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Mantle cell lymphoma R-BAC (rituximab, bendamustine, cytarabine)

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

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

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

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Cycle 1 to 6

Drug Dose Route Day
Rituximab 375 mg/m2 IV infusion ** 1
Bendamustine * 70 mg/m2 IV infusion 2 and 3
Cytarabine (Ara-C) 500 mg/m2 *** IV infusion 2 to 4
Pegfilgrastim **** 6 mg Subcut 7

*Bendamustine doses in this protocol are expressed as bendamustine hydrochloride

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

*** Dose is based on Visco et al. 2017r

**** Pegfilgrastim or equivalent G-CSF can be used.

Frequency:
28 days 
Cycles:
6 cycles, unless disease progression or unacceptable toxicity.
Drug status:

Bendamustine: (PBS authority)

Rituximab SC: TGA registered but not PBS listed.

Cytarabine and rituxumab: (PBS general schedule)

Cost:
~ $3,100 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 to 6

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Hydrocortisone 100 mg (IV) 30 minutes before treatment
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate**
Day 2
Dexamethasone 8 mg (PO) ONCE a day with or after food (or in divided doses).
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Bendamustine 70 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes *
Cytarabine (Ara-C) 500 mg/m2 (IV infusion) in 250mL sodium chloride 0.9% over 2 hours. Administer 2 hours after the bendamustine infusion on days 2 and 3.***
Day 3
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 70 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes *
Cytarabine (Ara-C) 500 mg/m2 (IV infusion) in 250mL sodium chloride 0.9% over 2 hours. Administer 2 hours after the bendamustine infusion on days 2 and 3.***
Day 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. ****
Cytarabine (Ara-C) 500 mg/m2 (IV infusion) in 250mL sodium chloride 0.9% over 2 hours. Administer 2 hours after the bendamustine infusion on days 2 and 3.***
Day 7
Pegfilgrastim 6 mg (Subcut) inject subcutaneously on day 7.*****

*Bendamustine doses in this protocol are expressed as bendamustine hydrochloride

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

*** Dose is based on Visco et al. 2017r

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

***** Pegfilgrastim or equivalent G-CSF can be used.

Frequency:
28 days 
Cycles:
6 cycles, unless disease progression or unacceptable toxicity.

Cycle 1 to 6

Drug Dose Route Day
Rituximab 375 mg/m2 IV infusion ** 1
Bendamustine * 70 mg/m2 IV infusion 2 and 3
Cytarabine (Ara-C) 500 mg/m2 *** IV infusion 2 to 4
Pegfilgrastim **** 6 mg Subcut 7

*Bendamustine doses in this protocol are expressed as bendamustine hydrochloride

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

*** Dose is based on Visco et al. 2017r

**** Pegfilgrastim or equivalent G-CSF can be used.

Frequency:
28 days 
Cycles:
6 cycles, unless disease progression or unacceptable toxicity.
Drug status:

Bendamustine: (PBS authority)

Rituximab SC: TGA registered but not PBS listed.

Cytarabine and rituxumab: (PBS general schedule)

Cost:
~ $3,100 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 to 6

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Hydrocortisone 100 mg (IV) 30 minutes before treatment
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate**
Day 2
Dexamethasone 8 mg (PO) ONCE a day with or after food (or in divided doses).
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Bendamustine 70 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes *
Cytarabine (Ara-C) 500 mg/m2 (IV infusion) in 250mL sodium chloride 0.9% over 2 hours. Administer 2 hours after the bendamustine infusion on days 2 and 3.***
Day 3
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 70 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes *
Cytarabine (Ara-C) 500 mg/m2 (IV infusion) in 250mL sodium chloride 0.9% over 2 hours. Administer 2 hours after the bendamustine infusion on days 2 and 3.***
Day 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. ****
Cytarabine (Ara-C) 500 mg/m2 (IV infusion) in 250mL sodium chloride 0.9% over 2 hours. Administer 2 hours after the bendamustine infusion on days 2 and 3.***
Day 7
Pegfilgrastim 6 mg (Subcut) inject subcutaneously on day 7.*****

*Bendamustine doses in this protocol are expressed as bendamustine hydrochloride

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

*** Dose is based on Visco et al. 2017r

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

***** Pegfilgrastim or equivalent G-CSF can be used.

Frequency:
28 days 
Cycles:
6 cycles, unless disease progression or unacceptable toxicity.

Indications:

  • Previously untreated CD20-positive, stage III-IV mantle cell lymphoma in patients ineligible for autologous stem cell transplantation

Cautions/exclusions:

  • In-situ mantle cell lymphoma
  • Non-nodal leukaemic mantle cell lymphoma
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 rituximab 
Premedication

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

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

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

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

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

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

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

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

Read more about the rapid infusion of rituximab
Progressive multifocal leukoencephalopathy

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

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

Assess patient for risk of developing tumour lysis syndrome.

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

­

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

­

Read more about antiviral prophylaxis drugs and doses
Antifungal prophylaxis ­

Read more about antifungal prophylaxis drugs and doses.
Growth factor support

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

Access the PBS website
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
Biosimilar drug

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

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

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

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

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

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

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

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

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

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

Haematological toxicity
ANC x 109/L (pre-treatment blood test)
less than 1.0 Delay treatment until recovery and 25% reduction of bendamustine and cytarabine
Platelets x 109/L (pre-treatment blood test)
less than 50 Delay treatment until recovery to greater than 100 and 25% reduction of bendamustine and cytarabine
between 50 and 75 Delay treatment until recovery to greater than 100
Renal impairment
Creatinine clearance (mL/min)​*                              
15 to less than 30      Monitor cytarabine more closely for neurotoxicity. Reconsider the protocol if severe liver dysfunction present concurrently.
less than 15    ​  Caution - If on dialysis consider the type of dialysis and timing of doses in relation to dialysis sessions. Cytarabine doses may need to be adjusted.

