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GMALL 2002 block A (patients under 55 years)

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.

This protocol has been developed to replace ID 1651 Burkitt lymphoma GMALL 2002 block A (patients under 55 years) as teniposide is no longer available. This protocol has replaced teniposide with etoposide.
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Cycle 1 and 2

Drug Dose Route Day
Rituximab 375 mg/m2 * IV infusion 1
Dexamethasone 10 mg/m2 ONCE a day PO 2 to 6
vinCRISTine 2 mg IV infusion 2
Mesna 160 mg/m2 THREE times a day ** IV infusion 2 to 6
iFOSFamide 800 mg/m2 IV infusion 2 to 6
Methotrexate 150 mg/m2 IV infusion 2
Methotrexate 1,350 mg/m2 IV infusion 2
Calcium folinate (Leucovorin) 30 mg/m2 *** IV bolus 3
Calcium folinate (Leucovorin) 15 mg/m2 every 6 hours*** IV bolus 3
Cytarabine (Ara-C) 40 mg Intrathecal 2 and 6
Methotrexate 15 mg Intrathecal 2 and 6
Dexamethasone 4 mg Intrathecal 2 and 6
Cytarabine (Ara-C) 150 mg/m2 TWICE a day IV infusion 5 and 6
Etoposide **** 100 mg/m2 IV infusion 5 and 6
Filgrastim ***** 5 micrograms/kg Subcut 8 and continue daily until neutrophil recovery

* From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. For more information see the Non-Hodgkin lymphoma subcutaneous rituximab document.

** Daily dose of mesna to be calculated to equal 60% of the total daily dose of ifosfamide, administered as three bolus doses given 15 minutes before and 4 and 8 hours after completion of each dose of ifosfamide.

*** 30 mg/m2 followed by 15 mg/m2 every 6 hours until methotrexate level is less than 0.05 micromol/L. Commence 42 hours after the start of methotrexate infusion.

**** Doses in this protocol are expressed as etoposide; however Etopophos (etoposide phosphate) is the preferred formulation.
Note: 1 mg of etoposide = 1.136 mg Etopophos (etoposide phosphate). Use actual body weight.

***** Pegfilgrastim may be given instead of filgrastim on day 8.

Frequency:
21 days 
Cycles:
2 
Stage I/II disease Total of 4 cycles (A1-B1-C1-A2) followed by two additional doses of rituximab every 21 days after completion of A2.1
Stage III/IV disease or mediastinal and extra-nodal involvement Total of 6 cycles (A1-B1-C1-A2-B2-C2) followed by two additional doses of rituximab every 21 days after completion of C2.1
Notes:
  • Before each cycle, haematologic regeneration with granulocytes >1000/mL, platelets >50000/mL, the absence of grade 3/4 mucositis, or other severe organ toxicities was required.r
  • This treatment should only be carried out in a major centre as intense monitoring and support is required.
  • Central nervous system (CNS) irradiation (24 Gy) was recommended after 6 cycles for all patients with initial CNS involvement; mediastinal irradiation (36 Gy) was recommended for those with residual tumours at other sites.r
Drug status:

Filgrastim: (PBS authority)

Rituximab, Dexamethasone, vincristine, methotrexate, calcium folinate, ifosfamide, mesna (IV), etoposide and cytarabine are on the PBS general schedule

Mesna (oral) is TGA approved but not PBS reimbursed

Dexamethasone is available as 0.5 mg and 4 mg tablets

Cost:
~ $1,640 "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.

Cycle 1 and 2

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Hydrocortisone 100 mg (IV) 30 minutes before treatment
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate *
Day 2
Dexamethasone 10 mg/m2 (PO) ONCE a day on days 2 to 6. Take in the morning with food.
vinCRISTine 2 mg (IV infusion) in 50 mL sodium chloride 0.9% over 5 to 10 minutes

via minibag
Mesna 160 mg/m2 (IV infusion) THREE times a day in 100 mL sodium chloride 0.9% over 15 minutes, starting 15 minutes before ifosfamide infusion and then at hour 4 and 8 post completion of ifosfamide infusion.
iFOSFamide 800 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 1 hour
Methotrexate 150 mg/m2 (IV infusion) in 250 mL sodium chloride 0.9% over 30 minutes.
Methotrexate 1,350 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 23.5 hours
Cytarabine (Ara-C) 40 mg (Intrathecal) adhere to local institution intrathecal policy
Methotrexate 15 mg (Intrathecal)

