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Acute myeloid leukaemia low dose cytarabine 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.

This protocol is not exportable and does not have a calculator.

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

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Cycle 1

Drug Dose Route Day
Venetoclax 100 mg PO 1
Venetoclax 200 mg PO 2
Venetoclax 400 mg PO 3
Venetoclax 600 mg PO 4 to 28
Cytarabine (Ara-C) 20 mg/m2 ONCE a day Subcut 1 to 10

Cycle 2 and further cycles

Drug Dose Route Day
Venetoclax 600 mg PO 1 to 28
Cytarabine (Ara-C) 20 mg/m2 ONCE a day Subcut 1 to 10
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.
  • Consider initiation as an inpatient during dose escalation with cycle 1.
  • It is the view of the reference committee that a bone marrow assessment be considered on day 21 of cycle 1 for all patients to guide dose and duration of venetoclax treatment for subsequent cycles.
Drug status:

Cytarabine: PBS general schedule

Venetoclax: TGA approved but not PBS listed for this indication

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

Cost:
~ $10,970 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 tablets whole with a glass of water.
Cytarabine (Ara-C) 20 mg/m2 (Subcut) ONCE a day subcutaneously.
Day 2
Venetoclax 200 mg (PO) ONCE a day with food. Swallow tablets whole with a glass of water.
Cytarabine (Ara-C) 20 mg/m2 (Subcut) ONCE a day subcutaneously.
Day 3
Venetoclax 400 mg (PO) ONCE a day with food. Swallow tablets whole with a glass of water.
Cytarabine (Ara-C) 20 mg/m2 (Subcut) ONCE a day subcutaneously.
Day 4 to 10
Venetoclax 600 mg (PO) ONCE a day with food. Swallow tablets whole with a glass of water.
Cytarabine (Ara-C) 20 mg/m2 (Subcut) ONCE a day subcutaneously.
Day 11 to 28
Venetoclax 600 mg (PO) ONCE a day with food. Swallow tablets whole with a glass of water.

Cycle 2 and further cycles

Day 1 to 10
Venetoclax 600 mg (PO) ONCE a day with food. Swallow tablets whole with a glass of water.
Cytarabine (Ara-C) 20 mg/m2 (Subcut) ONCE a day subcutaneously.
Day 11 to 28
Venetoclax 600 mg (PO) ONCE a day with food. Swallow tablets whole with a glass of water.
Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity

Cycle 1

Drug Dose Route Day
Venetoclax 100 mg PO 1
Venetoclax 200 mg PO 2
Venetoclax 400 mg PO 3
Venetoclax 600 mg PO 4 to 28
Cytarabine (Ara-C) 20 mg/m2 ONCE a day Subcut 1 to 10

Cycle 2 and further cycles

Drug Dose Route Day
Venetoclax 600 mg PO 1 to 28
Cytarabine (Ara-C) 20 mg/m2 ONCE a day Subcut 1 to 10
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.
  • Consider initiation as an inpatient during dose escalation with cycle 1.
  • It is the view of the reference committee that a bone marrow assessment be considered on day 21 of cycle 1 for all patients to guide dose and duration of venetoclax treatment for subsequent cycles.
Drug status:

Cytarabine: PBS general schedule

Venetoclax: TGA approved but not PBS listed for this indication

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

Cost:
~ $10,970 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 tablets whole with a glass of water.
Cytarabine (Ara-C) 20 mg/m2 (Subcut) ONCE a day subcutaneously.
Day 2
Venetoclax 200 mg (PO) ONCE a day with food. Swallow tablets whole with a glass of water.
Cytarabine (Ara-C) 20 mg/m2 (Subcut) ONCE a day subcutaneously.
Day 3
Venetoclax 400 mg (PO) ONCE a day with food. Swallow tablets whole with a glass of water.
Cytarabine (Ara-C) 20 mg/m2 (Subcut) ONCE a day subcutaneously.
Day 4 to 10
Venetoclax 600 mg (PO) ONCE a day with food. Swallow tablets whole with a glass of water.
Cytarabine (Ara-C) 20 mg/m2 (Subcut) ONCE a day subcutaneously.
Day 11 to 28
Venetoclax 600 mg (PO) ONCE a day with food. Swallow tablets whole with a glass of water.

