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GMALL 2002 block A (patients over 55 years) SUPERSEDED

This protocol has been superseded due to unavailability of teniposide. It has been replaced by ID 3929 GMALL 2002 block A (patients over 55 years)

 Teniposide drug supply:

Teniposide was removed from the Australian Register of Therapeutic Goods (ARTG) in June 2017 as global production was ceased. Access to teniposide may still be available via the Special Access Scheme. 

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 have been updated with the ADDIKD guideline recommendations (if applicable). Recommendations may differ from other protocols which have not been updated. For further information refer to the dedicated eviQ ADDIKD guideline webpage.

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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
iFOSFamide 400 mg/m2 IV infusion 2 to 6
Mesna 400 mg/m2 IV infusion 2 to 6
Mesna 400 mg at 2 and 6 hours post completion of ifosfamide infusion PO 2 to 6
Methotrexate 50 mg/m2 IV infusion 2
Methotrexate 450 mg/m2 IV infusion 2
Methotrexate 12 mg Intrathecal 2
Calcium folinate (Leucovorin) 50 mg every 6 hours ** IV bolus 3
Cytarabine (Ara-C) 60 mg/m2 TWICE a day IV infusion 5 and 6
Teniposide 60 mg/m2 IV infusion 5 and 6
Filgrastim 5 micrograms/kg Subcut 8 and continue daily until neutrophil recovery

* Dosing may require rounding to the nearest tablet strength to enable delivery of a measurable dose.

** for 24 hours, followed by 15 mg every 6 hours until methotrexate level is less than 0.1 micromol/L. Commence 42 hours after the start of methotrexate infusion.

Frequency:
21 days 
Cycles:
2 to 3 depending on the stage of disease.
Stage I/II disease Total of 4 cycles (A1-B1-A2-B2) followed by two additional doses of rituximab every 21 days after completion of B2.1
Stage III/IV disease or mediastinal and extra-nodal involvement Total of 6 cycles (A1-B1-A2-B2-A3-B3) followed by two additional doses of rituximab every 21 days after completion of B3.1
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, methotrexate, calcium folinate, ifosfamide, mesna (IV) and cytarabine are on the PBS general schedule

Mesna (oral) is TGA approved but not PBS reimbursed

Teniposide was removed from the ARTG in June 2017 due to worldwide production cessation. Access to teniposide may still be available via the Special Access Scheme. opens in a new tab or window

Dexamethasone is available as 0.5 mg and 4 mg tablets

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.*
iFOSFamide 400 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 400 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with ifosfamide)
Mesna 400 mg (PO) at 2 hours and 6 hours after completion of ifosfamide infusion
Methotrexate 50 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% over 30 minutes.
Methotrexate 450 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 23.5 hours
Methotrexate 12 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.*
iFOSFamide 400 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 400 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with ifosfamide)
Mesna 400 mg (PO) at 2 hours and 6 hours after completion of ifosfamide infusion
Calcium folinate (Leucovorin) 50 mg (IV bolus) over 1 to 2 minutes every 6 hours for 24 hours, followed by 15 mg every 6 hours until methotrexate level is less than 0.1 micromol/L. Commence 42 hours after the start of methotrexate infusion.
Day 4
Dexamethasone 10 mg/m2 (PO) ONCE a day on days 2 to 6. Take in the morning with food.*
iFOSFamide 400 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 400 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with ifosfamide)
Mesna 400 mg (PO) at 2 hours and 6 hours after completion of ifosfamide infusion
Day 5 and 6
Dexamethasone 10 mg/m2 (PO) ONCE a day on days 2 to 6. Take in the morning with food.*
Cytarabine (Ara-C) 60 mg/m2 (IV infusion) TWICE a day in 100 mL sodium chloride 0.9% over 60 minutes (12 hours apart)
Teniposide 60 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes

(in non-PVC containers only)
iFOSFamide 400 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 400 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with ifosfamide)
Mesna 400 mg (PO) at 2 hours and 6 hours after completion of ifosfamide infusion
Day 8
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously on day 8 and continue daily until neutrophil recovery.