adhere to local institution intrathecal policy
Dexamethasone 4 mg (Intrathecal) adhere to local institution intrathecal policy
Day 3
Dexamethasone 10 mg/m2 (PO) ONCE a day on days 2 to 6. Take in the morning with food.
Mesna 160 mg/m2 (IV infusion) THREE times a day in 100 mL sodium chloride 0.9% over 15 minutes, starting 15 minutes before ifosfamide infusion and then at hour 4 and 8 post completion of ifosfamide infusion.
iFOSFamide 800 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 1 hour
Calcium folinate (Leucovorin) 30 mg/m2 (IV bolus) over 1 to 2 minutes, commence 42 hours after the start of methotrexate infusion. Followed by 15 mg/m2 every 6 hours until methotrexate level is less than 0.05 micromol/L.
Calcium folinate (Leucovorin) 15 mg/m2 (IV bolus) over 1 to 2 minutes every 6 hours until methotrexate level is less than 0.05 micromol/L.
Day 4
Dexamethasone 10 mg/m2 (PO) ONCE a day on days 2 to 6. Take in the morning with food.
Mesna 160 mg/m2 (IV infusion) THREE times a day in 100 mL sodium chloride 0.9% over 15 minutes, starting 15 minutes before ifosfamide infusion and then at hour 4 and 8 post completion of ifosfamide infusion.
iFOSFamide 800 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 1 hour
Day 5
Dexamethasone 10 mg/m2 (PO) ONCE a day on days 2 to 6. Take in the morning with food.
Cytarabine (Ara-C) 150 mg/m2 (IV infusion) TWICE a day in 500 mL sodium chloride 0.9% over 60 minutes (12 hours apart)
Etoposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes **
Mesna 160 mg/m2 (IV infusion) THREE times a day in 100 mL sodium chloride 0.9% over 15 minutes, starting 15 minutes before ifosfamide infusion and then at hour 4 and 8 post completion of ifosfamide infusion.
iFOSFamide 800 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 1 hour
Day 6
Dexamethasone 10 mg/m2 (PO) ONCE a day on days 2 to 6. Take in the morning with food.
Cytarabine (Ara-C) 150 mg/m2 (IV infusion) TWICE a day in 500 mL sodium chloride 0.9% over 60 minutes (12 hours apart)
Etoposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes **
Mesna 160 mg/m2 (IV infusion) THREE times a day in 100 mL sodium chloride 0.9% over 15 minutes, starting 15 minutes before ifosfamide infusion and then at hour 4 and 8 post completion of ifosfamide infusion.
iFOSFamide 800 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 1 hour
Cytarabine (Ara-C) 40 mg (Intrathecal) adhere to local institution intrathecal policy
Methotrexate 15 mg (Intrathecal)

adhere to local institution intrathecal policy
Dexamethasone 4 mg (Intrathecal) adhere to local institution intrathecal policy
Day 8
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously on day 8 and continue daily until neutrophil recovery.***

* From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. For more information see the Non-Hodgkin lymphoma subcutaneous rituximab document.

** Doses in this protocol are expressed as etoposide; however Etopophos (etoposide phosphate) is the preferred formulation.
Note: 1 mg of etoposide = 1.136 mg Etopophos (etoposide phosphate). Use actual body weight.

*** Pegfilgrastim may be given instead of filgrastim on day 8.

Frequency:
21 days 
Cycles:
2 
Stage I/II disease Total of 4 cycles (A1-B1-C1-A2) followed by two additional doses of rituximab every 21 days after completion of A2.1
Stage III/IV disease or mediastinal and extra-nodal involvement Total of 6 cycles (A1-B1-C1-A2-B2-C2) followed by two additional doses of rituximab every 21 days after completion of C2.1

Cycle 1 and 2

Drug Dose Route Day
Rituximab 375 mg/m2 * IV infusion 1
Dexamethasone 10 mg/m2 ONCE a day PO 2 to 6
vinCRISTine 2 mg IV infusion 2
Mesna 160 mg/m2 THREE times a day ** IV infusion 2 to 6
iFOSFamide 800 mg/m2 IV infusion 2 to 6
Methotrexate 150 mg/m2 IV infusion 2
Methotrexate 1,350 mg/m2 IV infusion 2
Calcium folinate (Leucovorin) 30 mg/m2 *** IV bolus 3
Calcium folinate (Leucovorin) 15 mg/m2 every 6 hours*** IV bolus 3
Cytarabine (Ara-C) 40 mg Intrathecal 2 and 6
Methotrexate 15 mg Intrathecal 2 and 6
Dexamethasone 4 mg Intrathecal 2 and 6
Cytarabine (Ara-C) 150 mg/m2 TWICE a day IV infusion 5 and 6
Etoposide **** 100 mg/m2 IV infusion 5 and 6
Filgrastim ***** 5 micrograms/kg Subcut 8 and continue daily until neutrophil recovery

* From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. For more information see the Non-Hodgkin lymphoma subcutaneous rituximab document.

** Daily dose of mesna to be calculated to equal 60% of the total daily dose of ifosfamide, administered as three bolus doses given 15 minutes before and 4 and 8 hours after completion of each dose of ifosfamide.

*** 30 mg/m2 followed by 15 mg/m2 every 6 hours until methotrexate level is less than 0.05 micromol/L. Commence 42 hours after the start of methotrexate infusion.

**** Doses in this protocol are expressed as etoposide; however Etopophos (etoposide phosphate) is the preferred formulation.
Note: 1 mg of etoposide = 1.136 mg Etopophos (etoposide phosphate). Use actual body weight.

