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Chronic lymphocytic leukaemia venetoclax and rituximab

 Warning: Life threatening tumour lysis syndrome with venetoclax:

Tumour lysis syndrome (TLS), which may be life threatening or fatal, has been reported in patients treated with venetoclax.

TLS prophylaxis and stringent blood chemistry monitoring is important. 

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

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Titration Phase (Week 1 to 5)

Drug Dose Route Day
Venetoclax 20 mg ONCE a day PO 1 to 7 (week 1)
Venetoclax 50 mg ONCE a day PO 8 to 14 (week 2)
Venetoclax 100 mg ONCE a day PO 15 to 21 (week 3)
Venetoclax 200 mg ONCE a day PO 22 to 28 (week 4)
Venetoclax 400 mg ONCE a day PO 29 to 35 (week 5)

Cycle 1 (Week 6 to 9)

Drug Dose Route Day
Venetoclax 400 mg ONCE a day PO 1 to 28
Rituximab 375 mg/m2 IV infusion 1

Cycle 2 to 6 (Week 10 to 29)

Drug Dose Route Day
Venetoclax 400 mg ONCE a day PO 1 to 28
Rituximab 500 mg/m2 IV infusion 1

Cycle 7 to 24 (Week 30 onwards)

Drug Dose Route Day
Venetoclax 400 mg ONCE a day PO 1 to 28

Frequency: 28 days 


Cycles: 24 or until disease progression or unacceptable toxicity.

Notes:
  • Tumour lysis syndrome (TLS), which may be life threatening or fatal, have been reported in patients treated with venetoclax.
  • TLS prophylaxis, stringent blood chemistry monitoring and adherence to dose modifications for toxicity is imperative. (see Dose modification)
  • Consider initiating venetoclax treatment as an inpatient for patients with high tumour burden
Drug status:

Venetoclax and rituximab: (PBS authority)

Venetoclax is available as 10 mg, 50 mg and 100 mg tablets

Cost:
~ $3,600 (titration phase) and $10,187 per month (cycle 1 to 6) "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes antineoplastic 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 antineoplastic 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.

Titration Phase (Week 1 to 5)

Day 1 to 7
Venetoclax 20 mg (PO) ONCE a day

with food. Swallow tablets whole with a glass of water.
Day 8 to 14
Venetoclax 50 mg (PO) ONCE a day

with food. Swallow tablet whole with a glass of water.
Day 15 to 21
Venetoclax 100 mg (PO) ONCE a day

with food. Swallow tablet(s) whole with a glass of water.
Day 22 to 28
Venetoclax 200 mg (PO) ONCE a day

with food. Swallow tablet(s) whole with a glass of water.
Day 29 to 35
Venetoclax 400 mg (PO) ONCE a day

with food. Swallow tablet(s) whole with a glass of water.

Cycle 1 (Week 6 to 9)

Day 1
Venetoclax 400 mg (PO)

ONCE a day with food. Swallow tablets whole with a glass of water.
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 to 28
Venetoclax 400 mg (PO)

ONCE a day with food. Swallow tablets whole with a glass of water.

Cycle 2 to 6 (Week 10 to 29)

Day 1
Venetoclax 400 mg (PO)

ONCE a day with food. Swallow tablets whole with a glass of water.
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
Day 2 to 28
Venetoclax 400 mg (PO)

ONCE a day with food. Swallow tablets whole with a glass of water.

Cycle 7 to 24 (Week 30 onwards)

Day 1 to 28
Venetoclax 400 mg (PO)

ONCE a day with food. Swallow tablets whole with a glass of water.

Frequency: 28 days

Cycles: 24 or until disease progression or unacceptable toxicity.

