To see all protocols that comply with the WHO Essential Medicine List 
  1. Home
  2. Haematology and BMT
  3. Lymphoma
  4. Non-Hodgkin lymphoma

Non-Hodgkin lymphoma bendamustine and oBINUTUZumab

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

Please note: dexamethasone supportive medication has been added to the treatment schedule as a default. Patients should be individually monitored and dexamethasone reduced or omitted as clinically appropriate, to avoid overmedication. 

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

On this page
Expand all Collapse all Back to top

Cycle 1

Drug Dose Route Day
oBINUTUZumab 1,000 mg IV infusion 1
Bendamustine * 90 mg/m2 IV infusion 1 and 2
oBINUTUZumab 1,000 mg IV infusion 8 and 15

Cycle 2 to 6

Drug Dose Route Day
oBINUTUZumab 1,000 mg IV infusion 1
Bendamustine * 90 mg/m2 IV infusion 1 and 2

*Bendamustine doses in this protocol are expressed as bendamustine hydrochloride

Frequency:
28 days 
Cycles:
6 depending on response or toxicity
Drug status:

Bendamustine and obinutuzumab: (PBS authority)

Cost:
~ $7,730 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), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

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

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

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

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

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

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

Cycle 1

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Dexamethasone 20 mg (IV) 60 minutes before treatment
oBINUTUZumab 1,000 mg (IV infusion) in 250 mL sodium chloride 0.9%. Start at 50 mg/hr. Rate can be increased by 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Bendamustine 90 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes *
Day 2
Dexamethasone 8 mg (PO) ONCE a day with or after food (or in divided doses).
Bendamustine 90 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes *
Day 3 and 4
Dexamethasone 8 mg (PO) with or after food (or in divided doses). Note: dexamethasone doses on day 3 and 4 may not be required and may be reduced or omitted at the clinician's discretion. **
Day 8 and 15
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment. *** May be omitted - please see below for criteria.
Dexamethasone 20 mg (IV) 60 minutes before treatment. *** May be omitted - please see below for criteria.
oBINUTUZumab 1,000 mg (IV infusion) in 250 mL sodium chloride 0.9%. Start at 100 mg/hr. Rate can be increased by 100 mg/hr every 30 minutes, to a maximum of 400 mg/hr. ****

Cycle 2 to 6

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment. *** May be omitted - please see below for criteria.
Dexamethasone 20 mg (IV) 60 minutes before treatment. *** May be reduced to 8 mg (as antiemetic)- please see below for criteria.
oBINUTUZumab 1,000 mg (IV infusion) in 250 mL sodium chloride 0.9%. Start at 100 mg/hr. Rate can be increased by 100 mg/hr every 30 minutes, to a maximum of 400 mg/hr. ****
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Bendamustine 90 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes *
Day 2
Dexamethasone 8 mg (PO) ONCE a day with or after food (or in divided doses).
Bendamustine 90 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes *
Day 3 and 4
Dexamethasone 8 mg (PO) with or after food (or in divided doses). Note: dexamethasone doses on day 3 and 4 may not be required and may be reduced or omitted at the clinician's discretion. **

*Bendamustine doses in this protocol are expressed as bendamustine hydrochloride

** Link to ID 7 Prevention of chemotherapy induced nausea and vomiting

*** For subsequent obinutuzumab infusions (cycle 1, day 8 onwards):

  • Antihistamine premedication may be omitted for subsequent infusions if no infusion related reactions (IRR) occurred with the previous infusion.
  • Intravenous corticosteroid premedication may be omitted for subsequent infusions if no grade 1 or 2 IRR occurred with the previous infusion. If a grade 3 IRR occurred OR lymphocyte count > 25 x109/L prior to next treatment, intravenous corticosteroid premedication should be continued.

**** If the patient experienced a grade 2 or higher infusion related reaction during the previous administration, commence at 50 mg/hr. The rate of infusion should be titrated up at 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.