***** Pegfilgrastim may be given instead of filgrastim on day 8.

Frequency:
21 days 
Cycles:
2 
Stage I/II disease Total of 4 cycles (A1-B1-C1-A2) followed by two additional doses of rituximab every 21 days after completion of A2.1
Stage III/IV disease or mediastinal and extra-nodal involvement Total of 6 cycles (A1-B1-C1-A2-B2-C2) followed by two additional doses of rituximab every 21 days after completion of C2.1
Notes:
  • Before each cycle, haematologic regeneration with granulocytes >1000/mL, platelets >50000/mL, the absence of grade 3/4 mucositis, or other severe organ toxicities was required.r
  • This treatment should only be carried out in a major centre as intense monitoring and support is required.
  • Central nervous system (CNS) irradiation (24 Gy) was recommended after 6 cycles for all patients with initial CNS involvement; mediastinal irradiation (36 Gy) was recommended for those with residual tumours at other sites.r
Drug status:

Filgrastim: (PBS authority)

Rituximab, Dexamethasone, vincristine, methotrexate, calcium folinate, ifosfamide, mesna (IV), etoposide and cytarabine are on the PBS general schedule

Mesna (oral) is TGA approved but not PBS reimbursed

Dexamethasone is available as 0.5 mg and 4 mg tablets

Cost:
~ $1,640 "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.

Cycle 1 and 2

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Hydrocortisone 100 mg (IV) 30 minutes before treatment
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate *
Day 2
Dexamethasone 10 mg/m2 (PO) ONCE a day on days 2 to 6. Take in the morning with food.
vinCRISTine 2 mg (IV infusion) in 50 mL sodium chloride 0.9% over 5 to 10 minutes

via minibag
Mesna 160 mg/m2 (IV infusion) THREE times a day in 100 mL sodium chloride 0.9% over 15 minutes, starting 15 minutes before ifosfamide infusion and then at hour 4 and 8 post completion of ifosfamide infusion.
iFOSFamide 800 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 1 hour
Methotrexate 150 mg/m2 (IV infusion) in 250 mL sodium chloride 0.9% over 30 minutes.
Methotrexate 1,350 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 23.5 hours
Cytarabine (Ara-C) 40 mg (Intrathecal) adhere to local institution intrathecal policy
Methotrexate 15 mg (Intrathecal)

adhere to local institution intrathecal policy
Dexamethasone 4 mg (Intrathecal) adhere to local institution intrathecal policy
Day 3
Dexamethasone 10 mg/m2 (PO) ONCE a day on days 2 to 6. Take in the morning with food.
Mesna 160 mg/m2 (IV infusion) THREE times a day in 100 mL sodium chloride 0.9% over 15 minutes, starting 15 minutes before ifosfamide infusion and then at hour 4 and 8 post completion of ifosfamide infusion.
iFOSFamide 800 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 1 hour
Calcium folinate (Leucovorin) 30 mg/m2 (IV bolus) over 1 to 2 minutes, commence 42 hours after the start of methotrexate infusion. Followed by 15 mg/m2 every 6 hours until methotrexate level is less than 0.05 micromol/L.
Calcium folinate (Leucovorin) 15 mg/m2 (IV bolus) over 1 to 2 minutes every 6 hours until methotrexate level is less than 0.05 micromol/L.
Day 4
Dexamethasone 10 mg/m2 (PO) ONCE a day on days 2 to 6. Take in the morning with food.
Mesna 160 mg/m2 (IV infusion) THREE times a day in 100 mL sodium chloride 0.9% over 15 minutes, starting 15 minutes before ifosfamide infusion and then at hour 4 and 8 post completion of ifosfamide infusion.
iFOSFamide 800 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 1 hour
Day 5
Dexamethasone 10 mg/m2 (PO) ONCE a day on days 2 to 6. Take in the morning with food.
Cytarabine (Ara-C) 150 mg/m2 (IV infusion) TWICE a day in 500 mL sodium chloride 0.9% over 60 minutes (12 hours apart)
Etoposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes **
Mesna 160 mg/m2 (IV infusion) THREE times a day in 100 mL sodium chloride 0.9% over 15 minutes, starting 15 minutes before ifosfamide infusion and then at hour 4 and 8 post completion of ifosfamide infusion.
iFOSFamide 800 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 1 hour
Day 6
Dexamethasone 10 mg/m2 (PO) ONCE a day on days 2 to 6. Take in the morning with food.
Cytarabine (Ara-C) 150 mg/m2 (IV infusion) TWICE a day in 500 mL sodium chloride 0.9% over 60 minutes (12 hours apart)
Etoposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes **
Mesna 160 mg/m2 (IV infusion) THREE times a day in 100 mL sodium chloride 0.9% over 15 minutes, starting 15 minutes before ifosfamide infusion and then at hour 4 and 8 post completion of ifosfamide infusion.
iFOSFamide 800 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 1 hour
Cytarabine (Ara-C) 40 mg (Intrathecal) adhere to local institution intrathecal policy
Methotrexate 15 mg (Intrathecal)

adhere to local institution intrathecal policy
Dexamethasone 4 mg (Intrathecal) adhere to local institution intrathecal policy
Day 8
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously on day 8 and continue daily until neutrophil recovery.***

* From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. For more information see the Non-Hodgkin lymphoma subcutaneous rituximab document.