* Creatine clearance is based on the KDIGO classification.

Hepatic impairmentr
Hepatic dysfunction                              
Moderate    Reduce bendamustine by 30%
Severe  Bendamustine not recommended. Monitor cytarabine more closely if using full dose. Reconsider the protocol if kidney dysfunction present concurrently.
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).
Cytarabine
No specific clinically significant drug-drug interactions
Rituximab
  Interaction Clinical management
Antihypertensives Additive hypotensive effect Consider withholding antihypertensive medications 12 hours prior to the rituximab 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: 4 hours (initial); 2.5 hours (subsequent)

General patient assessment prior to each day of treatment.

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

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

  • baseline weight 
  • baseline urinalysis 

Pre treatment medication

Verify premedication taken or administer as prescribed.

Rituximab

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

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

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

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

Subsequent infusions:

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

  • 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 ~ 100 mL of sodium chloride 0.9%

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

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

Read more about rapid infusion rituximab

Read more about subcutaneous rituximab

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Days 2, 3

Approximate treatment time: 6 hours

General patient assessment prior to each day of treatment.

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

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Hydration if prescribed.

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 ~ 50mL 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

Administer cytarabine 2 hours AFTER the bendamustine infusion

Cytarabine 

  • administer via IV infusion  over 2 hours
  • flush with ~50 mL of sodium chloride 0.9%

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

Day 4

Approximate treatment time: 2.5 hours

General patient assessment prior to each day of treatment.

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

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Hydration if prescribed.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Cytarabine 

  • administer via IV infusion  over 2 hours
  • flush with ~50 mL of sodium chloride 0.9%

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

Day 7

Pegfilgrastim

Administer pegfilgrastim:
  •  subcutaneously as prescribed

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)
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Cytarabine (Ara-C) syndrome

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

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

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

Read more about oral mucositis
Palmar-plantar erythrodysaesthesia (PPE) - hand-foot syndrome (HFS)

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

Read more about hand-foot syndrome associated with chemotherapy
Skin rash

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

Read more about skin rash

Late (onset weeks to months)
Anaemia

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

Read more about anaemia
Alopecia

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

Read more about alopecia
Cognitive changes (chemo fog)

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

Read more about cognitive changes (chemo fog) 
Progressive multifocal leukoencephalopathy (PML)

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

Read more about progressive multifocal leukoencephalopathy (PML)

A search of the literature did not find strong evidence to support the use of R-BAC in the treatment of mantle cell lymphoma. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the phase II trials from the Fondazione Italiana Linformi.r

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase II trials Visco et al. 2017r Yes Yes -
  Visco et al. 2013r Yes Yes -
Case series Branca et al. 2016 r Yes Yes -
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN V.5 Sep 2021 Yes Yes -
BCCA N/A N/A N/A -
CCO Aug 2020 Yes Yes -

Efficacy

After a median follow up of 35 months, 42 (74%) of patients were alive and disease free. The median progression-free survival was not reached (95% CI, 42 months – not reached), nor was the median duration of response (95% CI, 54 months – not reached). At 2 years, overall survival was 86% (95% CI, 74 – 93%), progression-free survival was 81% (95% CI, 68 – 89%) and duration of response was 90% (95% CI, 85 – 94%). The following figure describes overall survival, progression-free survival and duration of response.r

©  Lancet Haematol. 2017

In post-hoc subgroup analyses, adverse predictive factors affecting progression-free survival were high Mantle Cell Lymphoma International Prognostic Index (MIPI), elevated Ki67 (≥ 30%), and blastoid morphology. In multivariate analysis, elevated Ki67 (HR 7·43, 95% CI, 1.75 – 31.57; p=0·0062) and blastoid variant (HR 4·16, 95% CI, 1.12 – 18.52; p=0·043) were independent predictors of worse progression-free survival. Patients with either of these two features had a significantly worse 2-year progression-free survival (41%, 95% CI, 19 – 63%) compared with patients with classical or pleomorphic variants and low Ki67 (98%, 95% CI, 84 – 100).r

A summary of the evidence supporting the effect of this protocol is below:

Paper Study Phase Patient population Patient Number OS PFS CR

Visco 2017r

 Phase II Previously untreated, ineligible for intensive therapy/transplantation

57

86% at 2 years

81% at 2 years

91%

Visco 2013r

 Phase II Previously untreated or relapsed/refractory, ineligible for intensive therapy/stem cell transplantation, or one prior line (+/- transplantation)

40

20 previously untreated/20 relapsed/refractory

95% (previously untreated)

70% (relapsed/refractory)

95%(previously untreated)

70% (relapsed/refractory)

95% (previously untreated)

70% (relapsed/refractory)

Toxicity

A summary of the toxicities associated with this protocol are included in the tables below. The most clinically significant toxicities for this treatment are reduced blood counts and infection.rr


© Lancet Haematol. 2017


© JCO 2013

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Version 1

Date Summary of changes
27/03/2020 New protocol presented at the March 2020 Haematology reference committee meeting. Discussion continued over email and protocol approved for publication. For review in 1 year.
14/08/20 Irradiated blood components added to the clinical information section.
01/10/2021 Drug status updated: rituximab SC is TGA registered but no longer PBS listed.
22/10/2021 Protocol electronically reviewed by Haematology reference committee. Minor update to evidence. For review in 2 years.

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31 Mar 2023