* Dosing may require rounding to the nearest tablet strength to enable delivery of a measurable dose.

Frequency:
21 days 
Cycles:
2 to 3 depending on the stage of disease.
Stage I/II disease Total of 4 cycles (A1-B1-A2-B2) followed by two additional doses of rituximab every 21 days after completion of B2.1
Stage III/IV disease or mediastinal and extra-nodal involvement Total of 6 cycles (A1-B1-A2-B2-A3-B3) followed by two additional doses of rituximab every 21 days after completion of B3.1

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
iFOSFamide 400 mg/m2 IV infusion 2 to 6
Mesna 400 mg/m2 IV infusion 2 to 6
Mesna 400 mg at 2 and 6 hours post completion of ifosfamide infusion PO 2 to 6
Methotrexate 50 mg/m2 IV infusion 2
Methotrexate 450 mg/m2 IV infusion 2
Methotrexate 12 mg Intrathecal 2
Calcium folinate (Leucovorin) 50 mg every 6 hours ** IV bolus 3
Cytarabine (Ara-C) 60 mg/m2 TWICE a day IV infusion 5 and 6
Teniposide 60 mg/m2 IV infusion 5 and 6
Filgrastim 5 micrograms/kg Subcut 8 and continue daily until neutrophil recovery

* Dosing may require rounding to the nearest tablet strength to enable delivery of a measurable dose.

** for 24 hours, followed by 15 mg every 6 hours until methotrexate level is less than 0.1 micromol/L. Commence 42 hours after the start of methotrexate infusion.

Frequency:
21 days 
Cycles:
2 to 3 depending on the stage of disease.
Stage I/II disease Total of 4 cycles (A1-B1-A2-B2) followed by two additional doses of rituximab every 21 days after completion of B2.1
Stage III/IV disease or mediastinal and extra-nodal involvement Total of 6 cycles (A1-B1-A2-B2-A3-B3) followed by two additional doses of rituximab every 21 days after completion of B3.1
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, methotrexate, calcium folinate, ifosfamide, mesna (IV) and cytarabine are on the PBS general schedule

Mesna (oral) is TGA approved but not PBS reimbursed

Teniposide was removed from the ARTG in June 2017 due to worldwide production cessation. Access to teniposide may still be available via the Special Access Scheme. opens in a new tab or window

Dexamethasone is available as 0.5 mg and 4 mg tablets

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.*
iFOSFamide 400 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 400 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with ifosfamide)
Mesna 400 mg (PO) at 2 hours and 6 hours after completion of ifosfamide infusion
Methotrexate 50 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% over 30 minutes.
Methotrexate 450 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 23.5 hours
Methotrexate 12 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.*
iFOSFamide 400 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 400 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with ifosfamide)
Mesna 400 mg (PO) at 2 hours and 6 hours after completion of ifosfamide infusion
Calcium folinate (Leucovorin) 50 mg (IV bolus) over 1 to 2 minutes every 6 hours for 24 hours, followed by 15 mg every 6 hours until methotrexate level is less than 0.1 micromol/L. Commence 42 hours after the start of methotrexate infusion.
Day 4
Dexamethasone 10 mg/m2 (PO) ONCE a day on days 2 to 6. Take in the morning with food.*
iFOSFamide 400 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 400 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with ifosfamide)
Mesna 400 mg (PO) at 2 hours and 6 hours after completion of ifosfamide infusion
Day 5 and 6
Dexamethasone 10 mg/m2 (PO) ONCE a day on days 2 to 6. Take in the morning with food.*
Cytarabine (Ara-C) 60 mg/m2 (IV infusion) TWICE a day in 100 mL sodium chloride 0.9% over 60 minutes (12 hours apart)
Teniposide 60 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes

(in non-PVC containers only)
iFOSFamide 400 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 400 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with ifosfamide)
Mesna 400 mg (PO) at 2 hours and 6 hours after completion of ifosfamide infusion
Day 8
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously on day 8 and continue daily until neutrophil recovery.