** Doses in this protocol are expressed as etoposide; however Etopophos (etoposide phosphate) is the preferred formulation.
Note: 1 mg of etoposide = 1.136 mg Etopophos (etoposide phosphate). Use actual body weight.

*** Pegfilgrastim may be given instead of filgrastim on day 8.

Frequency:
21 days 
Cycles:
2 
Stage I/II disease Total of 4 cycles (A1-B1-C1-A2) followed by two additional doses of rituximab every 21 days after completion of A2.1
Stage III/IV disease or mediastinal and extra-nodal involvement Total of 6 cycles (A1-B1-C1-A2-B2-C2) followed by two additional doses of rituximab every 21 days after completion of C2.1
  • Burkitt lymphoma and/or mature B-cell acute lymphoblastic leukaemia in patients 18 to 55 years of age
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 and rituximab.
Premedication

The product information states that premedication is required for this treatment.

Please refer to the treatment schedule for suggested premedication regimen. This may be substituted to reflect institutional policy.
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. 

For patients with a prior episode of chemotherapy induced nausea or vomiting, a NK1 receptor antagonist is available on the PBS in combination with a 5HT3 receptor antagonist and dexamethasone.

As a steroid has been included as part of this protocol, additional antiemetic steroids are not 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
Subcutaneous rituximab

Please note that subcutaneous rituximab is no longer subsidised by the Pharmaceutical Benefit Scheme and is currently unavailable in Australia.

All patients must always receive their first dose of rituximab by intravenous administration. Subcutaneous (SC) rituximab must only be given at the second or subsequent doses. From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. If patient was not able to receive one full rituximab intravenous infusion dose, they should continue the subsequent dose with intravenous rituximab until a full IV dose is successfully administered.

Premedication consisting of an analgesic/antipyretic and an antihistamine should always be administered before each dose of rituximab SC. Premedication with glucocorticoids should also be considered, particularly if rituximab SC is not given in combination with steroid-containing chemotherapy.

 Read more about Non-Hodgkin lymphoma subcutaneous rituximab 
Rituximab rapid infusion

This regimen is not in line with the product monograph, however published literature indicates that it can be completed safely.

Read more about the rapid infusion of rituximab
Progressive multifocal leukoencephalopathy

Use of monoclonal antibodies may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal opportunistic viral infection of the brain. Patients must be monitored for any new or worsening neurological symptoms.

Read more about progressive multifocal leukoencephalopathy and the Therapeutic Goods Administration Medicines Safety update on progressive multifocal leukoencephalopathy from the Australian Government, Department of Health.
Pre-hydration

Pre-hydration with sodium bicarbonate 8.4% infusion. Urinary pH must be greater than 7 prior to commencing methotrexate infusion.
(Consider prescribing sodium bicarbonate oral capsules for administration prior to methotrexate infusion). Sodium bicarbonate 8.4% should continue until the methotrexate level is equal to or less than 0.05 micromol/L.
High dose methotrexate

Monitoring of methotrexate levels is essential as delayed methotrexate excretion is potentially an emergency situation. Methotrexate levels to be monitored every 24 hours until level is less than 0.05 micromol/L.

Methotrexate is renally eliminated. Renal function must be evaluated prior to treatment.

Methotrexate exits slowly from third space compartments (e.g. pleural effusions or ascites), resulting in a prolonged terminal plasma half-life and unexpected toxicity. In patients with significant third space accumulations, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels.

Glucarpidase is recommended in patients with high dose methotrexate (HDMTX)-induced acute kidney injury and delayed methotrexate clearance. It can rapidly lower methotrexate levels and early administration within 48 to 60 hours from the start of the HDMTX infusion is critical, as life-threatening toxicities may not be preventable beyond this time point.r

Read more about high dose methotrexate-induced toxicity.
Methotrexate interactions

Avoid administering the following drugs in combination with high dose methotrexate: ciprofloxacin, NSAIDs, probenecid, proton pump inhibitors (PPIs) (e.g. esomeprazole, omeprazole, pantoprazole), sulphonamides (e.g. sulfamethoxazole (in Bactrim®, Septrin®)), penicillins (e.g. piperacillin (in Tazocin®)) and trimethoprim. Severe mucositis may occur if administered together.
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
Peripheral neuropathy

Assess prior to each treatment. Based on clinical findings, temporary omission, dose reduction or cessation of the vinca alkaloid may be indicated; review by medical officer before commencing treatment.

Read more about peripheral neuropathy

Link to chemotherapy-induced peripheral neuropathy screening tool
Constipation

Prescribe prophylactic laxatives to prevent constipation related to the use of vinca alkaloids.
Corticosteroids

Diabetic patients should monitor their blood glucose levels closely. To minimise gastric irritation, advise patient to take immediately after food. Consider the use of a H2 antagonist or proton pump inhibitor if appropriate.

Read more about acute short term effects from corticosteroids
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.
Etoposide conversion factor

Note: Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg.
Doses in this protocol are expressed as etoposide.
Tumour lysis risk

Assess patient for risk of developing tumour lysis syndrome.

