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Non-Hodgkin lymphoma DA-R-EPOCH (dose adjusted rituximab etoposide prednisolone vinCRISTine CYCLOPHOSPHamide DOXOrubicin)

This protocol was published over 10 years ago and has been assessed by the reference committee as suitable to be reviewed as required. The review due date has been removed. If something in this protocol requires reference committee consideration, please click on the feedback button at the bottom of the page.

Read more about the as required review process in this factsheet.

Patients with lymphoma should be considered for inclusion into clinical trials. Link to ALLG website opens in a new tab or window, ANZCTR website opens in a new tab or window and Lymphoma Australia website. opens in a new tab or window

Some indications in this protocol are based on limited evidence; please refer to the individual evidence sections for more information.

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Cycle 1

Drug Dose Route Day
Prednisolone 60 mg/m2 TWICE a day * PO 1 to 5
Rituximab 375 mg/m2 IV infusion 1
DOXOrubicin 10 mg/m2 CIV over 24 hours (loaded with etoposide and vinCRISTine) ** 1 to 4
vinCRISTine 0.4 mg/m2 CIV over 24 hours (loaded with etoposide and DOXOrubicin) ** 1 to 4
Etoposide 50 mg/m2 CIV over 24 hours (loaded with DOXOrubicin and vinCRISTine) ** 1 to 4
CYCLOPHOSPHamide 750 mg/m2 IV infusion 5
Filgrastim 5 micrograms/kg Subcut 6 and continue daily until neutrophil recovery

* Prednisolone administered twice a day as per Bartlett et al.1 however dosing frequency may be adjusted based on patient tolerability. Dosing may require rounding to the nearest tablet strength to enable delivery of a measurable dose.

** See clinical information for further details about drug compatibilities.

Note:

  • The treatment schedule shows doses for cycle 1 ONLY. The doses for each cycle are determined by the ANC nadir of the previous cycle. Subsequent cycles may require dose adjustments as per dose-adjustment paradigm; see dose modifications section.
  • In aggressive NHL with HIV, subsequent cycles do not require dose adjustment, or may have adjustments limited to cyclophosphamide only; see evidence section.
Frequency:
21 days 
Cycles:
6 minimum and 8 maximum cycles. 2 cycles to be given beyond complete remission or stable disease.
For Burkitt lymphoma: patients received 3 to 6 cycles in the study by Roschewski et al. (see evidence section).
Notes:

CNS prophylaxis should be considered on a case by case basis for patients with high grade lymphoma who are at an increased risk of CNS relapse. See evidence section for diffuse large B-cell lymphoma for more details.

Drug status:

Filgrastim: (PBS authority opens in a new tab or window)

All other drugs in this protocol are on the PBS general schedule opens in a new tab or window

Prednisolone is available as 25 mg, 5 mg and 1 mg tablets

Cost:
~ $970 per cycle "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). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

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.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

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, growth factor support 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

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Prednisolone 60 mg/m2 (PO) TWICE a day on days 1 to 5.* Take with food.
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
DOXOrubicin 10 mg/m2 (CIV over 24 hours) loaded with vinCRISTine and etoposide in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours **
vinCRISTine 0.4 mg/m2 (CIV over 24 hours) loaded with DOXOrubicin and etoposide in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours **
Etoposide 50 mg/m2 (CIV over 24 hours) loaded with DOXOrubicin and vinCRISTine in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours **
Day 2 to 4
Prednisolone 60 mg/m2 (PO) TWICE a day on days 1 to 5.* Take with food.
DOXOrubicin 10 mg/m2 (CIV over 24 hours) loaded with vinCRISTine and etoposide in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours **
vinCRISTine 0.4 mg/m2 (CIV over 24 hours) loaded with DOXOrubicin and etoposide in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours **
Etoposide 50 mg/m2 (CIV over 24 hours) loaded with DOXOrubicin and vinCRISTine in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours **
Day 5
Prednisolone 60 mg/m2 (PO) TWICE a day on days 1 to 5.* Take with food.
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
CYCLOPHOSPHamide 750 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
Day 6
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously once daily starting day 6 and continue until neutrophils are 0.5 x 10 ^9/L above nadir

* One of the doses on day 1 should be taken 60 minutes before rituximab infusion. Prednisolone is administered twice a day as per Bartlett et al.1 however dosing frequency may be adjusted based on patient tolerability. Dosing may require rounding to the nearest tablet strength to enable delivery of a measurable dose.

** See clinical information for further details about drug compatibilities.

Note:

  • The treatment schedule shows doses for cycle 1 ONLY. The doses for each cycle are determined by the ANC nadir of the previous cycle. Subsequent cycles may require dose adjustments as per dose-adjustment paradigm; see dose modifications section.
  • In aggressive NHL with HIV, subsequent cycles do not require dose adjustment, or may have adjustments limited to cyclophosphamide only; see evidence section.

Frequency:
21 days 
Cycles:
6 minimum and 8 maximum cycles. 2 cycles to be given beyond complete remission or stable disease.
For Burkitt lymphoma: patients received 3 to 6 cycles in the study by Roschewski et al. (see evidence section).

Cycle 1

Drug Dose Route Day
Prednisolone 60 mg/m2 TWICE a day * PO 1 to 5
Rituximab 375 mg/m2 IV infusion 1
DOXOrubicin 10 mg/m2 CIV over 24 hours (loaded with etoposide and vinCRISTine) ** 1 to 4
vinCRISTine 0.4 mg/m2 CIV over 24 hours (loaded with etoposide and DOXOrubicin) ** 1 to 4
Etoposide 50 mg/m2 CIV over 24 hours (loaded with DOXOrubicin and vinCRISTine) ** 1 to 4
CYCLOPHOSPHamide 750 mg/m2 IV infusion 5
Filgrastim 5 micrograms/kg Subcut 6 and continue daily until neutrophil recovery

* Prednisolone administered twice a day as per Bartlett et al.1 however dosing frequency may be adjusted based on patient tolerability. Dosing may require rounding to the nearest tablet strength to enable delivery of a measurable dose.

** See clinical information for further details about drug compatibilities.

Note:

  • The treatment schedule shows doses for cycle 1 ONLY. The doses for each cycle are determined by the ANC nadir of the previous cycle. Subsequent cycles may require dose adjustments as per dose-adjustment paradigm; see dose modifications section.
  • In aggressive NHL with HIV, subsequent cycles do not require dose adjustment, or may have adjustments limited to cyclophosphamide only; see evidence section.
Frequency:
21 days 
Cycles:
6 minimum and 8 maximum cycles. 2 cycles to be given beyond complete remission or stable disease.
For Burkitt lymphoma: patients received 3 to 6 cycles in the study by Roschewski et al. (see evidence section).
Notes:

CNS prophylaxis should be considered on a case by case basis for patients with high grade lymphoma who are at an increased risk of CNS relapse. See evidence section for diffuse large B-cell lymphoma for more details.