* Dosing may require rounding to the nearest tablet strength to enable delivery of a measurable dose.

Frequency:
21 days 
Cycles:
2 to 3 depending on the stage of disease.
Stage I/II disease Total of 4 cycles (A1-B1-A2-B2) followed by two additional doses of rituximab every 21 days after completion of B2.1
Stage III/IV disease or mediastinal and extra-nodal involvement Total of 6 cycles (A1-B1-A2-B2-A3-B3) followed by two additional doses of rituximab every 21 days after completion of B3.1
  • Burkitt lymphoma and/or mature B-cell acute lymphoblastic leukaemia in patients over 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 rituximab and teniposide.

Read more about Hypersensitivity reaction
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

Patients being treated with multi-day anticancer protocols should receive antiemetics tailored to the emetogenic risk of the drugs administered each day during treatment and for two days after completion of the anticancer protocol.

No standard antiemetic regimen exists for multi-day anticancer protocols. 

As this protocol includes a steroid, additional antiemetic steroids may not be required, despite the PBS approved combination of an NK1 receptor antagonist, 5HT3, and a steroid for the prevention of nausea and vomiting associated with all moderate to highly emetogenic anti-cancer therapies.

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
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.
Methotrexate dosing and monitoring

Directly measured GFR is preferred for initial dosing when eGFR < 60 mL/min/1.73 m2, especially when methotrexate dose ≥ 500 mg/m2 or when eGFR is unreliable (e.g., extremes of body composition, amputees, paraplegia).

Monitor kidney function before, during and after methotrexate administration to identify signs of kidney function deterioration. 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 0.1 micromol/L.

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.

Read more about management of high-dose methotrexate toxicity.
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 0.1 micromol/L.

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.
Cytarabine syndrome

Treatment with cytarabine may cause a "cytarabine syndrome" characterised by flu-like symptoms, skin rash and occasionally chest pain.
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
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
Tumour lysis risk

Assess patient for risk of developing tumour lysis syndrome.

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

There is evidence supporting variations in mesna doses and administration timings, with no clear evidence that one particular regimen is superior to 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.

Read more about haemorrhagic cystitis 
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 ­

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, eGFR, 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 0.1 micromol/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 impact 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.

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.
Kidney dosing recommendations 
  • Suggested dose modifications are based on the International Consensus Guideline on Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).
  • Where one or more drugs in a protocol is recommended to be avoided, consider using a clinically appropriate alternative treatment protocol instead.
  • Before dose adjusting or omitting a drug, consider treatment intent.
  • In kidney replacement therapy consult a multidisciplinary team consisting of oncology/haematology with nephrology and/or clinical pharmacology for the management of dosing. 
  • For complete information on individual drug recommendations please review the individual drug monograph in the ADDIKD guideline.
eGFR
(mL/min/1.73m2)		 Cytarabine* Ifosfamide Methotrexate** Rituximab Vincristine Dexamethasone^ Tenoposide^
≥ 60

Full dose

Full dose

Full dose

Consideration may be given to a reduced dose for patients with eGFR 60 to 100 mL/min/1.73 m2

Full dose

Full dose

No dose reduction required in kidney dysfunction.

 

 

 

 

 

 

 

 

 

 

 

Adequate data in patients with hepatic insufficiency and/or kidney dysfunction are lacking, but dose adjustments may be necessary for patients with significant kidney dysfunction or hepatic impairment.