Read more about prevention and management of tumour lysis syndrome.
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 e.g. AmBisome 50 mg IV ONCE daily three times weekly (e.g. on Mondays, Wednesdays and Fridays) or fluconazole 200 mg to 400 mg PO daily.

Note: Extended spectrum azole antifungals (e.g. posaconazole, voriconazole and itraconazole) should be avoided with vinca alkaloids. Metabolism is inhibited by azoles and neurotoxicity can be potentiated.

Read more about antifungal prophylaxis drugs and doses.
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
Biosimilar drug

Read more about biosimilar drugs on the Biosimilar Awareness Initiative page
Blood tests

FBC, EUC, LFTs, LDH and BSL at baseline, prior to each treatment and regularly throughout treatment. Methotrexate levels to be monitored every 24 hours until level is less than 0.05 µ/L.
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
Dose reduction may be required at the discretion of the Haematologist
Renal impairment
Creatinine clearance must be greater than 50 mL/min prior to administration of high dose methotrexate
Creatinine clearance (mL/min)
30 to 50 Reduce etoposide by 25%
less than 30 Reduce etoposide by 50% and ifosfamide by 25%
Hepatic impairment
Hepatic dysfunction
Mild Reduce vincristine by 25%
Moderate Reduce vincristine by 50%
Severe Omit vincristine and reduce methotrexate by 25%

Elevations in liver function tests occur with both standard and high dose cytarabine. Significant liver function abnormalities may require discontinuation or a dose reduction.

Peripheral neuropathy
Grade 2 which is present at the start of the next cycle Reduce vincristine by 50%
Grade 3 or Grade 4 Omit vincristine
Mucositis, stomatitis and diarrhoea
Grade 3 or Grade 4 Diarrhoea and ulcerative stomatitis require interruption of therapy otherwise haemorrhagic enteritis and death from intestinal perforation may occur; reduce methotrexate by 25%

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
Dexamethasone
  Interaction Clinical management
CYP3A4 interactions Dexamethasone is a substrate of CYP3A4 and a weak to moderate inducer of CYP3A4. The clinical relevance of CYP3A4 induction by dexamethasone is unknown as the mechanism has yet to be established The effects of the concomitant use of dexamethasone with other CYP3A4 inducers, inhibitors or substrates is variable. If used concomitantly, monitor patients closely for adverse drug reactions
Warfarin Concurrent use may result in increased risk of bleeding or diminished effects of warfarin Monitor prothrombin time / INR (especially during initiation or discontinuation) and for signs of drug toxicity during concomitant use; adjust warfarin dose as required
Oral hypoglycaemics Corticosteroids may cause hyperglycaemia and worsen diabetes control Monitor blood glucose levels and adjust oral hypoglycaemic dose as required
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 
Methotrexate
  Interaction Clinical management
Ciprofloxacin

NSAIDS

Probenecid

Proton pump inhibitors (e.g. esomeprazole, omeprazole, pantoprazole)		 Increased toxicity of methotrexate possible due to reduced clearance Avoid combination or monitor for methotrexate toxicity

Important note: with high-dose methotrexate therapy, many of these drug combinations are contraindicated
Sulphonamides and penicillins (e.g. sulfamethoxazole (in Bactrim®, Septrin®), piperacillin (in Tazocin®) etc.) Increased toxicity of methotrexate possible due to displacement from serum protein binding Avoid combination or monitor for methotrexate toxicity
Trimethoprim Increased toxicity of methotrexate possible due to additive antifolate activity Avoid combination or monitor for methotrexate toxicity
Mercaptopurine Increased toxicity of mercaptopurine possible due to reduced clearance Avoid combination or monitor for mercaptopurine toxicity
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor renal function closely
Hepatotoxic drugs (e.g. azathioprine, leflunomide, retinoids, sulfasalazine) Additive hepatotoxicity Avoid combination or monitor liver function closely
Folic acid (e.g. as in multivitamins)

Asparaginase (administered immediately prior or concurrently)		 Reduced efficacy of methotrexate possible due antagonism of its action Avoid combination or monitor for decreased clinical response to methotrexate
Note: asparaginase administered shortly after methotrexate can enhance its efficacy and reduce its toxicity
Rituximab
  Interaction Clinical management
Antihypertensives Additive hypotensive effect Consider withholding antihypertensive medications 12 hours prior to the rituximab infusion
Vincristine
  Interaction Clinical management
CYP3A4 and P-gp inhibitors (e.g. amiodarone, aprepitant, azole-antifungals, ritonavir, lapatinib, nilotinib, sorafenib, macrolides, ciclosporin, grapefruit juice etc.) Increased toxicity of vincristine possible due to reduced clearance Monitor for vincristine toxicity (esp. neurotoxicity, paralytic ileus)
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of vincristine possible due to increased clearance Monitor for decreased clinical response to vincristine
Mitomycin Acute shortness of breath and severe bronchospasm has occurred following use of vincristine in patients who had received mitomycin simultaneously or within 2 weeks Use combination with caution
Ototoxic drugs (e.g. cisplatin, aminoglycosides, frusemide, NSAIDs) Additive ototoxicity Avoid combination or perform regular audiometric testing
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.