Frequency:
28 days 
Cycles:
6 depending on response or toxicity

Cycle 1

Drug Dose Route Day
oBINUTUZumab 1,000 mg IV infusion 1
Bendamustine * 90 mg/m2 IV infusion 1 and 2
oBINUTUZumab 1,000 mg IV infusion 8 and 15

Cycle 2 to 6

Drug Dose Route Day
oBINUTUZumab 1,000 mg IV infusion 1
Bendamustine * 90 mg/m2 IV infusion 1 and 2

*Bendamustine doses in this protocol are expressed as bendamustine hydrochloride

Frequency:
28 days 
Cycles:
6 depending on response or toxicity
Drug status:

Bendamustine and obinutuzumab: (PBS authority)

Cost:
~ $7,730 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), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

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

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

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

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

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

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

Cycle 1

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Dexamethasone 20 mg (IV) 60 minutes before treatment
oBINUTUZumab 1,000 mg (IV infusion) in 250 mL sodium chloride 0.9%. Start at 50 mg/hr. Rate can be increased by 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Bendamustine 90 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes *
Day 2
Dexamethasone 8 mg (PO) ONCE a day with or after food (or in divided doses).
Bendamustine 90 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes *
Day 3 and 4
Dexamethasone 8 mg (PO) with or after food (or in divided doses). Note: dexamethasone doses on day 3 and 4 may not be required and may be reduced or omitted at the clinician's discretion. **
Day 8 and 15
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment. *** May be omitted - please see below for criteria.
Dexamethasone 20 mg (IV) 60 minutes before treatment. *** May be omitted - please see below for criteria.
oBINUTUZumab 1,000 mg (IV infusion) in 250 mL sodium chloride 0.9%. Start at 100 mg/hr. Rate can be increased by 100 mg/hr every 30 minutes, to a maximum of 400 mg/hr. ****

Cycle 2 to 6

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment. *** May be omitted - please see below for criteria.
Dexamethasone 20 mg (IV) 60 minutes before treatment. *** May be reduced to 8 mg (as antiemetic)- please see below for criteria.
oBINUTUZumab 1,000 mg (IV infusion) in 250 mL sodium chloride 0.9%. Start at 100 mg/hr. Rate can be increased by 100 mg/hr every 30 minutes, to a maximum of 400 mg/hr. ****
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Bendamustine 90 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes *
Day 2
Dexamethasone 8 mg (PO) ONCE a day with or after food (or in divided doses).
Bendamustine 90 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes *
Day 3 and 4
Dexamethasone 8 mg (PO) with or after food (or in divided doses). Note: dexamethasone doses on day 3 and 4 may not be required and may be reduced or omitted at the clinician's discretion. **

*Bendamustine doses in this protocol are expressed as bendamustine hydrochloride

** Link to ID 7 Prevention of chemotherapy induced nausea and vomiting

*** For subsequent obinutuzumab infusions (cycle 1, day 8 onwards):

  • Antihistamine premedication may be omitted for subsequent infusions if no infusion related reactions (IRR) occurred with the previous infusion.
  • Intravenous corticosteroid premedication may be omitted for subsequent infusions if no grade 1 or 2 IRR occurred with the previous infusion. If a grade 3 IRR occurred OR lymphocyte count > 25 x109/L prior to next treatment, intravenous corticosteroid premedication should be continued.

**** If the patient experienced a grade 2 or higher infusion related reaction during the previous administration, commence at 50 mg/hr. The rate of infusion should be titrated up at 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.

Frequency:
28 days 
Cycles:
6 depending on response or toxicity
  • Previously untreated CD20-positive follicular lymphoma
  • CD20-positive follicular lymphoma in patients refractory to rituximab
Venous access required

IV cannula (IVC) or 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 bendamustine and obinutuzumab
Premedication

The product information states that the premedication for obinutuzumab should consist of an analgesic/antipyretic, an antihistamine and an intravenous corticosteroid for the first initial dose.

For subsequent infusions:

  • Antihistamine premedication may be omitted for subsequent infusions if no infusion related reactions (IRR) occurred with the previous infusion.
  • Intravenous corticosteroid* premedication may be omitted for subsequent infusions if no grade 1 or 2 infusion related reactions (IRR) occurred with the previous infusion. If a grade 3 IRR occurred OR lymphocyte counts > 25 x109/L prior to next treatment, intravenous corticosteroid premedication should be continued.
  • Analgesic/antipyretic premedication is given before all infusions.

