/IVAC based regimens combined with rituximab.rrr In view of this data, addition of rituximab seems reasonable, though ideal timing and dosing remains to be defined.

HIV-Associated Burkitt Lymphoma

HIV-associated Burkitt Lymphoma is a rare clinical entity outside of specialised centres.  There is no consensus regarding optimum treatment regimen, and CODOX-M/IVAC is one option employed.
There is limited data regarding the use of CODOX-M/IVAC in HIV-associated Burkitt Lymphoma. Wang et alrreported retrospective outcomes of 14 adults with complete response rate of 63%.  The AIDS Malignancy Consortiumr reported prospective outcomes in 34 patients, using a modified regimen, and PFS at one year was 69% with OS 72%. 

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase II trials Magrath et alr  Yes  Yes   - 
LY06 trialr Yes No Higher methotrexate dose of 6.7g / m2 was administered
LY10 trialr Yes  Yes  -
Guidelines  Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN V.5.2019 Yes - -
BCCA May 2019 Yes   - -
CCO June 2019 Yes  - -

Efficacy

Progression-free survival and overall survival in the LY06r and LY10r studies, with risk group defined as in LY10:

© Blood 2008

Toxicity

In the LY10 study,r there were 9 deaths (1 low risk, 8 high risk) reported to be treatment-related, of which 5 (all high-risk patients) died within 12 weeks of starting treatment; 2 of the 9 patients were aged over 65 (66 and 67, respectively).

© Blood 2008

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Flinders Filters has partnered with eviQ to build reliable, robust search filters to retrieve core high level evidence on topics of significance to eviQ. The project goal is the provision of a sustainable model for evidence retrieval to ensure ongoing currency of content.

These search filters have been developed to retrieve the most up to date evidence from PubMed, in real time, using specifically designed search filters built to meet our needs.

Searches can be used when a protocol is scheduled for review or at any time you choose. Please click on the Specific, Balanced and Sensitive tabs below to access the Pubmed searches.

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restricted to retrieving randomised control trials and systematic reviews.

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Version 8

Date Summary of changes
27/01/2022 Protocol superseded. Discussed at Haematology Reference Committee meeting 22 October 2021 - consensus to supersede due to superior alternative being available.Version number changed to v.8.
08/02/2022 PJP prophylaxis clinical information block updated.
19/07/2022 Dose modifications section: 'Age older than 65 years' updated.

Version 7

Date Summary of changes
22/09/2020 Biosimilar drug added to clinical information. Version number changed to v.7
24/01/2022 Pulmonary toxicity added to side effects.

Version 6

Date Summary of changes
16/04/2020 'Mesna dosing and administration' block added to clinical information. Version number changed to v.6

Version 5

Date Summary of changes
05/12/2019

Reviewed at the Haematology Reference Committee meeting with the following changes: 

  • Evidence updated to include published evidence in the HIV population. 
  • Limited evidence table included as all trials supporting this protocol are phase II.
  • Day 6 Mesna removed.
  • References list updated.
  • Version changed to v.5. 
  • Protocol to be reviewed in 2 years.

Version 4

Date Summary of changes
25/06/2008 Changes to the wording of the administration of vincristine to reflect the Australian Council for Safety and Quality in Health Care safety alert and the NSW Health safety alert.
09/11/2008 Review and reformatting of patient information sheet.
19/03/2010 Complete review by Haematology Reference Committee and update of protocol to reflect new evidence (LY10 trial, Mead et al 2008); change to schedule of additional intrathecal treatment for proven CNS disease to follow LY10 trial; update of evidence section; transferred to eviQ.
19/10/10

Protocol updated to incorporate the consideration of the addition of rituximab in CD20+ Burkitt lymphoma.
22/03/2011 New format to allow for export of protocol information.
Protocol version number changed to v.2.
Antiemetics and premedications added to the treatment schedule.
Additional Clinical Information, Key Prescribing table and Key Administration table combined into new section titled Clinical Considerations.
Drug specific information placed behind the drug name link.
Title of protocol amended to reflect acronym.
11/10/2013 Reviewed at Haematology Reference Committee meeting.
23/09/2014 Added link to ALLG, ANZCTR and Lymphoma Australia website with statement 'Patients with NHL should be considered for inclusion into clinical trials'.
28/01/2015 Additional Clinical Information "Additional intrathecal treatment for proven CNS disease with IVAC protocol" deleted. Content incorporated into the Treatment Schedule Summary section.
11/09/2015 Reviewed at Haematology Reference Committee meeting with no changes made. Review in 2 years. Drug costs updated.

31/05/2017

Transferred to new eviQ website. Version number change to v.4.
25/05/2018 Reviewed at Haematology Reference Committee meeting. with no significant changes, review in 2 years.
18/07/2018 Note added underneath the treatment schedule for dose modifications in patients older than 65 years. 
10/10/2019 Clinical information updated with PBS expanded indications for G-CSF. 

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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31 Mar 2023