 

 

 
45 - 59

Full dose

Full dose

Potential for increased risk of adverse events

Consult a multidisciplinary team consisting of oncology/haematology with nephrology and/or clinical pharmacology for the management of dosing

Full dose

Full dose
30 - 44

Full dose

Reduce by 20%

OR

Alternative protocol

Potential for increased risk of adverse events

Consult a multidisciplinary team consisting of oncology/haematology with nephrology and/or clinical pharmacology for the management of dosing

Full dose

Full dose
15 - 29

Full dose

Reduce by 20%

OR

Alternative protocol

Potential for increased risk of adverse events

Avoid

Not recommended - use alternative protocol

Full dose

Full dose
< 15
(without kidney replacement therapy)

Full dose

Consult a multidisciplinary team consisting of oncology/haematology with nephrology and/or clinical pharmacology for the management of dosing

Avoid

Not recommended - use alternative protocol

Full dose

Full dose

* Cytarabine dose modifications are based on low dose cytarabine (< 1000 mg/m2) recommendations.

** Methotrexate dosing is based on the ADDIKD guideline and RCM consensus.

^ This drug was not included in the ADDIKD guideline.

  
Hepatic impairment
Hepatic dysfunction
Severe 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.

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%

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:  

For more information see References & Disclaimer.

Cytarabine
  Interaction Clinical management
Cytidine deaminase (CDA) inhibitors (e.g. cedazuridine) Potential increased effect/toxicity of cytarabine due to reduced clearance Avoid combination or monitor for increased cytarabine effect/toxicity
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
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
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney function closely
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
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, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney 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
Infliximab Altered methotrexate concentration Monitor for signs of methotrexate toxicity or reduced efficacy
Rituximab
  Interaction Clinical management
Antihypertensives Additive hypotensive effect Consider withholding antihypertensive medications 12 hours prior to the rituximab infusion
Immunosuppressants (eg. abatacept and baricitinib etc.) Increased risk of infection Concurrent use not recommended. If an immunosuppressant must be used, monitor closely for signs of infection
Teniposide
  Interaction Clinical management
Anticonvulsants (e.g. phenytoin, phenobarbitone) Reduced efficacy of teniposide possible due to increased clearance Avoid combination or monitor for decreased clinical response to teniposide. Consider increasing the dose of teniposide
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
  • strict fluid balance
  • dipstick urinalysis prior to treatment

Pre treatment medication

Verify premedication 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 ~ 50 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 ~ 50 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

Day 2

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
  • strict fluid balance
  • dipstick urinalysis:
    • prior to treatment for haematuria and pH level
    • on all urine output to monitor pH

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.

Ifosfamide 

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) with mesna:
  • via IV infusion over 2 hours
  • flush with ~100 mL of sodium chloride 0.9%

Oral mesna

  • administer 400 mg orally at 2 hours and 6 hours post completion of ifosfamide/mesna infusion
  • if vomiting occurs within 2 hours of taking oral mesna, repeat the dose or give IV mesna
  • if patient cannot tolerate oral mesna, it may be given by IV bolus
  • the oral mesna dose is equivalent to twice the IV 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 0.1 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 0.1 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 0.1 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 0.1 micromol/L.

The intrathecal procedure is to be done separately to the administration of all IV drugs

Intrathecal therapy - Time out

Methotrexate

  • to be administered intrathecally as per local policy

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 AVPU/GCS
    • monitoring for 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

Any changes in neurological status must be immediately reviewed by a medical officer.

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.

  • daily weight
  • strict fluid balance
  • dipstick urinalysis:
    • prior to treatment for haematuria and pH level
    • on all urine output to monitor pH

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.

Ifosfamide 

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) with mesna:
  • via IV infusion over 2 hours
  • flush with ~100 mL of sodium chloride 0.9%

Oral mesna

  • administer 400 mg orally at 2 hours and 6 hours post completion of ifosfamide/mesna infusion
  • if vomiting occurs within 2 hours of taking oral mesna, repeat the dose or give IV mesna
  • if patient cannot tolerate oral mesna, it may be given by IV bolus
  • the oral mesna dose is equivalent to twice the IV dose.