Titration Phase (Week 1 to 5)

Drug Dose Route Day
Venetoclax 20 mg ONCE a day PO 1 to 7 (week 1)
Venetoclax 50 mg ONCE a day PO 8 to 14 (week 2)
Venetoclax 100 mg ONCE a day PO 15 to 21 (week 3)
Venetoclax 200 mg ONCE a day PO 22 to 28 (week 4)
Venetoclax 400 mg ONCE a day PO 29 to 35 (week 5)

Cycle 1 (Week 6 to 9)

Drug Dose Route Day
Venetoclax 400 mg ONCE a day PO 1 to 28
Rituximab 375 mg/m2 IV infusion 1

Cycle 2 to 6 (Week 10 to 29)

Drug Dose Route Day
Venetoclax 400 mg ONCE a day PO 1 to 28
Rituximab 500 mg/m2 IV infusion 1

Cycle 7 to 24 (Week 30 onwards)

Drug Dose Route Day
Venetoclax 400 mg ONCE a day PO 1 to 28

Frequency: 28 days 


Cycles: 24 or until disease progression or unacceptable toxicity.

Notes:
  • Tumour lysis syndrome (TLS), which may be life threatening or fatal, have been reported in patients treated with venetoclax.
  • TLS prophylaxis, stringent blood chemistry monitoring and adherence to dose modifications for toxicity is imperative. (see Dose modification)
  • Consider initiating venetoclax treatment as an inpatient for patients with high tumour burden
Drug status:

Venetoclax and rituximab: (PBS authority)

Venetoclax is available as 10 mg, 50 mg and 100 mg tablets

Cost:
~ $3,600 (titration phase) and $10,187 per month (cycle 1 to 6) "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes antineoplastic 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 antineoplastic 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.

Titration Phase (Week 1 to 5)

Day 1 to 7
Venetoclax 20 mg (PO) ONCE a day

with food. Swallow tablets whole with a glass of water.
Day 8 to 14
Venetoclax 50 mg (PO) ONCE a day

with food. Swallow tablet whole with a glass of water.
Day 15 to 21
Venetoclax 100 mg (PO) ONCE a day

with food. Swallow tablet(s) whole with a glass of water.
Day 22 to 28
Venetoclax 200 mg (PO) ONCE a day

with food. Swallow tablet(s) whole with a glass of water.
Day 29 to 35
Venetoclax 400 mg (PO) ONCE a day

with food. Swallow tablet(s) whole with a glass of water.

Cycle 1 (Week 6 to 9)

Day 1
Venetoclax 400 mg (PO)

ONCE a day with food. Swallow tablets whole with a glass of water.
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 to 28
Venetoclax 400 mg (PO)

ONCE a day with food. Swallow tablets whole with a glass of water.

Cycle 2 to 6 (Week 10 to 29)

Day 1
Venetoclax 400 mg (PO)

ONCE a day with food. Swallow tablets whole with a glass of water.
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
Day 2 to 28
Venetoclax 400 mg (PO)

ONCE a day with food. Swallow tablets whole with a glass of water.

Cycle 7 to 24 (Week 30 onwards)

Day 1 to 28
Venetoclax 400 mg (PO)

ONCE a day with food. Swallow tablets whole with a glass of water.

Frequency: 28 days

Cycles: 24 or until disease progression or unacceptable toxicity.

Indications:

  • Chronic lymphocytic leukaemia (CLL) in patients who have received at least one prior therapy 

Contraindication:

  • Concomitant use of venetoclax and strong CYP3A inhibitors at initiation and during the dose titration phase (see interactions below).
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
Caution with oral antineoplastic agents

Select links for information on the safe prescribing, dispensing and administration of orally administered antineoplastic agents. 

Read more about the COSA guidelines and oral anticancer therapy
Hypersensitivity/infusion related reaction

High risk with 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 LOW

Antiemetics are not routinely required; however should a patient experience 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 may be administered.

Read more about preventing antineoplastic induced nausea and vomiting
Tumour lysis risk

Tumour lysis syndrome (TLS), including renal failure requiring dialysis and fatal, have occurred in patients with high tumour burden treated with venetoclax. Consider initiating venetoclax treatment as an inpatient for patients with high tumour burden.

Assessment of TLS risk, prophylaxis and close monitoring is imperative. 

See Tumour lysis prophylaxis and monitoring during venetoclax treatment

If adverse events occur venetoclax interruption or discontinuation is recommended. See dose modifications section below
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.
Pneumocystis jiroveci pneumonia (PJP) prophylaxis

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

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

Antiviral prophylaxis is recommended.