Drug status:

Filgrastim: (PBS authority opens in a new tab or window)

All other drugs in this protocol are on the PBS general schedule opens in a new tab or window

Prednisolone is available as 25 mg, 5 mg and 1 mg tablets

Cost:
~ $970 per cycle "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). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

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.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

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, growth factor support 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

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Prednisolone 60 mg/m2 (PO) TWICE a day on days 1 to 5.* Take with food.
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
DOXOrubicin 10 mg/m2 (CIV over 24 hours) loaded with vinCRISTine and etoposide in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours **
vinCRISTine 0.4 mg/m2 (CIV over 24 hours) loaded with DOXOrubicin and etoposide in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours **
Etoposide 50 mg/m2 (CIV over 24 hours) loaded with DOXOrubicin and vinCRISTine in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours **
Day 2 to 4
Prednisolone 60 mg/m2 (PO) TWICE a day on days 1 to 5.* Take with food.
DOXOrubicin 10 mg/m2 (CIV over 24 hours) loaded with vinCRISTine and etoposide in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours **
vinCRISTine 0.4 mg/m2 (CIV over 24 hours) loaded with DOXOrubicin and etoposide in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours **
Etoposide 50 mg/m2 (CIV over 24 hours) loaded with DOXOrubicin and vinCRISTine in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours **
Day 5
Prednisolone 60 mg/m2 (PO) TWICE a day on days 1 to 5.* Take with food.
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
CYCLOPHOSPHamide 750 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
Day 6
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously once daily starting day 6 and continue until neutrophils are 0.5 x 10 ^9/L above nadir

* One of the doses on day 1 should be taken 60 minutes before rituximab infusion. Prednisolone is administered twice a day as per Bartlett et al.1 however dosing frequency may be adjusted based on patient tolerability. Dosing may require rounding to the nearest tablet strength to enable delivery of a measurable dose.

** See clinical information for further details about drug compatibilities.

Note:

  • The treatment schedule shows doses for cycle 1 ONLY. The doses for each cycle are determined by the ANC nadir of the previous cycle. Subsequent cycles may require dose adjustments as per dose-adjustment paradigm; see dose modifications section.
  • In aggressive NHL with HIV, subsequent cycles do not require dose adjustment, or may have adjustments limited to cyclophosphamide only; see evidence section.

Frequency:
21 days 
Cycles:
6 minimum and 8 maximum cycles. 2 cycles to be given beyond complete remission or stable disease.
For Burkitt lymphoma: patients received 3 to 6 cycles in the study by Roschewski et al. (see evidence section).
  • High grade B-cell lymphoma (including diffuse large B-cell lymphoma) with MYC and BCL-2 or BCL-6 translocation
  • Primary mediastinal diffuse large B-cell lymphoma
  • Burkitt lymphoma
  • Aggressive non-Hodgkin lymphoma in individuals diagnosed with HIV
Safety alert vincristine administration

For safe administration of vincristine refer to the safety alert issued by the Australian Commission on Safety and Quality in Health Care opens in a new tab or window
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.

Hypotension may occur during rituximab infusion. Evaluate individual patient benefits and risks and consider withholding antihypertensive treatments for 12 hours prior to and during, and for one hour after each infusion.

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.
Emetogenicity MODERATE

Suggested default antiemetics have been added to the treatment schedule, and may be substituted to reflect institutional policy.

Even though a combination of an NK1 receptor antagonist, 5HT3, and a steroid is available on the on the PBS for the prevention of nausea and vomiting associated with all moderate to highly emetogenic anti-cancer therapies, we have opted not to include the NK1 in the treatment schedule.  

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
Cumulative lifetime dose of anthracyclines

Cumulative doses should take into account all previous anthracyclines received during a patient’s lifetime (i.e. daunorubicin, doxorubicin, epirubicin, idarubicin and mitoxantrone). 

Criteria for reducing the total anthracycline cumulative lifetime dose include:

  • patient is elderly
  • prior mediastinal radiation
  • hypertensive cardiomegaly
  • concurrent therapy with high dose cyclophosphamide and some other cytotoxic drugs (e.g. bleomycin, dacarbazine, dactinomycin, etoposide, melphalan, mitomycin and vincristine).

Baseline clinical assessments include echocardiogram (ECHO) or gated heart pool scan (GHPS) and electrocardiogram (ECG) evaluation.

Patients with normal baseline cardiac function (left ventricular ejection fraction (LVEF) > 50%) and low risk patients require LVEF monitoring when greater than 70% of the anthracycline threshold is reached or if the patient displays symptoms of cardiac impairment. Post-treatment cardiac monitoring is recommended for patients who have received high levels of total cumulative doses of anthracyclines at the clinician's discretion.

Read more about cardiac toxicity associated with anthracyclines
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
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 opens in a new tab or window from the Australian Government, Department of Health.
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
Compatibility of drugs for DA-R-EPOCH protocol

There are various ways of administering doxorubicin, vincristine and etoposide/etoposide phosphate. e.g. vincristine and doxorubicin as an admixture and etoposide alone or as an admixture containing all three drugs.

Etoposide phosphate is more stable than etoposide in combination with doxorubicin and vincristine.2 Doxorubicin, vincristine and etoposide phosphate as an admixture is compatible and stable for up to 124 hours in a polyolefin-lined bag.2 Doxorubicin, vincristine and etoposide as an admixture is compatible and stable for up to 72 hours in a polyolefin-lined bag.3 

Administration in the outpatient setting via an elastomeric pump is feasible.4
Etoposide conversion factor

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

Consider CNS relapse assessment in patients with high grade lymphoma. 

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

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

Read more about the prevention and management of tumour lysis syndrome.
Pneumocystis jirovecii pneumonia (PJP) prophylaxis

PJP prophylaxis is recommended e.g. trimethoprim/sulfamethoxazole 160/800 mg PO one tablet twice daily, twice weekly (e.g. on Mondays and Thursdays) OR one tablet three times weekly (e.g. on Mondays, Wednesdays and Fridays).

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

­

Read more about antiviral 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 opens in a new tab or window
Biosimilar drug

Read more about biosimilar drugs on the Biosimilar Awareness Initiative opens in a new tab or window page
Blood tests

FBC, EUC, eGFR, LFTs, LDH and BSL baseline, and prior to each treatment. Repeat FBC twice weekly (3 days apart) to determine dose for next cycle. EUC, eGFR, LFTs, LDH and BSL regularly throughout treatment.
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. Possible suboptimal response to inactivated vaccines.