Calcium Folinate (Leucovorin)

Commence 42 hours after commencement of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.1 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)

Days 5 and 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 dipstick urinalysis
  • strict fluid balance

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

Teniposide

Administer teniposide (irritant):
  • via IV infusion over 30 to 60 minutes
  • use non PVC containers and tubing
  • rapid infusion may cause hypotension
  • observe for hypersensitivity
  • flush with ~ 100 mL sodium chloride 0.9%.
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 

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) with mesna:
  • via IV infusion over 2 hours
  • flush with ~100 mL of sodium chloride 0.9%

Oral mesna

  • administer 400 mg orally at 2 hours and 6 hours post completion of ifosfamide/mesna infusion
  • if vomiting occurs within 2 hours of taking oral mesna, repeat the dose or give IV mesna
  • if patient cannot tolerate oral mesna, it may be given by IV bolus
  • the oral mesna dose is equivalent to twice the IV dose.

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.
Growth factor support
  • Growth factor support arrangements for administration and detailed instructions of when to present for blood tests/monitoring.
Patient information
  • Ensure patient receives patient information sheet.
Prophylaxis medications
  • Prophylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antifungals, antivirals.

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)
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
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
Flu-like symptoms

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

An inflammatory process, characterised by diffuse bladder mucosal inflammation resulting in haemorrhage. Patients are at risk following blood and marrow transplant (BMT) or treatment with cyclophosphamide, ifosfamide and/or radiation therapy.

Read more about haemorrhagic cystitis
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
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
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
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

Late (onset weeks to months)
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 and scalp cooling
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)
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

This protocol has been superseded due to unavailability of teniposide. It has been replaced by ID 3929 GMALL 2002 block A (patients over 55 years)

This GMALL B-ALL/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 in the addition of 8 doses of rituximab and of cycle 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 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 to 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 years 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 Twenty-five percent 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 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 9

Date Summary of changes
20/03/2024

Protocol updated with ADDIKD guideline recommendations. New kidney dosing recommendation table added to dose modification section.

PDF of previous protocol.

Version number changed to V.9.
02/04/2024 Extravasation, tissue or vein injury added to side effects per updates to extravasation document.

Version 8

Date Summary of changes
05/06/2023 Subcutaneous rituximab information removed from the following sections – treatment schedule, clinical information, administration, patient information. Increased to version 8.

Version 7

Date Summary of changes
04/05/2023

Methotrexate target level updated. Version number changed to v.7

Version 6

Date Summary of changes
23/08/2021 Protocol superseded due to unavailability of teniposide. This protocol has been replaced with ID 3929 GMALL 2002 block A (patients over 55 years).
20/01/2022 Interactions updated.
08/02/2022 PJP prophylaxis clinical information block updated.
11/11/2022 Reviewed electronically by the Haematology Reference Committee. Minor formatting changes. Rituximab PBS status changed to general schedule. Review in 2 years.

Version 5

Date Summary of changes
16/04/2020 'Mesna dosing and administration' block added to clinical information. Version number changed to v.5

Version 4

Date Summary of changes
09/03/2020 Biosimilar rituximab added to clinical information. Version number changed to v.4     

Version 3

Date Summary of changes
08/11/2016 Approved and published on eviQ.

31/05/2017

Transferred to new eviQ website. Version number change to v.2.
21/09/2018

Reviewed by Haematology Reference Committee with changes to teniposide drug status, review in 1 year:

  • Teniposide drug status updated.
  • Flag added to the top of the protocol to reflect global production cessation.

Reference to subcutaneous rituximab added:

  • Link to subcutaneous​ rituximab document underneath the treatment schedule.
  • Clinical information block on subcutaneous rituximab.
  • Link to the subcutaneous rituximab document into administration section.
  • Injection-site reaction side effect.
  • Note about subcutaneous rituximab to the patient information.
  • Version number changed to v.3.
13/09/2019 Reviewed by Haematology Reference Committee, no changes made. Review in 5 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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19 Apr 2024