A suggested default premedication has been added to the treatment schedule, and may be substituted to reflect institutional policy.

Note: hydrocortisone is not recommended as it has not been effective in reducing the rate of infusion reactions.

* IV corticosteroid (may be substituted by oral corticosteroids if contained within the chemotherapy regimen)
Emetogenicity MODERATE

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

A steroid has been included both as an antiemetic and premedication for hypersensitivity in this protocol.

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
Cardiac toxicity

In patients with cardiac disorders the concentration of potassium in the blood must be closely monitored and ECG measurement must be performed during treatment with bendamustine. Potassium supplementation must be given when K+ < 3.5 mEq/L.

Read more about cardiac toxicity associated with anti-cancer drugs
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.
Obinutuzumab short duration infusion (SDI)

Administration of obinutuzumab by short duration infusion is not in line with the product monograph, however published literature indicates that it can be completed safely in patients who meet the appropriate criteria.

Read more about obinutuzumab short duration infusion
Thrombocytopenia

Severe and life-threatening thrombocytopenia, including acute thrombocytopenia (occurring within 24 hours after the infusion), has been observed during treatment with obinutuzumab. Fatal haemorrhagic events have also been reported in cycle one of treatment.

Patients should be closely monitored for thrombocytopenia throughout treatment, especially during the first cycle.
Correlating the timing of thrombocytopenia after obinutuzumab can assist in differentiating from other causes.
In clinical trials, thrombocytopenia was reported in 10.4% of patients treated with obinutuzumab.
Tumour lysis risk

Assess patient for risk of developing tumour lysis syndrome.

Read more about prevention and management of tumour lysis syndrome.
Infection Prophylaxis

Serious and even fatal infections, have occurred with bendamustine + anti-CD20 treatment, including Pneumocystis jiroveci pneumonia and varicella zoster virus. Prophylaxis should be considered during induction treatment and for 6-12 months post induction, and for 6-12 months beyond the completion of obinutuzumab maintenance therapy.

Consider the use of G-CSF prophylaxis in patients with prolonged neutropenia.
 

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

Read more about antiviral prophylaxis.
Irradiated blood components

The use of irradiated of blood components is recommended for patients receiving this treatment.

Read more about the indications for the use of irradiated blood components
Blood tests

FBC, EUC, LFTs and LDH at baseline, and prior to each cycle and as clinically indicated. Consider mid cycle FBC to determine the need for G-CSF support. 
Hepatitis B screening and prophylaxis

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

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

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

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

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

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

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

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

Haematological toxicity
ANC x 109/L (pre-treatment blood test)
less than 1.0 Delay treatment until recovery
Platelets x 109/L (pre-treatment blood test)
less than 75 Delay treatment until recovery to greater than 100
Renal impairment
Creatinine clearance (mL/min)
greater than 10 No dose reduction

There is limited data available in patients with severe renal impairment

Hepatic impairment
Serum bilirubin (mg/dL) 
less than 1.2 No dose reduction
1.2 to 3.0 Consider reducing bendamustine dose by 30%
> 3.0 bendamustine contraindicated

No data is available in patients with severe hepatic impairment

Non-haematological toxicity
Grade 3 Delay treatment until recovery consider reducing bendamustine dose by 50%

If the toxicity resolves and the previous dose is tolerated the reduced dose may be increased again
Grade 4 Withhold chemotherapy

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

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

Bendamustine
No specific clinically significant drug-drug interactions. No formal clinical drug interaction studies with bendamustine have been conducted however there is potential for CYP1A2 inhibitors (e.g. aciclovir, ciprofloxacin and fluvoxamine).
Obinutuzumab
  Interaction Clinical management
Antihypertensives Additive hypotensive effect Consider withholding antihypertensive medications 12 hours prior to, throughout and 1 hour after the obinutuzumab infusion
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

Approximate treatment time: 7 to 8 hours

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) with sodium chloride 0.9%.