For more information about vaccinations in people with cancer refer to the Australian Immunisation Handbook opens in a new tab or window.
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 fetal 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 opens in a new tab or window
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) opens in a new tab or window 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.
  • Commence treatment on day 21 if ANC is 1.0 x 109/L or higher and platelets is 100 x 109/L or higher.
  • Dose modifications based on 2019 study by Bartlett et al.1, eviQ standard recommendations and individual drug product information.
Dose adjustment paradigm
  • Dose adjustments above starting dose level (Level 1) apply to etoposide, doxorubicin and cyclophosphamide
  • Dose adjustments below starting dose level (Level 1) apply to cyclophosphamide only
  • Measurement of ANC nadir based on twice weekly FBC only (3 days apart). Only use twice weekly FBC for dose-adjustment even if additional FBCs are obtained.

Drugs (mg/m2/day)		 Drug doses per dose level
-3 -2 -1 1* 2 3 4 5 6
Doxorubicin 10 10 10 10 12 14.4 17.3 20.7 24.8
Etoposide 50 50 50 50 60 72 86.4 103.7 124.4
Cyclophosphamide 384 480 600 750 900 1080 1296 1555 1866

*Starting dose level 

Drug doses are based on previous cycle ANC and platelet nadirs:
Notes: 
  • On day 21:
    • start treatment if ANC 1.0 x 109/L or higher and platelets 100 x 109/L or higher
    • delay treatment up to 2 weeks if ANC less than 1.0 x 109/L or platelets less than 100 x 109/L
  • G-CSF may be started and stopped 24 hours before treatment. If counts are still low after 1 week, delay treatment and reduce 1 dose level below last cycle. 
ANC x 109/L (nadir)
0.5 or higher on all measurements Increase 1 dose level above last cycle
less than 0.5 on 1 or 2 measurements Same dose level as last cycle
less than 0.5 on 3 or more measurements Reduce 1 dose level below last cycle
Platelets x 109/L (nadir)
less than 25 Reduce 1 dose level below last cycle
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)		 Cyclophosphamide Doxorubicin Etoposide Rituximab Vincristine Prednisolone*
≥ 60

Full dose

Full dose

Full dose

Full dose

 Full dose

No dose reduction required in kidney dysfunction.

 

 

 

 

 

 

 

 

 

 

 

 

 

 
45 - 59

Full dose

Full dose 

Full dose

Increased risk of adverse events

Full dose 

Full dose
30 - 44

Full dose

Full dose

Reduce by 25%

OR 

Full dose

Increased risk of adverse events

Full dose

Full dose
15 - 29

Full dose

Potential for increased risk of adverse events

Full dose

Reduce by 25%

OR

Full dose^

Increased risk of adverse events

Full dose

Full dose
< 15
(without kidney replacement therapy)

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

Full dose

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

Full dose

Full dose

* This drug was not included in the ADDIKD guideline.

^ This differs from ADDIKD guideline and is based on ADDIKD Lymphoma RCM consensus 2023.
Hepatic impairment
Bilirubin (micromol/L)
20 to 50 Reduce doxorubicin dose by 50% and vincristine dose by 25%. Consider dose reducing etoposide.
51 to 85 Reduce doxorubicin dose by 75% and vincristine dose by 50%. Consider dose reducing etoposide.
greater than 85 Omit doxorubicin and etoposide
Peripheral neuropathy
Motor neuropathy
Grade 2 Reduce vincristine dose by 25%
Grade 3 Reduce vincristine dose by 50%
Grade 4 Omit vincristine
Sensory neuropathy
Grade 3 Reduce vincristine dose by 25%
Grade 4 Omit vincristine

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.

Cyclophosphamide
  Interaction Clinical management
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Increased toxicity of cyclophosphamide possible due to increased conversion to active (and inactive) metabolites Avoid combination or monitor for cyclophosphamide toxicity
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Reduced efficacy of cyclophosphamide possible due to decreased conversion to active (and inactive) metabolites Avoid combination or monitor for decreased clinical response to cyclophosphamide
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney function closely
Amiodarone Possible additive pulmonary toxicity with high-dose cyclophosphamide (i.e. doses used prior to stem cell transplant; 60 mg/kg daily or 120 to 270 mg/kg over a few days) Avoid combination or monitor closely for pulmonary toxicity
Allopurinol, hydrochlorothiazide, indapamide Delayed effect. Increased risk of bone marrow depression; probably due to reduced clearance of active metabolites of cyclophosphamide Avoid combination, consider alternative antihypertensive therapy or monitor for myelosuppression
Ciclosporin Reduced efficacy of ciclosporin due to reduced serum concentration Monitor ciclosporin levels; adjust dosage as appropriate; monitor response to ciclosporin
Suxamethonium Prolonged apnoea due to marked and persistent inhibition of cholinesterase by cyclophosphamide Alert the anaesthetist if a patient has been treated with cyclophosphamide within ten days of planned general anaesthesia
Doxorubicin
  Interaction Clinical management
Cardiotoxic drugs (eg. bevacizumab, calcium channel blockers, propranolol, trastuzumab etc.) Increased risk of doxorubicin-induced cardiotoxicity Avoid combination or monitor closely for cardiotoxicity
Cyclophosphamide Sensitises the heart to the cardiotoxic effects of doxorubicin; also, doxorubicin may exacerbate cyclophosphamide induced cystitis Monitor closely for cardiotoxicity and ensure adequate prophylaxis for haemorrhagic cystitis when combination is used
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs etc.) Additive nephrotoxicity Avoid combination or monitor kidney function closely
Glucosamine Reduced efficacy of doxorubicin (due to induction of glucose-regulated stress proteins resulting in decreased expression of topoisomerase II in vitro) The clinical effect of glucosamine taken orally is unknown. Avoid combination or monitor for decreased clinical response to doxorubicin
CYP2D6 inhibitors (e.g. SSRIs (esp. paroxetine), perhexiline, cinacalcet, doxepin, flecainide, quinine, terbinafine, ritonavir etc.) Increased toxicity of doxorubicin possible due to reduced clearance Monitor for doxorubicin toxicity
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of doxorubicin possible due to reduced clearance Monitor for doxorubicin toxicity
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John's wort etc.) Reduced efficacy of doxorubicin possible due to increased clearance Monitor for decreased clinical response to doxorubicin
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
Prednisolone
  Interaction Clinical management
Antidiabetic agents (e.g. insulin, glibenclamide, glicazide, metformin, pioglitazone, etc) The efficacy of antidiabetic agents may be decreased Use with caution and monitor blood glucose
Azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, posaconazole) Increased toxicity of prednisolone possible due to reduced clearance Avoid combination or monitor for prednisolone toxicity
Oestrogens (e.g. oral contraceptives) Increased toxicity of prednisolone possible due to reduced clearance Avoid combination or monitor for prednisolone toxicity. Dose reduction of prednisolone may be required
Ritonavir Increased toxicity of prednisolone possible due to reduced clearance Avoid combination or monitor for prednisolone toxicity
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
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 opens in a new tab or window and P‑gp opens in a new tab or window inhibitors. If treating VTE, avoid use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window  inhibitors.