Day 1

General patient assessment prior to each day of treatment.

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

Prime IV line(s).

Access TIVAD or CVAD.

  • baseline weight
  • baseline urinalysis
  • strict fluid balance input and output

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Rituximab

Prior to administration:
  • check baseline observations
  • check for previous adverse events during previous infusions
  • verify premedication has been taken. If not, administer 30 to 60 minutes prior to rituximab administration:
    • paracetamol 1000 mg orally AND
    • loratadine 10 mg orally (or similar antihistamine)
    • a steroid may also be included as a premed according to local guidelines: dexamethasone (part of this protocol) or hydrocortisone 100 mg IV
Initial infusion:
  • commence rituximab infusion at 50 mg/hr for 30 minutes
  • repeat observations prior to each rate increase
  • increase rate by 50 mg/hr every 30 minutes, up to a maximum of 400 mg/hr if observations are stable
  • flush with ~ 100 mL of sodium chloride 0.9%

If an infusion reaction occurs, temporarily discontinue the infusion and notify medical officer

  • when symptoms have completely resolved, recommence the infusion at half the rate prior to the reaction
  • for severe reactions stop infusion and manage as per emergency

Transient hypotension may occur. Consider withholding antihypertensive medication for 12 hours before and during infusion.

Subsequent infusions:

If an adverse event was experienced with initial infusion recommence infusion at the same rate as initial infusion

If no adverse event experienced with initial infusion:

  • perform baseline observations and repeat observations prior to each rate increase
  • commence rituximab infusion at 100 mg/hr
  • increase rate by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr if observations are stable
  • flush with ~ 100 mL of sodium chloride 0.9%

If an infusion reaction occurs, temporarily discontinue the infusion and notify medical officer

  • when symptoms have resolved, recommence the infusion at half the rate prior to the reaction
  • for severe reactions stop infusion and manage as per emergency

Read more about rapid infusion rituximab

Read more about subcutaneous rituximab

Day 2

General patient assessment prior to each day of treatment.

Peripheral neuropathy assessment tool

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

  • continue daily weight
  • monitor pH on all urine output
  • 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.

Dexamethasone

  • administer orally ONCE a day in the morning on days 2 to 6
  • to be taken with or immediately after food.

Note: if a dose is forgotten or vomited, contact treating team.

Vincristine

Administer vincristine (vesicant)
  • via a minibag over 5 to 10 minutes
  • ensure vein is patent and monitor for signs of extravasation throughout administration
  • flush with ~150 mL of sodium chloride 0.9%.

Mesna (loading dose) 

  • administer via IV infusion over 15 minutes
  • 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%

Mesna

  • administer via IV infusion over 15 minutes
  • at 4 and 8 hours post completion of each ifosfamide dose.

Methotrexate infusion

Prehydration:
  • administer 100 mL sodium bicarbonate 8.4% in 1000 mL glucose 5% OR sodium chloride 0.9% over 4 hours
  • continuous hydration with sodium bicarbonate 8.4% as prescribed
  • when urine pH is greater than 7 commence methotrexate
If the urine pH drops below 7 during the methotrexate infusion:
  • administer stat dose of 100 mL sodium bicarbonate 8.4% over 15 minutes
  • continue to test all urine for pH, if the pH continues to drop below 7 seek medical review as further doses of sodium bicarbonate may be required

Note: A large volume of intravenous fluid is 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 is present review by medical officer (diuretics may be required)

First dose of methotrexate:
  • administer via IV infusion over 30 minutes 
  • the starting time of the methotrexate infusion must be documented as the calcium folinate (leucovorin) rescue is to commence exactly 42 hours after the commencement of the methotrexate and continue until the methotrexate level is less than 0.05 micromol/L.
Second dose of methotrexate (to commence immediately after the first dose):
  • administer via IV infusion over 23 and a half hours
  • flush with ~50 mL of sodium chloride 0.9%
  • Stop the methotrexate infusion after 23 and a half hours even if the infusion is not completed
Post methotrexate:
  • continue hydration over 8 hours with sodium bicarbonate 8.4% until methotrexate level is less than 0.05 micromol/L
  • a minimum of 3 litres of fluid should be administered daily
  • continue to monitor all urine pH and fluid input and output
  • monitor methotrexate concentration every 24 hours until the level is less than 0.05 micromol/L

Note: Start calcium folinate (leucovorin) rescue 42 hours after commencement of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L.

Intrathecal methotrexate, cytarabine and dexamethasone

Intrathecal methotrexate, cytarabine and dexamethasone are to be administered today. The intrathecal procedure is to be done separately to IV administration of all other cytotoxic drugs.

Read more about the procedure for intrathecal methotrexate and cytarabine 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)

Days 3 and 4

General patient assessment prior to each day of treatment.

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

  • continue daily weight
  • monitor pH on all urine output
  • 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.

Dexamethasone

  • administer orally ONCE a day in the morning on days 2 to 6
  • to be taken with or immediately after food.

Note: if a dose is forgotten or vomited, contact treating team.

