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Acute myeloid leukaemia azacitidine and venetoclax

 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. 

 Venetoclax azole interaction:

Azole antifungals reduce the clearance of venetoclax. If the combination is used, the dose of venetoclax should be adjusted as outlined in the protocol below.

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

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Cycle 1

Drug Dose Route Day
Venetoclax 100 mg ONCE a day PO 1
Venetoclax 200 mg ONCE a day PO 2
Venetoclax 400 mg ONCE a day PO 3 to 28
Azacitidine 75 mg/m2 Subcut * 1 to 7 **

Cycle 2 and further cycles

Drug Dose Route Day
Venetoclax 400 mg ONCE a day PO 1 to 28
Azacitidine 75 mg/m2 Subcut * 1 to 7 **

*Azacitidine can also be administered as an intravenous infusion. 

**While the dosing schedule for azacitidine is recommended as 7 consecutive days, this is not practical for all cancer units and alternative scheduling may be used i.e. azacitidine for 5 days, followed by 2 day weekend break, followed by azacitidine for 2 days.rr

Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity
Notes:
  • Tumour lysis syndrome (TLS), which may be life threatening or fatal, has been reported in patients treated with venetoclax. TLS prophylaxis, stringent blood chemistry monitoring and adherence to dose modifications for toxicity is imperative. TLS blood monitoring is recommended at baseline and 6-8 hrs after each dose during dose escalation and at 24 hours after maximum intended dose reached. If clinical or biochemical TLS occurs, the next dose of treatment should be held until evidence of TLS resolves.
  • It is the recommendation of the Haematology Reference Committee that venetoclax treatment is initiated as an inpatient during dose escalation during cycle 1.
Drug status:

Azacitidine: (PBS authority)

Venetoclax: is TGA registered but not PBS listed

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

Cost:
~ $14,950 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
Venetoclax 100 mg (PO) ONCE a day

with food. Swallow tablet(s) whole with a glass of water.
Granisetron 2 mg (PO) 60 minutes before azacitidine
Azacitidine 75 mg/m2 (Subcut) Inject subcutaneously*. Roll the syringe between the palms to re-suspend. Rotate the site of injection.
Day 2
Venetoclax 200 mg (PO) ONCE a day

with food. Swallow tablet(s) whole with a glass of water.
Granisetron 2 mg (PO) 60 minutes before azacitidine
Azacitidine 75 mg/m2 (Subcut) Inject subcutaneously*. Roll the syringe between the palms to re-suspend. Rotate the site of injection.
Day 3 to 7
Venetoclax 400 mg (PO) ONCE a day

with food. Swallow tablet(s) whole with a glass of water.
Granisetron 2 mg (PO) 60 minutes before azacitidine
Azacitidine 75 mg/m2 (Subcut) Inject subcutaneously*. Roll the syringe between the palms to re-suspend. Rotate the site of injection.
Day 8 to 28
Venetoclax 400 mg (PO) ONCE a day

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

Cycle 2 and further cycles

Day 1 to 7
Venetoclax 400 mg (PO) ONCE a day

with food. Swallow tablet(s) whole with a glass of water.
Granisetron 2 mg (PO) 60 minutes before azacitidine
Azacitidine 75 mg/m2 (Subcut) Inject subcutaneously*. Roll the syringe between the palms to re-suspend. Rotate the site of injection.
Day 8 to 28
Venetoclax 400 mg (PO) ONCE a day

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

*Azacitidine can also be administered as an intravenous infusion. 

Note: While the dosing schedule for azacitidine is recommended as 7 consecutive days, this is not practical for all cancer units and alternative scheduling may be used i.e. azacitidine for 5 days, followed by 2 day weekend break, followed by azacitidine for 2 days.rr 

Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity

Cycle 1

Drug Dose Route Day
Venetoclax 100 mg ONCE a day PO 1
Venetoclax 200 mg ONCE a day PO 2
Venetoclax 400 mg ONCE a day PO 3 to 28
Azacitidine 75 mg/m2 Subcut * 1 to 7 **

Cycle 2 and further cycles

Drug Dose Route Day
Venetoclax 400 mg ONCE a day PO 1 to 28
Azacitidine 75 mg/m2 Subcut * 1 to 7 **

*Azacitidine can also be administered as an intravenous infusion. 