Dabigatran: avoid combination with strong P‑gp opens in a new tab or window 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 opens in a new tab or window

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 or address chemical compatibilities related to IV drug preparation and administration. 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 opens in a new tab or window and Australian Injectable Drugs Handbook opens in a new tab or window websites for further information.

eviQ is currently updating the way information is presented in the administration section, if you notice any discrepancies please let us know, via feedback@eviq.org.au.

Day 1

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

Anti-cancer drug patient assessment tool prior to each day of treatment.

Anti-cancer drug induced neuropathy screening tool prior to each treatment.

Prime IV line(s).

Access TIVAD or CVAD.

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

  • baseline weight
  • strict fluid balance
  • dipstick urinalysis prior to treatment

Hydration if prescribed

Prednisolone

Administer prednisolone:
  • orally TWICE a day (morning and midday) on scheduled days
  • to be taken with or immediately after food.

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

Potential adverse events:
  • prednisolone can cause sleep disturbance, if this occurs a daily morning dose is recommended.

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: prednisolone orally 60 mg/m2 (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

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:

  • commence rituximab infusion at 100 mg/hr
  • repeat observations prior to each rate increase
  • 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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Doxorubicin, vincristine and etoposide 

 Extravasation of a vesicant is a medical emergency. Monitor for signs of extravasation during administration as per policy.

Administer doxorubicin, vincristine and etoposide (vesicant):
  • via IV infusion over 24 hours
  • via one line attached to one lumen of the CVAD
  • these drugs are mixed together (by the pharmacy department) in the same bag, check the amount in the bag is the amount prescribed for a 24 hour period only
  • verify the correct rate of infusion via the ambulatory infusion pump
  • read more information about the different ambulatory infusion pumps.

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

Days 2 to 4

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

Anti-cancer drug patient assessment tool prior to each day of treatment.

Anti-cancer drug induced neuropathy screening tool prior to each treatment.

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

  • daily weight
  • daily dipstick urinalysis
  • strict fluid balance

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Prednisolone

Administer prednisolone:
  • orally TWICE a day (morning and midday) on scheduled days
  • to be taken with or immediately after food.

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

Potential adverse events:
  • prednisolone can cause sleep disturbance, if this occurs a daily morning dose is recommended.

Doxorubicin, vincristine and etoposide 

 Extravasation of a vesicant is a medical emergency. Monitor for signs of extravasation during administration as per policy.

Administer doxorubicin, vincristine and etoposide (vesicant):
  • via IV infusion over 24 hours
  • via one line attached to one lumen of the CVAD
  • these drugs are mixed together (by the pharmacy department) in the same bag, check the amount in the bag is the amount prescribed for a 24 hour period only
  • verify the correct rate of infusion via the ambulatory infusion pump
  • read more information about the different ambulatory infusion pumps.

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

Day 5

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

Anti-cancer drug patient assessment tool prior to each day of treatment.

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

  • daily weight
  • daily dipstick urinalysis
  • strict fluid balance

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Prednisolone

Administer prednisolone:
  • orally TWICE a day (morning and midday) on scheduled days
  • to be taken with or immediately after food.

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

Potential adverse events:
  • prednisolone can cause sleep disturbance, if this occurs a daily morning dose is recommended.

Cyclophosphamide

Administer cyclophosphamide:
  • via IV infusion over 30 to 60 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%.
Potential adverse events:
  • rapid infusion can cause dizziness, rhinitis, nausea and perioral numbness, if symptoms develop slow infusion rate.

Deaccess TIVAD or CVAD.

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

Day 6

Anti-cancer drug patient assessment tool prior to each day of treatment.

Filgrastim

  • administer filgrastim by subcutaneous injection once daily at least 24 hours after last dose of chemotherapy and continue until neutrophil recovery

Discharge information

Prednisolone tablets - with written instructions on how to take them.

Antiemetics - as/if prescribed.

Laxatives - ensure patient has prophylactic laxatives.

Growth factor support - as/if prescribed, and arrangements for administration.

Prophylaxis medications - as/if prescribed, i.e. antifungals, antivirals, PJP prophylaxis, tumour lysis prophylaxis.

Patient information

Ensure patient receives protocol patient information sheet.

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

Immediate (onset hours to days)
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Nausea and vomiting

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

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

Anthracycline flare reaction is caused by a localised allergic reaction. It is characterised by erythematous vein streaking, urticaria and pruritus which may occur during drug administration and is often associated with too rapid an infusion. Extravasation must be ruled out if flare occurs.
Flu-like symptoms
Red-orange discolouration of urine

Pink/red/orange discolouration of the urine. This can last for up to 48 hours after some anthracycline drugs.
Taste and smell alteration

Read more about taste and smell changes

Early (onset days to weeks)
Neutropenia

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

Read more about immediate management of neutropenic fever
Thrombocytopenia

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

Read more about thrombocytopenia
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Constipation
Diarrhoea

Read more about treatment induced diarrhoea
Fatigue

Read more about fatigue
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
Oral mucositis

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following anti-cancer treatment, 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 and stomatitis
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
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.

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
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)

Delayed (onset months to years)
Cardiotoxicity

Anthracyclines are the most frequently implicated anti-cancer drugs associated with cardiotoxicity, which typically manifests as a reduction in left ventricular ejection fraction (LVEF), cardiomyopathy, or symptomatic CHF. Anthracycline induced cardiotoxicity has been categorised into acute, early-onset chronic progressive and late-onset chronic progressive and is usually not reversible. The risk of clinical cardiotoxicity increases with a number of risk factors including higher total cumulative doses. 

Read more about cardiac toxicity associated with anthracyclines
Menopausal symptoms

Irregular or absent periods, hot flushes, mood swings, sleep disturbance, night sweats, vaginal dryness, decreased libido and dyspareunia. This is caused by ovarian failure and may be temporary or permanent.
Pulmonary toxicity

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

Read more about pulmonary toxicity associated with anti-cancer drugs

The evidence supporting the use of this protocol in high-grade diffuse large B-cell lymphoma (DLBCL) is summarised in the table below. At present, there is no evidence to support the routine use of DA-R-EPOCH in patients with DLBCL, either germinal centre B-cells (GCB) or non-GCB, without demonstrated MYC rearrangements.5 Failure to identify a survival advantage in all-comers means that there is insufficient evidence to recommend dose intensification in this group at this time. Currently, some of the main areas of interest include (1) improvement of cure rates in poorer prognosis disease, (2) improving outcomes in primary mediastinal B-cell lymphoma, (3) the treatment of Burkitt lymphoma, (4) the treatment of aggressive NHL in HIV-infected individuals.