Read more about antiviral prophylaxis drugs and doses
Growth factor support

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

Access the PBS website
Blood tests

Stringent blood chemistry monitoring during titration phase is imperative. 

Post titration phase, consider FBC, EUC, LFTs, LDH and urate prior to each treatment or 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.
Effects of cancer treatment on fertility

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive age prior to commencing treatment.

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 antineoplastic 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 on venetoclax:

  • If a dose interruption greater than 1 week during the first 5 weeks of the dose titration phase, or greater than 2 weeks after completing the dose titration phase, the risk of tumour lysis syndrome needs to be reassessed to determine if re-initiation with a reduced dose is necessary.  
  •  all dose reductions are calculated as a percentage of the starting dose.
Tumour lysis syndrome (TLS)
Blood chemistry suggestive of TLS

Withhold the next day's venetoclax dose and if resolution occurs within 24 to 48 hours of last dose resume at the same dose

Clinical TLS

OR

Blood chemistry changes for more than 48 hours

Delay treatment until recovery

Resume at lower venetoclax  dose depending on when dose interruption occurred, if dose interruption at:
          400 mg: restart dose at 300 mg
          300 mg: restart dose at 200 mg
          200 mg: restart dose at 100 mg
          100 mg: restart dose at 50 mg
          50 mg: restart dose at 20 mg
          20 mg: restart dose at 10 mg

Continue the reduced dose for 1 week before increasing the dose. Consider ceasing treatment if dose reductions to less than 100 mg occur for more than 2 weeks. 

Read more about Tumour lysis prophylaxis and monitoring during venetoclax treatment
Haematological toxicity
ANC x 109/L
Less than 1.0 with infection or fever
OR
Less than 0.5
 

Delay venetoclax treatment until recovery. Consider adding G-CSF if clinically indicated. 

1st occurrence: resume at the same venetoclax  dose

2nd and subsequent occurrence: resume at lower venetoclax dose depending on when dose interruption occurred, if dose interruption at:
          400 mg: restart dose at 300 mg
          300 mg: restart dose at 200 mg
          200 mg: restart dose at 100 mg
          100 mg: restart dose at 50 mg
          50 mg: restart dose at 20 mg
          20 mg: restart dose at 10 mg
Continue the reduced dose for 1 week before increasing the dose.

A larger venetoclax dose reduction may be necessary at the discretion of the physician. Consider ceasing treatment if dose reductions to less than 100 mg occur for more than 2 weeks. 
Platelets x 109/L
Less than 25

Delay venetoclax treatment until recovery.

1st occurrence: resume at the same venetoclax dose

2nd and subsequent occurrence: resume at lower venetoclax dose depending on when dose interruption occurred, if dose interruption at:
          400 mg: restart dose at 300 mg
          300 mg: restart dose at 200 mg
          200 mg: restart dose at 100 mg
          100 mg: restart dose at 50 mg
          50 mg: restart dose at 20 mg
          20 mg: restart dose at 10 mg

Continue the reduced dose for 1 week before increasing the dose.
​A larger venetoclax dose reduction may be necessary at the discretion of the physician. Consider ceasing treatment if dose reductions to less than 100 mg occur for more than 2 weeks. 
Renal impairment
Creatinine clearance (mL/min)
30 to 50 No dose adjustments necessary
Less than 30 There is no data for venetoclax in patients with severe renal impairment
Hepatic impairment
Hepatic dysfunction 

Moderate

 No dose adjustments necessary

Severe 

 Reduce venetoclax dose by 50% and monitor for signs of toxicity
Concomitant use with CYP3A4 inhibitor
Dose titration phase
Strong CYP3A4 inhibitor Concomitant use with venetoclax is contraindicated
Moderate CYP3A4 inhibitor Reduce venetoclax dose by at least 50% 
Week 6 onwards (post titration phase)
Strong CYP3A4 inhibitor Reduce venetoclax dose by at least 75% 
Moderate CYP3A4 inhibitor Reduce venetoclax dose by at least 50% 
Non-Haematological toxicity
Greater than or equal to grade 3

Delay venetoclax treatment until recovery.