Insert IV cannula or access TIVAD or CVAD.

Hydration if prescribed.

  • baseline weight

Obinutuzumab 

Prior to administration:
  • check baseline observations
  • check for previous adverse events with drug infusions
  • verify premedication has been taken. If not, administer 60 minutes prior to obinutuzumab administration:
    • paracetamol 1000 mg orally AND
    • loratadine 10 mg orally (or similar antihistamine)
    • IV corticosteroid (may be substituted by oral corticosteroids if contained within the chemotherapy regimen)
Initial infusion:
  • commence obinutuzumab infusion at 50 mg/hr for 30 minutes
  • repeat observations prior to each rate increase
  • increase rate by 50 mg/hr every 30 minutes to a maximum of 400 mg/hr if observations are stable
  • flush with ~ 100 mL of sodium chloride 0.9%

Hypotension may occur during obinutuzumab intravenous infusion. Consider withholding antihypertensive medication for 12 hours before and throughout each infusion.

If a patient experiences any grade infusion related reaction (IRR) during infusion, adjust the infusion as outlined below:

Grade 4 (life threatening)

  • stop infusion and permanently discontinue therapy

Grade 3 (severe)

  • temporarily interrupt infusion and treat symptoms
  • upon resolution of symptoms, restart the infusion at no more than half the previous rate (the rate being used at the time that the IRR occurred)
  • if patient dose not experience any further IRR symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment dose.
  • stop infusion and permanently discontinue therapy if patients experience a second occurrence of a grade 3 IRR

Grade 1-2 (mild to moderate)

  • reduce infusion rate and treat symptoms
  • upon resolution of symptoms, continue infusion
  • if patient dose not experience any IRR symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment dose.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Bendamustine

Prior to administration check:
  • blood pressure (hypertensive crisis has been reported with bendamustine, hypertension should be well controlled prior to treatment with bendamustine)
  • baseline ECG, then regularly throughout treatment for patients with cardiac disorders
  • monitor potassium levels throughout treatment, potassium supplements must be given when K+ < 3.5 mEq/L.
Administer bendamustine (irritant with vesicant properties):
  • via IV infusion over 30 to 60 minutes
  • flush with ~ 100 mL of 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
  • hypersensitivity are more common after the first cycle

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

Day 2

Approximate treatment time: 60 minutes

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).

Insert IV cannula or access TIVAD or CVAD.

  • weigh patient before each treatment 

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Bendamustine

Prior to administration check:
  • blood pressure (hypertensive crisis has been reported with bendamustine, hypertension should be well controlled prior to treatment with bendamustine)
  • baseline ECG, then regularly throughout treatment for patients with cardiac disorders
  • monitor potassium levels throughout treatment, potassium supplements must be given when K+ < 3.5 mEq/L.
Administer bendamustine (irritant with vesicant properties):
  • via IV infusion over 30 to 60 minutes
  • flush with ~ 100 mL of 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
  • hypersensitivity are more common after the first cycle

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

Day 8 and 15

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) with sodium chloride 0.9%.

Insert IV cannula or access TIVAD or CVAD.

  • weigh patient before each treatment 

Obinutuzumab

Prior to administration:
  • check baseline observations
  • check for previous adverse events with drug infusions
  • verify premedication has been taken. If not, administer 60 minutes prior to obinutuzumab administration:
  • paracetamol 1000 mg orally AND
  • loratadine 10 mg orally (or similar antihistamine premedication may be omitted for subsequent infusions if no infusion related reactions (IRR) occurred with the previous infusion)
  • IV corticosteroid if a grade 3 IRR occurred with the previous infusion OR lymphocyte counts > 25 x 109 /L prior to next treatment. 
Subsequent infusions: 

If no IRR or a Grade 1 IRR occurred with the previous infusion:

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

If a Grade 2 IRR or higher occurred with the previous infusion: 

  • commence obinutuzumab infusion at 50 mg/hr 
  • repeat observations prior to each rate increase 
  • increase rate by 50 mg/hr every 30 minutes to a maximum of 400 mg/hr if observations are stable
  • flush with ~100 mL of sodium chloride 0.9%

Hypotension may occur during obinutuzumab intravenous infusion. Consider withholding antihypertensive medication for 12 hours before and throughout each infusion. 