Mesna (loading dose) 

  • administer via IV infusion over 15 minutes
  • 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%

Mesna

  • administer via IV infusion over 15 minutes
  • at 4 and 8 hours post completion of each ifosfamide dose.

Calcium Folinate (Leucovorin)

Commence 42 hours after commencement of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L

  • administer via IV bolus via the side port of the IV line over 1 to 2 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%

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

Day 5

General patient assessment prior to each day of treatment.

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

  • daily weight
  • daily urinalysis
  • strict fluid balance input and output

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Dexamethasone

  • administer orally ONCE a day in the morning on days 2 to 6
  • to be taken with or immediately after food.

Note: if a dose is forgotten or vomited, contact treating team.

Cytarabine infusion:

  • administer via IV infusion over 60 minutes
  • flush with ~50 mL of sodium chloride 0.9%.

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.
Administer second dose of cytarabine 12 hours after first dose.

Mesna (loading dose) 

  • administer via IV infusion over 15 minutes
  • 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%

Mesna

  • administer via IV infusion over 15 minutes
  • at 4 and 8 hours post completion of each ifosfamide dose.

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

Day 6

General patient assessment prior to each day of treatment.

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

  • daily weight
  • daily urinalysis
  • strict fluid balance input and output

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Dexamethasone

  • administer orally ONCE a day in the morning on days 2 to 6
  • to be taken with or immediately after food.

Note: if a dose is forgotten or vomited, contact treating team.

Cytarabine infusion:

  • administer via IV infusion over 60 minutes
  • flush with ~50 mL of sodium chloride 0.9%.

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.
Administer second dose of cytarabine 12 hours after first dose.

Mesna (loading dose) 

  • administer via IV infusion over 15 minutes
  • 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%

Mesna

  • administer via IV infusion over 15 minutes
  • at 4 and 8 hours post completion of each ifosfamide dose.

Intrathecal methotrexate, cytarabine and dexamethasone

Intrathecal methotrexate, cytarabine and dexamethasone are to be administered today. The intrathecal procedure is to be done separately to IV administration of all other cytotoxic drugs.

Read more about the procedure for intrathecal methotrexate and cytarabine 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

Deaccess TIVAD or CVAD.

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

Day 8

Filgrastim

  • inject subcutaneously ONCE daily, starting on day 8 and continue until neutrophil recovery

Discharge information

Antiemetics
  • Antiemetics as prescribed.
Laxatives
  • Ensure patient has prophylactic laxatives.
Growth factor support
  • Growth factor support arrangements for administration and detailed instructions of when to present for blood tests/monitoring.
Prophylaxis medications
  • Prophylaxis medications (if prescribed) e.g. 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)
Extravasation, tissue or vein injury

The unintentional instillation or leakage of a drug or substance out of a blood vessel into surrounding tissue. This has the potential to cause damage to affected tissue.

Read more about extravasation management
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
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
Flu-like symptoms

Symptoms include fever, chills, rigors, diaphoresis, malaise, myalgia, arthralgia, loss of appetite, dry cough and headache.
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Taste and smell alteration

Read more about taste and smell changes
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.

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
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
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Constipation
Diarrhoea

Read more about treatment induced diarrhoea
Fatigue

Read more about fatigue
Hepatotoxicity

Anti-cancer drugs administered either alone or in combination with other drugs and/or radiation may cause direct or indirect hepatotoxicity. Hepatic dysfunction can alter the metabolism of some drugs resulting in systemic toxicity.
Nephrotoxicity

Renal dysfunction resulting from damage to the glomeruli, tubules or renal vasculature.
Palmar-plantar erythrodysaesthesia (PPE) - hand-foot syndrome (HFS)

Bilateral erythema, tenderness, pain, swelling, tingling, numbness, pruritus, dry rash, or moist desquamation and ulceration of the palms and soles. It is also known as hand-foot syndrome (HFS). Symptoms appear to be dose dependent and palms are affected more than soles.

Read more about hand-foot syndrome associated with chemotherapy
Peripheral neuropathy

Typically symmetrical sensory neuropathy, affecting the fingers and toes, sometimes progressing to the hands and feet.  It is associated with several classes of anti-cancer drugs. These include taxanes, platinum-based compounds, vinca alkaloids and some drugs used to treat multiple myeloma.

Read more about peripheral neuropathy
Photosensitivity

Increased sensitivity to ultraviolet (UV) light resulting in an exaggerated sunburn-like reaction accompanied by stinging sensations and urticaria.
Side effects of corticosteroids

Insomnia, oedema, increased risk of infection e.g. oral thrush, gastric irritation, worsening of peptic ulcer disease, increased blood sugar levels, loss of diabetic control, mood and behavioural changes - including anxiety, euphoria, depression, mood swings, increased appetite and weight gain, osteoporosis and fractures (long term use), bruising and skin fragility are associated with corticosteroid use.
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
Injection-site reaction

Inflammation of or damage to the tissue surrounding the area where a drug was injected.