**While the dosing schedule for azacitidine is recommended as 7 consecutive days, this is not practical for all cancer units and alternative scheduling may be used i.e. azacitidine for 5 days, followed by 2 day weekend break, followed by azacitidine for 2 days.rr

Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity
Notes:
  • Tumour lysis syndrome (TLS), which may be life threatening or fatal, has been reported in patients treated with venetoclax. TLS prophylaxis, stringent blood chemistry monitoring and adherence to dose modifications for toxicity is imperative. TLS blood monitoring is recommended at baseline and 6-8 hrs after each dose during dose escalation and at 24 hours after maximum intended dose reached. If clinical or biochemical TLS occurs, the next dose of treatment should be held until evidence of TLS resolves.
  • It is the recommendation of the Haematology Reference Committee that venetoclax treatment is initiated as an inpatient during dose escalation during cycle 1.
Drug status:

Azacitidine: (PBS authority)

Venetoclax: is TGA registered but not PBS listed

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

Cost:
~ $14,950 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
Venetoclax 100 mg (PO) ONCE a day

with food. Swallow tablet(s) whole with a glass of water.
Granisetron 2 mg (PO) 60 minutes before azacitidine
Azacitidine 75 mg/m2 (Subcut) Inject subcutaneously*. Roll the syringe between the palms to re-suspend. Rotate the site of injection.
Day 2
Venetoclax 200 mg (PO) ONCE a day

with food. Swallow tablet(s) whole with a glass of water.
Granisetron 2 mg (PO) 60 minutes before azacitidine
Azacitidine 75 mg/m2 (Subcut) Inject subcutaneously*. Roll the syringe between the palms to re-suspend. Rotate the site of injection.
Day 3 to 7
Venetoclax 400 mg (PO) ONCE a day

with food. Swallow tablet(s) whole with a glass of water.
Granisetron 2 mg (PO) 60 minutes before azacitidine
Azacitidine 75 mg/m2 (Subcut) Inject subcutaneously*. Roll the syringe between the palms to re-suspend. Rotate the site of injection.
Day 8 to 28
Venetoclax 400 mg (PO) ONCE a day

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

Cycle 2 and further cycles

Day 1 to 7
Venetoclax 400 mg (PO) ONCE a day

with food. Swallow tablet(s) whole with a glass of water.
Granisetron 2 mg (PO) 60 minutes before azacitidine
Azacitidine 75 mg/m2 (Subcut) Inject subcutaneously*. Roll the syringe between the palms to re-suspend. Rotate the site of injection.
Day 8 to 28
Venetoclax 400 mg (PO) ONCE a day

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

*Azacitidine can also be administered as an intravenous infusion. 

Note: While the dosing schedule for azacitidine is recommended as 7 consecutive days, this is not practical for all cancer units and alternative scheduling may be used i.e. azacitidine for 5 days, followed by 2 day weekend break, followed by azacitidine for 2 days.rr 

Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity

Indication:

  • Acute myeloid leukaemia in patients deemed unfit for intensive chemotherapy

Exclusions:

  • Patients with myelofibrosis associated AML
Caution with oral anti-cancer drugs

Select links for information on the safe prescribing, dispensing and administration of orally administered anti-cancer drugs. 

Read more about the COSA guidelines and oral anti-cancer therapy
Emetogenicity MODERATE

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

Note: due to the risk of opportunistic infection daily, dexamethasone which is usually recommended for moderately emetogenic chemotherapy has been omitted in this protocol.

For patients with a prior episode of chemotherapy induced nausea or vomiting, a NK1 receptor antagonist is available on the PBS in combination with a 5HT3 antagonist and steroid (which may be omitted). 

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
Injection site reactions

Injection site reactions are common with subcutaneous azacitidine. Ensure injection sites are rotated and that new injections are at least 2.5 cm from the previous site.
Gastrointestinal toxicity

Both diarrhoea and constipation are common side effects of treatment. 

Patients should be monitored closely, and prophylactic or symptom control anti-diarrhoeal/laxatives prescribed accordingly. 
Tumour lysis risk

Tumour lysis syndrome (TLS), including renal failure requiring dialysis and fatal events, has occurred in patients with high tumour burden or high leukaemic burden being treated with venetoclax. Consider initiating venetoclax treatment as an inpatient for at risk patients.

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

See Tumour lysis prophylaxis and monitoring during venetoclax treatment.

If adverse events occur venetoclax interruption or discontinuation is recommended. See dose modifications section below.
Antifungals and antivirals

There are no specific recommendations for the use of antifungal or antiviral prophylaxis with this treatment. The use of prophylaxis should be at the discretion of the treating clinician and based on patient risk factors and local guidelines.