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase II trials Wilson et al. 20026 Yes No Does not include rituximab
Jermann et al. 20047 Yes No Rituximab 375 mg/m2 day 1, doxorubicin 15 mg/m2 + etoposide 65 mg/m2 + vincristine 0.5 mg as a continuous IV infusion days 2-4, cyclophosphamide 750 mg/m2 day 5 and prednisone 60 mg/m2 orally days 1-14.

Garcia-Suarez et al. 20078

 Yes Yes Prednisone 60 mg/m2 daily
Purroy et al. 20159 Yes - -

Wilson et al. 201210

 Yes Yes -
Garcia-Suarez et al. 201311 Yes - -

Dunleavy et al. 201312

 Yes Yes -

Barta et al. 201213

 Yes No Rituximab 375 mg/m2 given day -2, cyclophosphamide is dose-escalated up to 750 mg/m2, prednisone 60 mg/m2 PO daily days 1-5
Phase III trials  CALGB/Alliance 50303. Bartlett et al. 20191

Yes 

 Yes 

Active Comparator Arm A - R-CHOP 

Experimental Arm B - DA-EPOCH-R

Retrospective studies 

 Petrich et al. 201414 Yes  N/A N/A
Oki et al. 201415 Yes  N/A R-CHOP v R-EPOCH v R-hyper CVAD in patients with double hit lymphoma (DHL) 
Dodero et al. 202216 Yes N/A Double expressor
Othman et al. 202217 Yes N/A R-CHOP v DA-R-EPOCH
Double expressor, excluding double-hit

Case studies 

 Friedberg 201718 Yes  N/A - 
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN July 202219 Yes Yes  - 
BCCA Aug 2020 Yes Yes  -
CCO Jan 2022 Yes  Yes  -

Efficacy

DA-R-EPOCH was prospectively compared to R-CHOP for unselected DLBCL patients in a CALGB trial.1 This prospective phase III study of 491 patients showed more early discontinuations in the DA-R-EPOCH arm with increased toxicity and no difference in either progression-free survival (PFS) (hazard ratio, 0.93; 95% CI, 0.68 to 1.27; p = 0.65) or overall survival (OS) (2-year 86.5% versus 85.7%). Factors such as MYC, BCL2 and BCL6 expression or rearrangement on fluorescence in situ hybridisation (FISH) were not included prospectively and only analysed on a subset of patients, with only three identified cases of double-hit lymphoma (DHL) found. 35 patients with primary mediastinal B-cell lymphoma were included in the analysis.

Figure 1. PFS, OS and PFS by subset in the Phase III Intergroup Trial Alliance/CALGB 503031

© Journal of Clinical Oncology 2019

Several studies have looked at dose intensification utilising DA-R-EPOCH as a means of improving outcomes in patients with non-GCB tumours which have shown poorer response to therapy and inferior survival compared to GCB type DLBCL. Wilson et al. looked at 69 patients with previously untreated DLBCL who received DA-R-EPOCH, and compared outcomes between different prognostic groups according to international prognostic index (IPI) and to germinal centre (GC) vs non-GC phenotype.10 High-risk by IPI had 54% event-free survival (EFS) at 62 months compared with 92% and 87% in the high-intermediate and low-intermediate groups, respectively. EFS was 94% vs 58% for GC vs non-GC phenotype, respectively.

Outcomes in GCB type DLBCL over two trials show 100% EFS at 5 years in HIV-negative GCB DLBCL,10 and 95% EFS at 5 years in HIV-positive GCB DLBCL. A modification of the DA-EPOCH regime substituting high-dose dexamethasone for prednisolone, and administering cycles at 14-day intervals, also achieved encouraging PFS and OS rates, especially in high-risk disease.11

High-grade B-cell lymphoma (including DLBCL) with MYC and BCL-2 or BCL-6 translocations (WHO 2016) 

Garcia-Suarez et al.8 studied 33 patients with poor prognosis previously untreated DLBCL who received DA-R-EPOCH. All patients had at least 2 adverse prognostic factors on the IPI. 24% had bulky disease. Overall response rate (ORR) was 97%, with complete response (CR) 81% and partial response (PR) 16%. Long-term follow-up of this study demonstrated 10-year EFS and OS rates of 47.8% and 63.6%, respectively.9 Patients with BCL6 rearrangement had an OS of 100%, with the authors postulating that the addition of etoposide may downregulate BCL6 expression.

The utility of “aggressive” chemoimmunotherapy regimens in the treatment of double- and triple-hit lymphomas (DHL/THLs) is broadly supported in view of the poor outcomes of such patients with R-CHOP alone.18 There were insufficient numbers of DHL/THLs for post hoc subset analysis in the CALGB study to assess superiority of DA-R-EPOCH over R-CHOP for unselected DLBCL,1 however, there is some data to suggest superior response rates (improved PFS) of “intensive” immunochemotherapy regimens over R-CHOP.14 These retrospective, pooled data appears to support a more intensive regimen (DA-R-EPOCH, hyper CVAD/MA, R-CODOX-M/IVAC), however, utility of one regimen over another is not suggested, and difference in results may be attributed to other issues studied e.g. patient population. Consolidation with autologous stem cell transplant (ASCT) appears not to improve survival in the de novo setting. 

A phase II, multicentre prospective study by Dunleavy et al. examined DA-R-EPOCH in patients with MYC rearranged DLBCL.20 Of the 53 patients treated, 19 patients had sole rearrangement of MYC, and 24 had additional rearrangement of BCL2, BCL6 or both. There were 3 treatment-related deaths. The 48-month EFS and OS were 71% and 76.7% respectively.

Oki et al. published a case series of DHL which included retrospective analysis of 129 patients with DHL confirmed by FISH.15 Similar to the Petrich data,14 there is a suggestion that DA-R-EPOCH is a superior regimen to R-CHOP for DHL, certainly with respect to EFS, (see below) however, this is retrospective data, and relevant biases need to be therefore considered. CNS relapse occurred in 10 - 15%, and CNS prophylaxis could be considered.  

