3811-Chronic lymphocytic leukaemia bendamustine and rituximab

Patients with leukaemia should be considered for inclusion into clinical trials. Link to ALLG website and ANZCTR website.

Treatment schedule Treatment schedule

Overview
Detail

Cycle 1

Drug	Dose	Route	Day
Rituximab	375 mg/m²	IV infusion *	1
Bendamustine	90 mg/m²	IV infusion	1 and 2

Cycle 2 to 6

Drug	Dose	Route	Day
Rituximab	500 mg/m²	IV infusion *	1
Bendamustine	90 mg/m²	IV infusion	1 and 2

* From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,600 mg. Note: the 1,600 mg subcutaneous product is currently not available in Australia. For more information see the Chronic lymphocytic leukaemia subcutaneous rituximab document.

Frequency:: 28 days

Cycles:: 6 unless disease progression or unacceptable toxicity

Drug status:

Rituximab: (PBS authority)

Rituximab SC: TGA registered but not PBS listed.

Bendamustine is TGA registered but not PBS listed for this indication.

Cost:: ~ $4,630 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
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 *
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. **

Cycle 2 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	500 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
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. **

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

Frequency:: 28 days

Cycles:: 6 unless disease progression or unacceptable toxicity

Treatment schedule - Overview

Cycle 1

Drug	Dose	Route	Day
Rituximab	375 mg/m²	IV infusion *	1
Bendamustine	90 mg/m²	IV infusion	1 and 2

Cycle 2 to 6

Drug	Dose	Route	Day
Rituximab	500 mg/m²	IV infusion *	1
Bendamustine	90 mg/m²	IV infusion	1 and 2

Frequency:: 28 days

Cycles:: 6 unless disease progression or unacceptable toxicity

Drug status:

Rituximab: (PBS authority)

Rituximab SC: TGA registered but not PBS listed.

Bendamustine is TGA registered but not PBS listed for this indication.

Cost:: ~ $4,630 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.

Treatment schedule - Detail

Cycle 1

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 *
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. **

Cycle 2 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	500 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
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. **

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

Frequency:: 28 days

Cycles:: 6 unless disease progression or unacceptable toxicity

Indications and patient population

Previously untreated CD20 positive B-cell chronic lymphocytic leukaemia (CLL)
- Alternative therapy should be considered for patients with 17p deletion.

Clinical information

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
Subcutaneous rituximab (CLL)	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 1,600 mg. Note: the 1,600 mg subcutaneous product is currently not available in Australia.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 Chronic lymphocytic leukaemia rituximab subcutaneous
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.
Biosimilar drug	Read more about biosimilar drugs on the Biosimilar Awareness Initiative page
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.
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.
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, including BCG, MMR, zoster and varicella 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.
Effects of cancer treatment on fertility	Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive potential prior to commencing treatment. Read more about the effect of cancer treatment on fertility

Dose modifications

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 and reference committee consensus. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

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

Haematological toxicity
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%

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

Interactions

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:

MIMS - interactions tab (includes link to a CYP-450 table) (login required)
Australian Medicines Handbook (AMH) – interactions tab (login required)
Micromedex Drug Interactions (login required)
Cancer Drug Interactions
Cytochrome P450 Drug Interactions

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).

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

Administration

Day 1

Approximate treatment time: 8 hours (initial); 4 to 6 hours (subsequent)

Safe handling and waste management

Safe administration

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

Hydration if prescribed.

Treatment - Time out

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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Chemotherapy - Time out

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

Safe handling and waste management

Safe administration

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.

Chemotherapy - Time out

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)

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.

Side effects

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)
Flu-like symptoms
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
Headache
Taste and smell alteration	Read more about taste and smell changes
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

Early (onset days to weeks)
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
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 neutropenia
Thrombocytopenia	A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding. Read more about thrombocytopenia
Fatigue	Read more about fatigue
Diarrhoea	Read more about treatment induced diarrhoea
Anorexia	Loss of appetite accompanied by decreased food intake. Read more about anorexia
Constipation
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.
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
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.

Late (onset weeks to months)
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)
Anaemia	Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. Read more about anaemia

Evidence

The evidence supporting this protocol is provided by a phase 3 multicentre non-inferiority international randomised trial by Eichhorst et al. involving 564 patients comparing bendamustine and rituximab with fludarabine, cyclophosphamide and rituximab (FCR) in patients with symptomatic non-del (17p) chronic lymphocytic leukaemia (CLL).^r Patients were randomly assigned to receive 6 cycles of either FCR (fludarabine 25 mg/m² for 3 days, cyclophosphamide 250 mg/m² for 3 days and rituximab 375 mg/m² on day 0 for cycle 1 and then 500 mg/m² day 1 for further cycles) or bendamustine and rituximab (bendamustine 90 mg/m² for 2 days and rituximab as per FCR dosing). The primary endpoint was progression-free survival (PFS) with the objective to assess non-inferiority of bendamustine and rituximab to standard therapy.^r

Efficacy

After a median follow up of 37.1 months, the median PFS for bendamustine and rituximab at 41.7 months which did not meet criteria for non-inferiority compared with FCR at 55.2 months (HR 1.643, 90.4% CI 1.308-2.064). However, PFS in age >65 was not significantly different between both groups.^r

Figure 1: Progression-free survival for (A) all patients (B) per age of FCR vs. bendamustine and rituximab^r

Toxicity

Toxicities of bendamustine and rituximab are similar to that described in other studies in indolent lymphoma. However, when compared with FCR there was less severe infection.

Table 1: Comparison of severe adverse events for all patients^r

	Bendamustine and rituximab	FCR
Death	N = 29	N = 30
Severe infection CTCAE ≥ 3	N = 74	N = 111
Grade ≥ 3 neutropenia	59%	85%

Figure 2: Adverse events for all patients^r

References References

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History

Version 1

Date	Summary of changes
01/09/2020	This protocol was briefly in the ID 3794 Bendmustine and rituximab multi indication protocol prior to being developed into a new protocol with the correct rituximab dose increasing from cycle 2. Approved and published on eviQ. Review in 1 year.
21/10/2020	Note added that the 1,600mg subcutaneous product is not available in Australia.
01/10/2021	Drug status updated: rituximab SC is TGA registered but no longer PBS listed.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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First approved:: 1 September 2020
Review due:: 31 December 2021

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/3811

18 May 2022