Read more about antifungal and antiviral prophylaxis
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

FBC, EUC, LFTs, LDH and urate at baseline. 

TLS prophylaxis and stringent blood chemistry monitoring daily during dose escalation phase of venetoclax ​and adherence to dose modifications for toxicity is imperative.

Repeat FBC, EUC, LFTs, LDH and urate prior to each cycle and throughout treatment 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
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. 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.
  • The haematological dose modifications in this section are based on the study by DiNardo et al.r and venetoclax PI.
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

Manage TLS per institutional guidelines and withhold venetoclax dose until recovery. For more information, see Prevention and management of tumour lysis syndrome.
Haematological toxicity 
Bone marrow assessment at the end of cycle Recommend a bone marrow assessment between days 21-28 of the first cycle. If marrow blasts have been cleared (<5%),  withhold venetoclax until commencement of cycle 2. If persistent AML is detected, cycle 2 should commence and an end of cycle bone marrow repeated.
Incomplete count recovery after cycle 1

If the patient has responded to treatment with <5% marrow blasts, withhold the next cycle until ANC ≥0.5 x 109/L and platelets ≥50 x109/L or up to 14 days after cycle completion. If neutrophils have not recovered by day 35, commence G-CSF thrice weekly to assist marrow recovery. If haematologic recovery has not occurred by day 42, further treatment is at the discretion of the treating haematologist.

Cycle 2 onwards:
ANC <0.5 x 109/L for ≥1 week (not due to underlying disease)

Withhold venetoclax and commence next cycle when ANC ≥0.5 x 109/L and platelets ≥50 x109/L. Commence next cycle at the same venetoclax dose level if recovery occurs within 14 days of ceasing venetoclax.
If the time to recovery after ceasing venetoclax exceeds 14 days, reduce the duration of venetoclax by 7 days for subsequent cycles (e.g. from 28 days to 21 days to 14 day to 10 days).

Venetoclax may interrupted at the discretion of the haematologist and intermittent G-CSF commenced if ANC <0.2 x 109/L until recovery to ANC ≥0.5 x 109/L.
Cycle 5 onwards:

If haematologic recovery has not occurred 14 days after completing therapy

Withhold next cycle and monitor and assess counts every 7 days or as needed.

If haematologic recovery takes > 21 days after completing therapy, consider a reduction in the azacitidine dose according to bone marrow cellularity.
  % dose of azacitidine next cycle
Bone marrow cellularity Recovery > 21 days
15 to 50% 50%
< 15% 33%
Hepatic impairment
Hepatic dysfunction

Severe (Child-Pugh C)

Reduce venetoclax dose by 50% and monitor for signs of toxicity
No formal studies have been conducted in patients with hepatic impairment receiving azacitidine
Renal impairment
Unexplained clinically significant elevations in serum creatinine or blood urea nitrogen (BUN) Delay next cycle until values return to normal or baseline and reduce azacitidine by 50% for the next cycle
Unexplained reduction in serum bicarbonate levels to less than 20 mmol/L

Reduce azacitidine by 50%

No dose adjustments of venetoclax necessary, however patients are at greater risk of TLS.  Intensive TLS monitoring and prophylaxis may be required during venetoclax dose titration phase
Severe renal impairment (creatinine clearance <30 mL/min)

Azacitidine contraindicated according to the Australian product information. However, its use has been reported in patients with CrCl<30mL/min and is associated with a higher incidence of toxicity.r

There is no data available for venetoclax in patients with severe renal impairment
Concomitant use with CYP3A4 inhibitor or P-gp inhibitor
Dose escalation phase (Cycle 1 days 1 to 4)
Strong CYP3A4 inhibitor

Modify dose to:

  • Day 1: 10 mg
  • Day 2: 20 mg
  • Day 3: 50 mg
  • Day 4: 100 mg or less
Moderate CYP3A4 inhibitor or P-gp inhibitor

Reduce daily venetoclax dose by at least 50%
Post escalation phase (Cycle 1 day 5 onwards)
Strong CYP3A4 inhibitor Reduce venetoclax dose to 100 mg or less*
Moderate CYP3A4 inhibitor or P-gp inhibitor Reduce venetoclax dose by at least 50% 

* Note: It is consensus of the reference committee, that if venetoclax 50 mg strength is unavailable, consider an early bone marrow assessment  on day 21. Withhold venetoclax if blast clearance is documented until commencement of cycle 2.