Howlett et al. published a systematic review and meta-analysis of the use of R-CHOP, DA-R-EPOCH and intensive dose chemotherapy protocols such as CODOX-M/R-IVAC, R-hyper CVAD/R-M/C. They included 394 patients from 11 studies in the analysis, of which 180 received R-CHOP, 91 received DA-R-EPOCH, and 123 received dose-intensive protocols. The median PFS for the groups was 12.1, 22.2 and 18.9 months, respectively, with a significant improvement in PFS with DA-R-EPOCH compared to R-CHOP, however, there was no significant improvement in OS.21

Figure 2. (A) Progression-free and (B) overall survival curves estimated from the meta-analysis 21

© British Journal of Haematology 2015

There is interest in determining whether the use of dose escalation confers an advantage in double- or triple-expressor lymphomas. An Italian multicentre retrospective series of 122 sequential patients with double-expressor lymphoma (DEL) treated with DA-R-EPOCH demonstrated 2-year PFS 74% and OS 84%.16 Of these, 19 were double-hit cytogenetics with trend towards poorer survival in this subgroup (66%). TP53 mutation was found in 16 patients with statistically significant poorer PFS (58%) and OS (62%).  A University of California study compared 122 sequential DELs receiving DA-R-EPOCH (61%) or R-CHOP (39%), specifically excluding double-hit. There was no difference between R-CHOP and DA-R-EPOCH for 3-year PFS (33% vs 57%) and OS (72% vs 72%), however it appeared that the poorer PFS in R-CHOP did not translate to reduced OS due to salvage chemotherapy and ASCT.17 Other smaller series similarly have not demonstrated clear advantage in DA-R-EPOCH over R-CHOP in DELs. Thus recommendations remain to consider DA-R-EPOCH in cases demonstrating MYC, BCL2 and/or BCL6 rearrangements only.

CNS prophylaxis

CNS disease poses a particular challenge in patients with DLBCL, including patients with CNS involvement at the time of presentation, as well as the risk of CNS relapse. DA-R-EPOCH does not demonstrate good CNS penetration so additional measures could be considered for patients with CNS involvement, or deemed to be at high risk of CNS involvement. Several strategies have been explored, including use of intrathecal methotrexate incorporated into the DA-R-EPOCH protocol, and use of high-dose methotrexate given in between cycles.22, 23, 24

In the prospective trial of DA-R-EPOCH in DLBCL with MYC rearrangements, IT methotrexate 12 mg was delivered on days 1 and 5 of cycles three to six as CNS prophylaxis for a total of 8 doses.20 There are only small studies evaluating intravenous methotrexate in combination with DA-R-EPOCH. A prospective trial of 47 patients with poor prognostic CD5+ DLBCL delivered four cycles of DA-R-EPOCH followed by two cycles of IV methotrexate at a dose of 3.5 g/m2 on a 14-day cycle, then completed a further four cycles of DA-R-EPOCH.25 Patients did not receive IT methotrexate. The 2-year CNS relapse rate was 9%.  A common practice is to administer 2 doses of IV methotrexate 3.5 g/m2 two weeks apart following completion of the DA-R-EPOCH regimen, however, there are no published studies evaluating efficacy and toxicity with this approach.

Toxicity

DA-R-EPOCH is generally well tolerated, with the major toxicities being neutropenia, febrile neutropenia and thrombocytopenia. Toxic deaths have been rarely reported, and secondary AML has also been rarely reported, usually in pre-treated patients.8

Table 1. Grade 3 and 4 toxicity profile of DA-R-EPOCH8

© British Journal of Haematology 2007

In the phase III trial comparing upfront R-CHOP versus DA-R-EPOCH in unselected patients with DLBCL, there was a significant increase in grade 3-4 toxicities, including haematological, infective and neuropathy in those assigned to DA-R-EPOCH.1

Table 2. Selected treatment-related toxicities that differed by treatment arm1

© Journal of Clinical Oncology 2019

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase II trials Dunleavy et al. 201312 Yes Yes -
Retrospective studies Shah et al. 201726 Yes Yes R-CHOP (n= 56) vs DA-R-EPOCH (n=76)
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN V.5., 2023 Yes Yes -
BCCA April 2023 Yes Yes -
CCO August 2020 Yes Yes -

Efficacy

A single-arm, phase II study showed excellent outcomes using DA-R-EPOCH for 51 patients with newly diagnosed primary mediastinal B-cell lymphoma, with the aim of being able to omit adjuvant mediastinal radiation therapy.12 OS was 97% at 5 years, with 1 death due to secondary acute myeloid leukaemia. EFS was 93%. Only 2 patients did not achieve CR, and these subsequently entered CR after receiving radiation therapy.

A subsequent multicentre, retrospective analysis with propensity scoring of 56 patients receiving R-CHOP and 76 receiving DA-R-EPOCH revealed similar 2-year OS (89% vs 91%).26 Fewer patients receiving DA-R-EPOCH were given consolidative radiation therapy (13.2% versus 58.9% for R-CHOP, p<0.001).

Figure 1. OS and PFS by treatment arm (DA-R-EPOCH and R-CHOP)26

© Br J Haematol 2017

A randomised, open-label, multicentre trial to assess the role of radiation therapy in patients achieving a PET CR post at least 6 cycles of chemoimmunotherapy (R-CHOP, DA-R-EPOCH and others) is ongoing (Clinicaltrials.gov NCT01599559 opens in a new tab or window). The potential to omit radiation therapy is appealing, particularly in younger female patients.

Toxicity

Shah et al. reported that patients receiving DA-R-EPOCH were more likely to develop neutropenic fever (33% vs 13%, P < 0.01) and require hospitalisation for acute toxicities (35% vs 16%, P = 0.02) compared to patients treated with R-CHOP.26 Infection rates were higher in the DA-R-EPOCH arm however this was not statistically significant. There were a total of 13 deaths in the DA-R-EPOCH group, 11 due to progressive lymphoma.

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase II trials Dunleavy et al. 201327 Yes Yes 2 EPOCH-R regimens:
DA-EPOCH-R group (standard dose-adjusted combination in HIV-negative patients) and SC-EPOCH-RR group (lower-dose short-course combination with a double dose of rituximab in HIV-positive patients)
  Roschewski et al. 202028 Yes Yes Low-risk patients: 3 cycles DA-EPOCH-RR (rituximab on day 1 and 5) 
High-risk patient: 6 cycles DA-R-EPOCH + intrathecal CNS prophylaxis (or extended intrathecal treatment if leptomeninges involved)
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN V.5., 2023 Yes Yes -
BCCA April 2023 Yes Yes -
CCO August 2020 Yes Yes -

Efficacy

DA-R-EPOCH has been utilised in the treatment of Burkitt lymphoma in both HIV-positive and HIV-negative patients. Compared to many other Burkitt lymphoma protocols, DA-R-EPOCH is less toxic and shows excellent response rates regardless of HIV status, age or disseminated disease. A single-arm phase II study of 19 HIV-negative patients using DA-R-EPOCH demonstrated 95% freedom from progression (FFP) and 100% EFS.27 A modified (reduced-intensity chemotherapy with double-dose rituximab) "short course" regimen was given to 11 HIV patients, achieving 100% FFP and 90% OS. 