1st occurrence: resume at the same venetoclax dose

2nd and subsequent occurrence: resume at lower venetoclax dose depending on when dose interruption occurred, if dose interruption at:
          400 mg: restart dose at 300 mg
          300 mg: restart dose at 200 mg
          200 mg: restart dose at 100 mg
          100 mg: restart dose at 50 mg
          50 mg: restart dose at 20 mg
          20 mg: restart dose at 10 mg

Continue the reduced dose for 1 week before increasing the dose.
​A larger venetoclax dose reduction may be necessary at the discretion of the physician. Consider ceasing treatment if dose reductions to less than 100 mg occur for more than 2 weeks. 

References & Disclaimer

Rituximab
  Interaction Clinical management
Antihypertensives Additive hypotensive effect Consider withholding antihypertensive medications 12 hours prior to the rituximab infusion
Venetoclax
  Interaction Clinical management
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, fluvoxamine, grapefruit juice, ritonavir, seville oranges etc.) Increased toxicity of venetoclax possible due to reduced clearance

Dose titration phase:

  • Concomitant administration with a strong CYP3A4 inhibitor (e.g. ritonavir, vorinconazole, posaconazole) is contraindicated. 
  • Concomitant administration with a moderate CYP3A4 inhibitor (e.g. ciprofloxacin, fluconazole) should be avoided or alternative treatments considered. If a moderate CYP3A4 inhibitor must be used, venetoclax dose should be reduced by at least 50%. 

 

Week 6 onwards

Once titration phase is complete and steady daily dose achieved venetoclax dose should be:

  • Reduced by at least 75% when administered with a strong CYP3A4 inhibitor.
  • Reduced by at least 50% when administered concomitantly with a moderate CYP3A4 inhibitor.
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St Johns wort etc.) Reduced efficacy of venetoclax due to increased clearance Avoid combination with strong or moderate CYP3A4 inducers, or consider alternative agents with less CYP3A4 induction.
P-glycoprotein inhibitors (e.g. verapamil, ciclosporin) Increased toxicity of venetoclax possible due to reduced clearance

Avoid combination. 
If combination must be used monitor patients closely
P-glycoprotein and BCRP substrates (e.g. digoxin, morphine, topotecan) Venetoclax may alter the absorption of the substrate 

Avoid combination with narrow therapeutic index drugs. 
If combination must be used administer at least 6 hours before venetoclax
Warfarin Increased risk of bleeding Monitor international normalised ratio (INR) closely when used in combination
General
  Interaction Clinical management
Antiepileptics Both altered antiepileptic and antineoplastic 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 antineoplastic 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 10th Edition (updated 2018)

Days 1 to 35

This is an oral treatment

General patient assessment prior to each day of treatment.

  • baseline weight
  • urinalysis each visit

Venetoclax

  • administer orally ONCE daily with food
  • to be swallowed whole with a glass of water; do not break, crush or chew

Note: if a dose is missed and within 8 hours of the usual dose time, it should be taken as soon as the patient remembers. If it is more than 8 hours the patient should not take the missed dose.

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

Discharge information

Venetoclax tablets
  • Venetoclax tablets with written instructions on how to take them.
Antiemetics
  • Antiemetics if required or prescribed. 
Prophylaxis medications
  • Prophylaxis medications (if prescribed) i.e. antivirals, tumour lysis prophylaxis, PJP prophylaxis and medication for constipation.
Patient information
  • Ensure patient receives patient information sheet.

Day 1

Approximate treatment time: 4 to 6 hours (initial); 3 to 4 hours (subsequent) 

General patient assessment prior to each day of treatment.

  • baseline weight 
  • baseline urinalysis 

Insert IV cannula or access port or CVC.

Venetoclax

  • administer orally ONCE daily with food
  • to be swallowed whole with a glass of water; do not break, crush or chew

Note: if a dose is missed and within 8 hours of the usual dose time, it should be taken as soon as the patient remembers. If it is more than 8 hours the patient should not take the missed dose.

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 port or CVC.