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Discharge information

Antiemetics
  • Antiemetics as prescribed.
Prophylaxis medications
  • Prophylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antifungals, antivirals.
Patient information
  • Ensure patient receives patient information sheet.

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

Approximate treatment time: 4 to 5 hours

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) with sodium chloride 0.9%.

Insert IV cannula or access TIVAD or CVAD.

  • weigh patient before each treatment 

Obinutuzumab

Prior to administration:
  • check baseline observations
  • check for previous adverse events with drug infusions
  • verify premedication has been taken. If not, administer 60 minutes prior to obinutuzumab administration:
  • paracetamol 1000 mg orally AND
  • loratadine 10 mg orally (or similar antihistamine premedication may be omitted for subsequent infusions if no infusion related reactions (IRR) occurred with the previous infusion)
  • IV corticosteroid if a grade 3 IRR occurred with the previous infusion OR lymphocyte counts > 25 x 109 /L prior to next treatment. 
Subsequent infusions: 

If no IRR or a Grade 1 IRR occurred with the previous infusion:

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

If a Grade 2 IRR or higher occurred with the previous infusion: 

  • commence obinutuzumab infusion at 50 mg/hr 
  • repeat observations prior to each rate increase 
  • increase rate by 50 mg/hr every 30 minutes to a maximum of 400 mg/hr if observations are stable
  • flush with ~100 mL of sodium chloride 0.9%

Hypotension may occur during obinutuzumab intravenous infusion. Consider withholding antihypertensive medication for 12 hours before and throughout each infusion. 

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Bendamustine

Prior to administration check:
  • blood pressure (hypertensive crisis has been reported with bendamustine, hypertension should be well controlled prior to treatment with bendamustine)
  • baseline ECG, then regularly throughout treatment for patients with cardiac disorders
  • monitor potassium levels throughout treatment, potassium supplements must be given when K+ < 3.5 mEq/L.
Administer bendamustine (irritant with vesicant properties):
  • via IV infusion over 30 to 60 minutes
  • flush with ~ 100 mL of 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
  • hypersensitivity are more common after the first cycle

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

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.

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

  • weigh patient before each treatment 

Bendamustine

Prior to administration check:
  • blood pressure (hypertensive crisis has been reported with bendamustine, hypertension should be well controlled prior to treatment with bendamustine)
  • baseline ECG, then regularly throughout treatment for patients with cardiac disorders
  • monitor potassium levels throughout treatment, potassium supplements must be given when K+ < 3.5 mEq/L.
Administer bendamustine (irritant with vesicant properties):
  • via IV infusion over 30 to 60 minutes
  • flush with ~ 100 mL of 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
  • hypersensitivity are more common after the first cycle

Note: Bendamustine is given only on days 1 and 2 of each 28 day cycle.

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

Discharge information

Antiemetics
  • Antiemetics as prescribed.
Prophylaxis medications
  • Prophylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antifungals, antivirals.
Patient information
  • Ensure patient receives patient information sheet.

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

Immediate (onset hours to days)
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
Headache
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Hypotension

Low blood pressure can occur with this treatment.
Nausea and vomiting

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

Dull ache, cramping or sharp pains are common with some anti-cancer drugs. These are caused by either increased or decreased gastrointestinal motility and can be associated with diarrhoea or constipation.
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Arthralgia and myalgia

Generalised joint pain or and/or stiffness and muscle aches, often worse upon waking or after long periods of inactivity. Can improve with movement. May be mild or severe, intermittent or constant and accompanied by inflammation. 