A follow-up multicentre study aimed to risk stratify further with the presence of Stage 3 or more, ECOG PS 2 or more, elevated LDH or tumour >7 cm classified as high-risk.28 High-risk were treated as per the original protocol. Low-risk patients received 2 cycles of DA-R-EPOCH with an extra rituximab dose on day 5, followed by a PET scan. PET-negative patients (n=15) received one further cycle of DA-R-EPOCH with extra rituximab on day 5. PET-positive patients (n=98) received a further four cycles of standard DA-R-EPOCH with IT methotrexate on day 1 and 5. With median follow-up of 58.7 months, EFS for high- and low-risk groups were 84.5% vs 100% respectively.

The IT methotrexate prophylaxis schedule in the DA-R-EPOCH for Burkitt lymphoma in the initial NCI study was 12 mg on day 1 and 5 from cycles three to six.27 In the multicentre study, IT prophylaxis was only given in high-risk disease. Where there was cerebrospinal fluid involvement, active treatment with IT methotrexate 12 mg was administered twice weekly for 4 weeks, once weekly for 6 weeks, and then once monthly for 4 months.28

Figure 1. 4-year EFS of low-risk (C) and high-risk patients (D)28

© Journal of Clinical Oncology 2020

Toxicity

Table 1. Adverse events27

© N Engl J Med 2013

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase II trials Barta et al. 201213 Yes No Rituximab 375 mg/m2 given day -2, cyclophosphamide dose-escalated up to 750 mg/m2, prednisone 60 mg/m2 PO daily days 1-5
Little et al. 200329 Yes No No rituximab; cyclophosphamide dose-escalated up to 750 mg/m2, prednisone 60 mg/m2 PO daily days 1-5
Sparano et al. 202130 Yes No Rituximab 375 mg/m2 given either concurrently prior to EPOCH each cycle, or sequentially (weekly x 6) following completion of all EPOCH
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN V.5. 2023 Yes Yes -
BCCA - N/A - -
CCO - N/A - -

Efficacy

A pooled analysis of aggressive lymphomas in the patients with HIV compared treatment using DA-R-EPOCH with R-CHOP and found improved EFS and OS with DA-R-EPOCH (HRs 0.4 [95% CI 0.23-0.69] and 0.38 [95%CI 0.21-0.69] respectively).13 CD4 counts of < 50 /µL or aaIPI (age-adjusted IPI) were markers of poor outcome.

Earlier studies evaluated DA-EPOCH in this setting.29 This prospective single-arm trial evaluated DA-EPOCH in 39 patients with newly diagnosed AIDS-related lymphoma (80% DLBCL). Antiretroviral therapy was deferred until completion of chemotherapy. Results showed CR in 74% and at median follow-up (53 months) estimated PFS was 73% and OS 60%. 5-year OS for patients with CD4 counts >100 /µL and ≤100 /µL were 87% and 16%, respectively.

Other prospective studies in patients with HIV have used R-EPOCH without dose-adjustments, or adjustments limited to cyclophosphamide only in an effort to reduce toxicities.30 2-year EFS was 78% in patients who received four cycles compared with 85% who received five to six cycles.

Figure. EFS and OS for all patients (A and B), stratified by low risk aaIPI (C and D) and high risk aaIPI (E and F)13

© Cancer 2012

Toxicity

In the pooled analysis of the AIDS Malignancy Consortium treatment mortality rate was 14% for R-CHOP vs 9% for R-EPOCH. Treatment-associated deaths were associated with CD4 count < 40 (Table 1).13

Table 1. Risk of treatment-associated deaths according to baseline CD4 count13

© Cancer 2012

Table 2 lists the rates of adverse effects in the AMC #24 trial.31

Table 2. Grade 3 or 4 adverse events occuring in at least 5% of patients for the entire population by treatment arm31