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:  

Azacitidine
No formal clinical drug interaction studies with azacitidine have been conducted
Venetoclax
  Interaction Clinical management
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, fluvoxamine, grapefruit juice, ritonavir, seville oranges etc.) Increased toxicity of venetoclax and increased risk of TLS at initiation and during dose escalation possible due to increased exposure

Avoid concomitant use with CYP3A inhibitors and consider alternative treatments.
If combination must be used, monitor patients closely and reduce venetoclax dose (see Dose modifications table).

Any venetoclax dose used prior to initiating a CYP3A4 inhibitor may be resumed 2 to 3 days after discontinuation of the inhibitor.

Avoid grapefruit products, seville oranges and starfruit during venetoclax treatment.
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 and reduce venetoclax dose (see Dose modifications table).
P-glycoprotein 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
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

Days 1 to 7

Approximate treatment time: Administer as an inpatient during dose escalation of venetoclax (initial); subcutaneous injection (subsequent)

General patient assessment prior to each treatment.

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

  • daily weight
  • daily urinalysis
  • strict fluid balance input and output

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Venetoclax

  • administer orally ONCE daily with food on days 1 to 28 (continuously)
  • 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.

Azacitidine

Prior to administration:
  • allow refrigerated drug to warm to room temperature for up to 30 minutes prior to administration
  • ensure there is an air bubble of 0.3-1.0 mL in between the syringe plunger and drug to ensure full administration of the desired volume.
Administer azacitidine:
  • via subcutaneous injection on days 1 to 7
  • vigorously roll the syringe between the palms until a uniform, cloudy suspension is achieved
  • rotate sites for each injection (thigh, abdomen, upper arm)
  • new injections should be given at least 2.5 cm from the previous site.

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

Days 8 to 28

This is an oral treatment

Venetoclax

  • administer orally ONCE daily with food on days 1 to 28 (continuously)
  • 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 as prescribed.
Antidiarrhoeals
  • Antidiarrhoeals as prescribed.
Laxatives
  • Ensure patient has prophylactic laxatives.
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)
Headache
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Injection-site reactions

Inflammation of or damage to the tissue surrounding the area where a drug was injected.
Metabolism and electrolyte imbalance

Tumour lysis syndrome, hyperphosphataemia, hyperkalaemia, hypocalcaemia and hyperuricaemia may occur with venetoclax.
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting

Early (onset days to weeks)
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
Atrial fibrillation
Constipation
Diarrhoea

Read more about treatment induced diarrhoea
Fatigue

Read more about fatigue
Fever
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
Respiratory tract infection
Thrombocytopenia

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

Read more about thrombocytopenia

Late (onset weeks to months)
Anaemia

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

Read more about anaemia

Acute myeloid leukaemia (AML) frequently affects older adults who are unsuitable for intensive therapies and is often associated with a poor prognosis and short survival. Azacitidine and venetoclax is a potent combination therapy that offers an opportunity to improve the previously dismal prognosis of these patients.

The evidence supporting this protocol comes from the VIALE-A studyr, a phase 3, multicentre, double blind, randomised controlled trial, involving 431 patients with AML, ineligible for standard induction therapy who had not received prior treatment. Patients with favourable cytogenetics and myelofibrosis associated AML were excluded. Patients of median age 76 years from 134 sites in 27 countries participated from February 2017 to May 2019 and were randomised in a 2:1 ratio to receive azacitidine 75 mg/m2 subcutaneously or intravenously, and either venetoclax 400 mg target dose (286 patients) or placebo (145 patents) in 28-day cycles. Daily dose escalation of venetoclax was done in cycle 1, following the dosing schedule established in earlier phase 1 trialsrr (100 mg day 1, 200 mg day 2, then the 400 mg target dose from day 3).  All patients were hospitalised for tumour lysis prophylaxis consisting of an oral uric acid reducing agent and oral hydration 72 hours prior to venetoclax, intravenous hydration 24 hours before venetoclax commencement.

The primary end point was overall survival (OS). Secondary end points included complete remission (CR), event-free survival (EFS) and composite complete remission(CRc)/complete remission with incomplete haematological recovery(CRi).

Clinical experience among patients with myelofibrosis associated AML remains minimal. Severe hypoplasia and prolonged pancytopenia has been noted in such patients. Therefore, it is recommended that patients with extensive myelofibrosis are excluded from treatment until more data is published.