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

Days 2 to 28

This is an oral treatment

General patient assessment prior to each day of treatment.

  • urinalysis each visit

Venetoclax

  • administer orally ONCE daily with food
  • to be swallowed whole with a glass of water; do not break, crush or chew

Note: if a dose is missed and within 8 hours of the usual dose time, it should be taken as soon as the patient remembers. If it is more than 8 hours the patient should not take the missed dose.

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

Discharge information

Venetoclax tablets
  • Venetoclax tablets with written instructions on how to take them.
Antiemetics
  • Antiemetics if required or prescribed. 
Prophylaxis medications
  • Prophylaxis medications (if prescribed) i.e. antivirals, tumour lysis prophylaxis, PJP prophylaxis and medication for constipation.
Patient information
  • Ensure patient receives patient information sheet.

Days 1 to 28

This is an oral treatment

General patient assessment prior to each day of treatment.

  • urinalysis each visit

Venetoclax

  • administer orally ONCE daily with food
  • to be swallowed whole with a glass of water; do not break, crush or chew

Note: if a dose is missed and within 8 hours of the usual dose time, it should be taken as soon as the patient remembers. If it is more than 8 hours the patient should not take the missed dose.

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

Discharge information

Venetoclax tablets
  • Venetoclax tablets with written instructions on how to take them.
Antiemetics
  • Antiemetics if required or prescribed. 
Prophylaxis medications
  • Prophylaxis medications (if prescribed) i.e. antivirals, tumour lysis prophylaxis, PJP prophylaxis and medication for constipation.
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 
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Metabolism and electrolyte imbalance

Tumour lysis syndrome, hyperphosphataemia, hyperkalaemia, hypocalcaemia and hyperuricaemia may occur with venetoclax.
Flu-like symptoms

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

Early (onset days to weeks)
Injection-site reaction

Inflammation of or damage to the tissue surrounding the area where a drug was injected.
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
Atrial fibrillation
Fever
Fatigue

Read more about fatigue
Skin rash

Antineoplastic agents 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
Respiratory tract infection
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
Diarrhoea

Read more about treatment induced diarrhoea
Constipation

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)

The evidence supporting this protocol is provided by a phase III multicentre international, open label randomised trial (MURANO) involving 389 patients comparing venetoclax plus rituximab with bendamustine plus rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia (CLL).r

Between March 31, 2014 and September 23, 2015, 389 patients were randomised in a 1:1 ratio. 194 received venetoclax-rituximab and 195 received bendamustine-rituximab. Venetoclax was administered in a 5-week schedule with gradual ramp up from 20 mg daily to 400 mg daily. Rituximab was commenced after the venetoclax ramp-up period (cycle 1: 375 mg/m2; cycle 2 to 6: 500 mg/m2) at 28 day treatment cycles. Venetoclax 400 mg was administered daily continuously for 2 years unless disease progression or toxicity occurs. In the bendamustine-rituximab arm, bendamustine was administered at 70 mg/m2 on day 1 and 2 of 28 day treatment cycles for a total of 6 cycles in combination with the same aforementioned rituximab dosing schedule.r

There was no crossover to venetoclax after disease progression. 

The primary end point was investigator-assessed progression free survival, defined as the time from randomisation to first occurrence of disease progression, relapse or death of any cause. Secondary efficacy end point included independent review committee-assessed progression free survival, investigator-assessed and independent review committee-assessed progression free survival in patients with chromosome 17p deletion, investigator-assessed and independent review committee-assessed overall response rate and complete response rate, overall survival, rates of clearance of minimal residual disease, duration of response, event free survival, and time to next treatment for CLL.r

Efficacy

After a median follow up of 23.8 months, the median progression free survival as assessed by investigator was 17 months in the bendamustine-rituximab arm and not reached in the venetoclax-rituximab group (Figure 1). The 2 year rate investigator-assessed progression free survival was 84.9% (95% CI, 79.1 to 90.6) in the venetoclax-rituximab group and 36.3% (95% CI, 28.5 to 44.0) in the bendamustine-rituximab group (HR for progression or death, 0.17; 95% CI ,0.11 to 0.25 p<0.001).