© Blood 2010

1
Bartlett, N. L., W. H. Wilson, S. H. Jung, et al. 2019. "Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303." J Clin Oncol 37(21):1790-1799.
2
Yuan, P., G. J. Grimes, S. E. Shankman, et al. 2001. "Compatibility and stability of vincristine sulfate, doxorubicin hydrochloride, and etoposide phosphate in 0.9% sodium chloride injection." Am J Health Syst Pharm 58(7):594-598.
3
Wolfe, J. L., L. A. Thoma, C. Du, et al. 1999. "Compatibility and stability of vincristine sulfate, doxorubicin hydrochloride, and etoposide in 0.9% sodium chloride injection." Am J Health Syst Pharm 56(10):985-989.
4
Svirskis, D., S. Behera, N. Naidoo et al. 2019. "Stability of vincristine sulfate, doxorubicin hydrochloride and etoposide phosphate admixtures in polyisoprene elastomeric pump supporting transition of the EPOCH regimen to outpatient care". J Oncol Pharm Pract. 25(4):831-840.
5
Miyazaki, K. 2016. "Treatment of Diffuse Large B-Cell Lymphoma." J Clin Exp Hematop 56(2):79-88.
6
Wilson, W. H., M. L. Grossbard, S. Pittaluga, et al. 2002. "Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy." Blood 99(8):2685-2693.
7
Jermann, M., L. M. Jost, Ch Taverna, et al. 2004. "Rituximab-EPOCH, an effective salvage therapy for relapsed, refractory or transformed B-cell lymphomas: results of a phase II study." Ann Oncol 15(3):511-516.
8
Garcia-Suarez, J., H. Banas, I. Arribas, et al. 2007. "Dose-adjusted EPOCH plus rituximab is an effective regimen in patients with poor-prognostic untreated diffuse large B-cell lymphoma: results from a prospective observational study." Br J Haematol 136(2):276-285.
9
Purroy, N., J. Bergua, L. Gallur, et al. 2015. "Long-term follow-up of dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphoma. A phase II study conducted by the Spanish PETHEMA Group." Br J Haematol 169(2):188-198.
10
Wilson, W. H., S. H. Jung, P. Porcu, et al. 2012. "A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype." Haematologica 97(5):758-765.
11
Garcia-Suarez, J., E. Flores, M. Callejas, et al. 2013. "Two-weekly dose-adjusted (DA)-EPOCH-like chemotherapy with high-dose dexamethasone plus rituximab (DA-EDOCH14-R) in poor-prognostic untreated diffuse large B-cell lymphoma." Br J Haematol 160(4):510-514.
12
Dunleavy, K., S. Pittaluga, L. S. Maeda, et al. 2013. "Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma." N Engl J Med 368(15):1408-1416.
13
Barta, S. K., J. Y. Lee, L. D. Kaplan, et al. 2012. "Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma." Cancer 118(16):3977-3983.
14
Petrich, A. M., M. Gandhi, B. Jovanovic, et al. 2014. "Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis." Blood 124(15):2354-2361.
15
Oki, Y., M. Noorani, P. Lin, et al. 2014. "Double hit lymphoma: the MD Anderson Cancer Center clinical experience." Br J Haematol 166(6):891-901.
16
Dodero, A., A. Guidetti, F. Marino et al. 2022. “Dose-adjusted EPOCH and rituximab for the treatment of double expressor and double-hit diffuse large B-cell lymphoma: impact of TP53 mutations on clinical outcome.” Haematologica. 107(5):1153-1162.
17
Othman, T., J. Penaloza, S. Zhang et al. 2022. “R-CHOP Vs DA-EPOCH-R for Double-Expressor Lymphoma: A University of California Hematologic Malignancies Consortium Retrospective Analysis”. Clin Lymphoma Myeloma Leuk. 22(10):e947-e957
18
Friedberg, J. W. 2017. "How I treat double-hit lymphoma." Blood 130(5):590-596.
19
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) - B-Cell Lymphomas, Version 5.2022
20
Dunleavy, K., M. A. Fanale, J. S. Abramson, et al. 2018. "Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC rearrangement: a prospective, multicentre, single-arm phase 2 study." Lancet Haematol 5(12):e609-e617.
21
Howlett, C., S. J. Snedecor, D. J. Landsburg, et al. 2015. "Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis." Br J Haematol 170(4):504-514.
22
Hall, K. H., E. H. Panjic, K. Valla, et al. 2018. "How to Decide Which DLBCL Patients Should Receive CNS Prophylaxis." Oncology (Williston Park) 32(6):303-309.
23
Kansara, R. 2018. "Central Nervous System Prophylaxis Strategies in Diffuse Large B Cell Lymphoma." Curr Treat Options Oncol 19(11):52.
24
Ferreri, A. J., M. Bruno-Ventre, G. Donadoni, et al. 2015. "Risk-tailored CNS prophylaxis in a mono-institutional series of 200 patients with diffuse large B-cell lymphoma treated in the rituximab era." Br J Haematol 168(5):654-662.
25
Miyazaki, K., N. Asano, T. Yamada et al . 2020. “DA-EPOCH-R combined with high-dose methotrexate in patients with newly diagnosed stage II-IV CD5-positive diffuse large B-cell lymphoma: a single-arm, open-label, phase II study.” Haematologica. 105(9):2308-2315.
26
Shah, N., A. Szabo, S. Huntington et al. 2017. "R-CHOP versus dose-adjusted R-EPOCH in frontline management of primary mediastinal B-cell lymphoma: a multi-centre analysis." Br J Haematol. 180(4):534-544.
27
Dunleavy, K., S. Pittaluga, M. Shovlin, et al. 2013. "Low-intensity therapy in adults with Burkitt's lymphoma." N Engl J Med 369(20):1915-1925.
28
Roschewski, M., K. Dunleavy, J.S. Abramson et al. 2020. “Multicenter study of risk-adapted therapy with dose-adjusted EPOCH-R in adults with untreated Burkitt lymphoma”. J Clin Oncol. 38(22):2519-2529.
29
Little, R. F., S. Pittaluga, N. Grant, et al. 2003. "Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology." Blood 101(12):4653-4659.
30
Sparano, J.A., J.Y. Lee, L.D. Kaplan et al. 2021. “Response-adapted therapy with infusional EPOCH chemotherapy plus rituximab in HIV-associated, B-cell non-Hodgkin's lymphoma.“ Haematologica. 106(3):730-735.
31
Sparano, J.A., J.Y. Lee, L.D. Kaplan et al. 2010. "Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma". Blood 115(15):3008-16

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Version 8

Date Summary of changes
11/04/2024

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

Protocol assessed by eviQ Haematology Reference Committee and deemed suitable to be reviewed as required. Flag added, review date removed. Read more about as required review protocol status in this factsheet.

Version number changed to V.8.

Version 7

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 7.
31/08/2023

Protocol reformatted as multi-indication protocol, for review in 2 years. Updates include:

  • prednisolone dosing note added to treatment schedule
  • note added regarding dosing in subsequent cycles for aggressive NHL in HIV and number of cycles (3 to 6) for Burkitt lymphoma
  • drug compatibility information moved to clinical information section and hydration information added.
  • evidence section reformatted into multi-indication and limited evidence format. 

Version 6

Date Summary of changes
16/03/2021 Dose modifications section updated. Link to dose adjustment paradigm under treatment schedule removed. Version number changed to v.6     
01/10/2021 Drug status updated: rituximab SC is TGA registered but no longer PBS listed.
24/01/2022 Pulmonary toxicity added to side effects.
11/11/2022 Evidence reviewed by Haematology Reference Committee, updates continued out of session.

Version 5

Date Summary of changes
09/03/2020 Biosimilar rituximab added to clinical information. Version number changed to v.5    
27/03/2020

Protocol presented and reviewed at the Haematology Reference Committee meeting. 

  • Updated CNS prophylaxis note.
  • Evidence section updated.

Version 4

Date Summary of changes
11/10/2013 New protocol taken to Haematology Reference Committee meeting.
14/11/2013 Approved and published on eviQ review in 2 years.
29/05/2014 References added to the notes section regarding the compatibility and stability of compounding vincristine + doxorubicin + etoposide/phosphate.
13/08/2014 Added link to ALLG, ANZCTR and Lymphoma Australia website with statement 'Patients with NHL should be considered for inclusion into clinical trials'.
11/09/2015

Reviewed at Haematology Reference Committee meeting with changes as below:

  • Indications section: removed elderly patients and added Burkitt lymphoma.
  • Notes re: outpatient administration being feasible and the need for a separate protocol for CNS prophylaxis added.
  • Added update from phase 3 study.
  • Added section in the evidence on treatment of Burkitt lymphoma.
31/05/2017 Transferred to new eviQ website. Version number change to v.3.Other changes include:
  • diluent volume of vincristine changed from ‘50 to 100 mL’ to ‘50 mL’ as per Australian Injectable Handbook Sixth Edition.
12/03/2018

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.4.
09/07/2018

Protocol presented and reviewed at the May Haematology Reference Committee meeting. Discussion continued over email and protocol approved for publication with the following changes: 

  • Removal of limited evidence flag due to inclusion of phase III trial. 
  • Updated indications to include double- and triple-hit lymphomas 
  • Evidence section updated.
13/09/2019

Protocol presented and reviewed at the Haematology reference committee meeting. 

  • Evidence section updated.
10/10/2019 Clinical information updated with PBS expanded indications for G-CSF. 

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