Read more about arthralgia and myalgia
Asthenia

Physical weakness characterised by loss of strength or lack of energy.
Constipation
Diarrhoea

Read more about treatment induced diarrhoea
Fatigue

Read more about fatigue
Fluid retention and oedema

An excess amount of fluid around the cells, tissues or serous cavities of the body, leading to swelling.
Insomnia
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
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)
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

Previously untreated follicular lymphoma

The evidence for obinutuzumab-bendamustine is predominately derived from the multicentre, phase 3, open labelled GALLIUM study, which compared the combination of obinutuzumab-chemotherapy (G-chemo) versus rituximab-chemotherapy (R-chemo) in previously untreated advanced stage follicular lymphoma.

1202 patients were randomised 1:1 to receive either G-chemo or R-chemo. The choice of chemotherapy regimen was left to investigators discretion between cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); cyclophosphamide, vincristine, and prednisone (CVP); or bendamustine. Responding patients (complete or partial response at the end of induction) continued on to receive maintenance treatment with the same antibody treatment every 2 months for 2 years, until disease progression or withdrawal from the trial. r

Primary end point was progression free survival (PFS), secondary end points included overall response rate at the end of induction therapy, event-free survival, disease-free survival, duration of response, overall survival (OS), time to new anti-lymphoma treatment (TTNAT), and safety. r​

Baseline data of each chemotherapy backbone showed some notable differences between groups. More patients receiving CHOP were in the FLIPI high-risk group (47% compared to 40% in bendamustine and 35% in CVP). Patients in the bendamustine arm had more comorbidities (24% with Charlson comorbid index score ≥1 vs 17% [CHOP] and 19% [CVP]). There was a higher population patient’s ≥ 80 years in the bendamustine and CVP group (3% in both groups) compared to CHOP (1%). r

A secondary analysis of the GALLIUM study was conducted to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction, were assessed prospectively by investigators and an independent review committee (IRC). Pet scans were done in 669 (65%) of 1029 patients enrolled after July 26, 2011, at 103 of the 177 recruiting centres. Results from the investigators and IRC found that PET is a better imaging modality with better predictive ability than contrast-enhanced CT for response assessment.r

Relapsed/refractory follicular lymphoma

The evidence supporting this protocol is provided by a phase 3 multicentre international randomised trial (GADOLIN study) involving 413 patients, refractory to rituximab, randomly assigned to obinutuzumab-bendamustine (G-B) or bendamustine alone (B). This trial however involved all patients with indolent Non Hodgkin’s lymphoma (iNHL), with 335/413 (80%) follicular lymphoma patients.rr

Rituximab refractory was defined as failure to respond to, or progression during any previous rituximab-containing regimen (monotherapy or combined with chemotherapy), or progression within 6 months of the last rituximab dose, in the induction or maintenance treatment settings. Exclusion criteria included previous treatment with bendamustine within 2 years of commencing cycle 1. rr

Median age of the patients with follicular lymphoma in both groups were 63 years of age. 130/164 (79.3%) patients in G-B arm and 124/171 (72.5%) patients in B arm had grade 1 or 2 disease. 115/164 (70.1%) in G-B arm and 129/170 (75.9%) in B arm had intermediate to high risk disease (FLIPI ≥ 2). r

Primary end point was PFS (time from randomization to the earliest of progression, relapse, or death as a result of any cause) as assessed by Independent review committee (IRC).Secondary end points assessed were PFS by investigator, OS (time from randomization to date of death),TTNT, and safety (adverse events [AEs]). r

Of note this study randomises patients to G-B and B monotherapy. It is possible that some patients may have responded to rituximab if rechallenged.

Efficacy

Previously untreated follicular lymphoma (GALLIUM study)

After a median follow up of 41.1 months, there was a significant increase in PFS in patients treated with G-chemo compared to R-chemo (HR, 0.68; 95% CI, 0.54 to 0.87; P =.0016).  No OS benefit was seen between these 2 groups. TTNAT was slightly better in the G-chemo group with 14% needing next line of treatment compared to 20% in the R-chemo group (HR 0.68, 95% CI 0.52-0.90, p=0.007). Complete or partial response rate was not significantly different between the two groups regardless of whether CT imaging or CT plus PET was used. rr