Figure 1: Kaplan Meier estimates of investigator assessed progression-free survival.

© NEJM 2018

There was consistent benefit in the venetoclax-rituximab group in prespecified subgroups (Figure 2), including 17p deletion, with two year investigator-assessed progression free survival being higher in the venetoclax-rituximab group than the bendamustine-rituximab group (81.5% vs 27.8%; HR 0.13; 95%CI, 0.05 to 0.29). Overall survival was higher in the venetoclax-rituximab group than in the bendamustine-rituximab group, with two year survival being 91.9% and 86.6%, respectively (HR, 0.48; 95% CI, 0.25 to 0.90).

Figure 2: Prespecified subgroup analysis of investigator assessed progression free survival

© NEJM 2018

The investigator assessed overall response rate (ORR) was 93.3% in the venetoclax-rituximab group and 67.7% in the bendamustine-rituximab group. Rate of investigator assessed complete response (CR) or complete response with incomplete haematologic recovery (CRi) was 26.8% in the venetoclax-rituximab group and 8.2% in the bendamustine-rituximab group. Of the 68 patients across the CR/CRi groups, 50 were classified as partial response and one as having stable disease (as assessed by the independent review committee). The main reasons for discordance in the rate of CR/CRi was due to divergent interpretation of residual adenopathy on competed tomography (Figure 3).

Figure 3: Reasons for the lower independent review committee CR/CRi rate relative to the investigator-assessed CR/CRi rate

© NEJM 2018

Toxicity

379 patients (99.2%) had at least one adverse event. 100% in the venetoclax-rituximab group and 98.4% in the bendamustine-rituximab group. Grade 3 or 4 adverse events were reported in 82% of the venetoclax-rituximab group and 70.2% of the bendamustine-rituximab group. The most common grade 3 or 4 adverse event was neutropenia with higher incidence in the venetoclax-rituximab group than in bendamustine-rituximab group (57.7% vs 38.8%), however the incident of grade 3 or 4 febrile neutropenia and infections were lower in the venetoclax-rituximab group. Grade 3 or 4 tumour lysis syndrome was reported in 6 (3.1%) in the venetoclax-rituximab group and in 2 patients (1.1%) in the bendamustine-rituximab group. 

© NEJM 2018

Richter’s transformation was confirmed in 6 patients in the venetoclax-rituximab group and in 5 patients in the bendamustine-rituximab group.

Death occurred in 10 (5.2%) patients in the venetoclax-rituximab group and in 11 (5.9% in the bendamustine-rituximab group (4 fatal infections in each group).

48 discontinued venetoclax and 13 discontinued rituximab in the venetoclax-rituximab arm while 27 discontinued bendamustine-rituximab. 

Follow up data from subsequent publication from Kater et al showed that 130 of the 194 patients randomised to venetoclax-rituximab arm (67%) completed two years of planned venetoclax. 11% had progressive disease, 1% died without progressive disease, 15% withdrew due to adverse events and 6% for other reasons.r

Adverse events (AEs) that lead to withdrawal during combination therapy were neutropenia (2.1%), thrombocytopenia (1.5%), neoplasm (1%), febrile neutropenia, anaemia, autoimmune haemolytic anaemia, acute respiratory failure, appendicitis, peritoneal tuberculosis, pneumonia, pyrexia, status epilepticus and sudden cardiac death, all accounting for 0.5% each. AEs leading to withdrawal during single agent therapy were neoplasms (2.6%), neutropenia (1.5%), thrombocytopenia (1%); whilst ALT increase, ascites, asthenia, autoimmune haemolytic anaemia, Crohn’s disease, diarrhoea, immune thrombocytopenic purpura, hydrothorax, pneumonia, sudden death and vertigo all accounting for 0.5% each.r

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Version 2

Date Summary of changes
27/03/2020 Protocol reviewed at Haematology Reference Committee meeting, severe renal dose modification recommendation added as per product information. Version increased to V.2. Review in 2 years.

Version 1

Date Summary of changes
29/07/2019

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Approved and published on eviQ. Version 1. 

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01 Mar 2021