Late (onset weeks to months)
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
Anaemia

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

Read more about anaemia
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
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) 
Progressive multifocal leukoencephalopathy (PML)

A rare opportunistic viral infection of the brain, usually leading to death or severe disability, can occur with monoclonal antibodies (e.g. rituximab, obinutuzumab, ofatumumab, brentuximab vedotin) and other targeted therapies (e.g. ibrutinib, ruxolitinib, idelalisib). Onset may occur up to months after the final dose.  

Read more about progressive multifocal leukoencephalopathy (PML)

This GMALL B cell-Acute Lymphoblastic Leukaemia (B-ALL)/Non Hodgkin Lymphoma (NHL) 2002 protocol was developed for treatment of mature (B-ALL) and Burkitt lymphoma and evolved from 3 preceding protocols: B-NHL83, B-NHL86 and B-NHL90.r The GMALL study group developed these protocols based on concepts employed successfully in the treatment of paediatric mature B-ALL. All used short, alternating cycles of intensive chemotherapy (in an ABABAB pattern) that included high doses of methotrexate and cyclophosphamide. The B-NHL90 protocol incorporated an increase in methotrexate doses to 3 g/m2, but this did not result in improvement in outcomes when compared with B-NHL86.r

GMALL B-ALL/NHL 2002 differs from the preceding protocols by the addition of 8 doses of rituximab and of block C - incorporating high dose cytarabine and methotrexate for patients ≤55 years (changing the schedule to ABCABC).rr The methotrexate dose is reduced back to 1.5 g/m2. In patients over 55 years, no high dose cytarabine is given, and the methotrexate dose is 500 mg/m2 (schedule ABABAB).r In all patients with stage I/II disease and complete response (CR) after 2 cycles, treatment is abbreviated to 4 cycles.r In addition to the chemo-immunotherapy, the GMALL group recommend radiation therapy to the CNS (24Gy; for CNS involvement) and large mediastinal tumours (36Gy; >7.5 cm mass).r

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase II trials Oriol et al. 2008r Yes Yes  
Prospective study Intermesoli et al. 2013r Yes Yes  
Hoelzer et al. 2014r Yes Yes  
Observational studies N/A N/A N/A  
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN N/A N/A N/A  
BCCA N/A N/A N/A  
CCO N/A N/A N/A  

Efficacy

The outcomes of 363 patients with Burkitt Lymphoma and Burkitt’s Leukaemia (mature B cell or L3-ALL) treated with the GMALL B-ALL/NHL 2002 protocol were reported in 2014.r The complete remission (CR) rate was 88% with 5-year progression-free survival (PFS) 75% and overall survival (OS) 80%. There were significant differences in CR, PFS and OS between the ≤55 and >55 years groups (see table).

© Blood 2014

Multivariate analysis revealed the following factors predicted overall survival in this group of patients: age (≤55 vs >55 years), bone marrow involvement, LDH, and gender.r

The GMALL B-ALL/NHL 2002 protocol has been trialled by other groups. The Northern Italy Leukemia Group (NILG) treated 105 patients with Burkitt lymphoma and leukaemia (mature B-ALL, 48%) with GMALL B-ALL/NHL 2002.r 25% of their cohort were over 55 years old, 14% were HIV positive and 37% had an ECOG >1.r The CR rate was 79%, 3 year OS 67% and disease free survival (DFS) 75%. Outcomes were better in the younger group (≤60 years), with OS 75% and DFS 82%. On multivariate analysis, the two significant indicators of prognosis were age (≤60 vs >60 years) and performance status (0-1 vs >1).r

Oriol et al. also reported CR rates of 84 to 88% in 36 patients with Burkitt’s lymphoma/leukaemia treated with the GMALL regimen. Nineteen (56%) of the patients were HIV positive, and there were no significant differences in response rates or 2-year survival in the HIV positive, compared with HIV negative patients.r

Toxicity

The GMALL group listed the major grade 3 and 4 toxicities of the GMALL B-ALL/NHL 2002 protocol as haematological, especially grade 3-4 neutropenia during cycle A1, and infections (occurring in 38% of patients in cycle A1). Liver toxicity was most common during the first cycle, and grade 3/4 mucositis was common during the first 2 cycles.r Therapy-related deaths occurred in 2% of the ≤55 years patients but 11% of the >55 group, with >90% of deaths caused by infection.r

The NILG reported treatment-related mortality in 14 (of 105) patients during induction (79% due to infection) and 5 patients during consolidation therapy. Severe neutropenia (<0.5x10^9/L) was present for a median of 7 days (0-25) in ≤55 year olds and 8 days (0-23) in the older patients. Thrombocytopenia (<20x10^9/L) was present for a median of 3(0-45) and 5(0-32) days, respectively.r The rate of infection was 48%. Chemotherapy-induced mucositis and severe infections were more common in HIV positive patients compared with HIV negative.r

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Version 1

Date Summary of changes
13/08/2021 New protocol developed to replace teniposide with etoposide. This protocol replaces protocol ID 1651. Protocol approved and published on eviQ
20/01/2022 Interactions updated.
08/02/2022 PJP prophylaxis clinical information block updated.
11/11/2022 Protocol electronically reviewed by the Haematology Reference Committee. Rituximab status changed to PBS general schedule. Minor reformatting changes. Review in 2 years.

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31 Mar 2023