The benefit of obinutuzumab over rituximab was seen with all three chemotherapy backbones with Hazard ratios for investigator-assessed PFS of 0.63 (95% CI, 0.46 to 0.88) for bendamustine, 0.72 (0.48 to 1.10) for CHOP, and 0.79 (0.42 to 1.47) for CVP. r

© Journal of Clinical Oncology 2018

Relapsed/refractory follicular lymphoma (GADOLIN study)

In patients with follicular lymphoma, at median follow-up of 31.8 months, PFS has occurred in 56.7% in the G-B arm compared to 73.1% in the B monotherapy arm. Median PFS was significantly longer in the G-B arm at 25.3 months (95% CI 17.4 - 36.0 months) versus 14.0 months (95% CI 11.3 - 15.3 months). A treatment benefit with G-B also was seen for OS; 23.8% in the G-B arm v 37.4% in the B arm died (HR, 0.58; 95% CI, 0.39 to 0.86; P = 0.0061). TTNT in the G-B arm was more than twice as long as in the B arm (33.6 v 18 months, respectively). r

Of note this study randomises patients to G-B and B monotherapy. It is possible that some patients may possibly respond if given rituximab again.

© Journal of Clinical Oncology 2018

Toxicity

Previously untreated follicular lymphoma (GALLIUM study)

There were more patients with Grade 3-5 AEs on the G-chemo arm compared to R-chemo (75% vs 69% respectively). The most common grade 3-5 AEs were neutropenia, leucopenia, infusion related reactions and pneumonia. Bendamustine group was noted to have higher proportion of serious AEs and fatal AEs. When compared to patients receiving CHOP or CVP patients treated with bendamustine showed marked reductions in CD3+ and CD3+CD4+ T cells seen during induction in both antibody arms, with prolonged recovery during and after maintenance. 

© Journal of Clinical Oncology 2018

Relapsed/refractory follicular lymphoma (GADOLIN study)

Results of the AEs were analysed as a whole (ie all iNHL patients). With the addition of antibody treatment, mild increase in toxicities were seen in the combination arm. Most common AEs of any grade throughout the study in both arms were infusion related reactions (IRRs), nausea and fatigue (mostly grade 1 or 2), and neutropenia (mostly grade 3 or 4). The proportions of patients in the two arms who reported grade 3 to 5 AEs throughout the study was slightly higher in the G-B arm (72.5%) than in the B arm (65.5%) partly due to higher rate of grade 3 and 4 IRRs. Overall frequency of fatal AEs in GADOLIN was similar for the two arms despite a longer treatment period in the G-B arm. Cardiac events were more common in the G-B arm than in the B arm, including those of grades 3 to 5.r

© Journal of Clinical Oncology 2018

[%id%]
[%title%]
[%abstract%]

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

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

Searches can be used when a protocol is scheduled for review or at any time you choose. Please click on this link to access the Pubmed searches.

Access Flinders Filters, a division of the Flinders Digital Health Research Centre at Flinders University to read more about research solutions to searching problems.

Troubleshooting

Occasionally the searches may not display correctly or take too long to load (and will eventually timeout). This may be caused by Internet Explorer being unable to handle long URL's. You can rectify this by using Firefox, Safari or Google chrome. It is always a good idea to clear the cache regularly to ensure you are getting the most up to date search.

Feedback

If you identify any new articles that you believe should be included in the content, please use the feedback button below to inform us of the name of the article(s). 

Version 2

Date Summary of changes
16/05/2022 "Obinutuzumab short duration infusion" block added to clinical information. Version number changed to v.2
11/11/2022 Protocol reviewed electronically by the Haematology Reference Committee, nil changes. Review in 2 years

Version 1

Date Summary of changes
11/03/2019

New protocol developed out of session, discussed by Haematology reference committee (discussed electronically via email).
19/03/2019 Protocol approved and published on eviQ V.1. Review in 1 year. 
15/04/2020 Evidence updated. Protocol for review in 2 years. 
14/08/2020 Irradiated blood componenets added to clinical information.

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

Send feedback for this page

First approved:
Last reviewed:
Review due:

The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/3554

31 Mar 2023