Efficacy

Azacitidine and venetoclax therapy is an effective and well-tolerated combination therapy for upfront treatment of elderly AML and has been found to be effective in AML with a variety of mutations. Following preclinical data suggesting synergistic activity between hypomethylating agents and venetoclax, a phase 1b study looked at the safety and preliminary efficacy of azacitidine/decitabine and venetoclax combination in elderly patients over age 65, with previously untreated AML, featuring intermediate or poor risk cytogenetics, unsuitable for standard induction therapy.r 

DiNardo et al.r confirmed the superiority of the venetoclax/azacitidine combination over azacitidine alone. The median duration of follow up was 20.5 months, OS 14.7 months (95% confidence interval [CI], 11.9 to 18.7) compared to 9.6 months (95% CI, 7.4 to 12.7) and statistically significant (p<0.001) better remission rate for the combination (hazard ratio for death, 0.66; 95% CI, 0.52 to 0.85; P<0.001). EFS was 9.8 months (95% CI, 8.4 to 11.8) in the combination group and 7.0 months (95% CI, 5.6 to 9.5) in the group receiving azacitidine alone (hazard ratio for death, 0.63; 95% CI, 0.50 to 0.80; P<0.001). 36.7% of patients receiving combination therapy achieved CR, compared to 17.9% of the patients receiving azacitidine alone (P<0.001), duration of CR was 17.5 months (95% CI, 15.3 to NR) and 13.3 months (95% CI, 8.5 to 17.6).Treatment continued until disease progression or unacceptable toxicity. Patients receiving combination therapy received a median of 7 cycles, compared to 4.5 in the control group.

Fig 1: Overall survivalr

©NEJM 2020

Overall, this study and its predecessors provided evidence for an effective treatment for elderly AML patients.rrr

Toxicity

Gastrointestinal toxicity, particularly nausea (in 44% of the patients in the azacitidine–venetoclax group and 35% of those in the control group), constipation (in 43% and 39%, respectively), diarrhoea (in 41% and 33%), and vomiting (in 30% and 23%), cytopenias (grade 3 or higher thrombocytopenia in 45% vs 38%; neutropenia in 42% vs 28%) and febrile neutropenia (42% vs 19%) were more prevalent with the combination treatment group and, as such, transfusion dependence was more common in the azacitidine/venetoclax combination group. Treatment delays between cycles and reduction in treatment duration from 28 to 21 days happened in 53% in the azacitidine-venetoclax group and 28% of the control group. Tumour lysis presenting as transient biochemical changes requiring simple measures and not interrupting dosing, occurred in 1% of patients during venetoclax dose escalation phase. Treatment interruption due to adverse events occurred in 72% patients with combination treatment compared to 57% in the control group. 30-day mortality was similar at 7% in the azacitidine venetoclax group and 6% in the control group. 

Fig 2: Adverse Eventsr

©NEJM 2020

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Bibliography

DiNardo, C. D. and A.H. Wei. 2020. "How I treat acute myeloid leukemia in the era of new drugs." Blood. 135(2):85-96

The acute myeloid leukemia (AML) treatment landscape has changed substantially since 2017. New targeted drugs have emerged, including venetoclax to target B-cell lymphoma 2, midostaurin and gilteritinib to target FLT3, and ivosidenib and enasidenib to target mutant isocitrate dehydrogenase 1 and 2, respectively. Other additions include reapproval of gemtuzumab ozogomycin to target CD33, glasdegib to target the hedgehog pathway, and a liposomal formulation of daunorubicin and cytarabine (CPX-351). Genomically heterogeneous AML has a tendency to evolve, particularly under selective treatment pressure. For decades, treatment decisions have largely centered around chemotherapy drug intensity. Physicians now have access to an increasing number of drugs with novel mechanisms of action and distinctive side-effect profiles. Key issues faced by hematologists in this era of new drugs include (1) the timely identification of actionable mutations at diagnosis and at relapse; (2) deciding which drug to use among several therapeutic options; and (3) increasing awareness of how to anticipate, mitigate, and manage common complications associated with these new agents. This article will use 3 case presentations to discuss some of the new treatment challenges encountered in AML management, with the goal of providing practical guidance to aid the practicing physician.

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Version 2

Date Summary of changes
15/06/2021 Granisetron added to treatment schedule to align with other azacitidine protocols.

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Date Summary of changes
23/10/2020 New protocols presented at Haematology Reference Committee meeting.

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18 May 2022