Cycle 2 and further cycles

Day 1 to 10
Venetoclax 600 mg (PO) ONCE a day with food. Swallow tablets whole with a glass of water.
Cytarabine (Ara-C) 20 mg/m2 (Subcut) ONCE a day subcutaneously.
Day 11 to 28
Venetoclax 600 mg (PO) ONCE a day with food. Swallow tablets whole with a glass of water.
Frequency:
28 days 
Cycles:
Continuous until disease progression or unacceptable toxicity
  • Acute myeloid leukaemia in previously untreated patients ineligible for intensive chemotherapy.
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 minimal or low

No routine prophylaxis required. If patients experience nausea and/or vomiting, consider using the low emetogenic risk regimen.

Read more about preventing anti-cancer therapy induced nausea and vomiting
Cytarabine syndrome

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

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.
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.
Hepatitis B screening and prophylaxis

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

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

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

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

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

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

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

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

Clinical TLS

OR

Blood chemistry changes for more than 48 hours

Manage TLS as per institutional guidelines and withhold venetoclax dose until recovery. For more information, see Prevention and management of tumour lysis syndrome.
Haematological toxicity
ANC x 109/L
Less than 0.5
 

Occurrences prior to achieving remission:

Consider interrupting treatment if neutropenia is considered clinically high risk.* Commence prophylactic anti-infectives if clinically indicated.

Occurrences after remission and lasting more than 7 days:

1st occurrence: delay treatment until recovery, then resume current dose. Consider adding G-CSF if clinically indicated.

2nd and subsequent occurrence: delay treatment until recovery and reduce venetoclax duration by 7 days for each subsequent cycle. Consider adding G-CSF if clinically indicated.
Platelets x 109/L
Less than 25

Occurrences prior to achieving remission:

Consider interrupting treatment if thrombocytopenia is considered clinically high risk. Administer platelet transfusion and/or antifibrinolytic agents if clinically indicated.

Occurrences after remission and lasting more than 7 days:

1st occurrence: delay treatment until recovery, then resume current dose.

2nd and subsequent occurrence: delay treatment until recovery and reduce venetoclax duration by 7 days for each subsequent cycle.

* If neutropenia occurs during cycle 1, consider a bone marrow assessment at Day 21 of cycle 1.

Renal impairment
Creatinine clearance (mL/min)
30 to 80 No dose adjustments necessary, however patients are at greater risk of TLS.  Intensive TLS monitoring and prophylaxis may be required during venetoclax dose titration phase
Less than 30

There is no data available for venetoclax in patients with severe renal impairment.

Updated pharmacokinetic studies included in product information for venetoclax suggest no dose modifications are required if CrCl >15mL/min.
Hepatic impairment
Hepatic dysfunction

Moderate

 No dose modifications necessary.

Severe 

 Reduce venetoclax dose by 50% and monitor for signs of toxicity.
Concomitant use with CYP3A4 inhibitor or P-gp inhibitor
Dose titration phase (Cycle 1 days 1 to 3)
Strong CYP3A4 inhibitors (e.g. azole antifungals)

Modify dose to 

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

Reduce daily venetoclax dose by at least 50%
Post titration phase (Cycle 1 day 4 onwards)
Strong CYP3A4 inhibitor (e.g. azole antifungals)

Reduce venetoclax dose to 50mg **
Moderate CYP3A4 inhibitor or P-gp inhibitor Reduce venetoclax dose by at least 50% 

**Note: Consider an early bone marrow assessment on day 21. If blast clearance is documented, withhold venetoclax until commencement of cycle 2. Resume venetoclax for subsequent cycles and, at the discretion of haematologist, either reduce venetoclax duration by 7 days per cycle or extend overall duration of cycle by 7 days.

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:  

Cytarabine
  Interaction Clinical management
Cytidine deaminase (CDA) inhibitors (e.g. cedazuridine) Potential increased effect/toxicity of cytarabine due to reduced clearance Avoid combination or monitor for increased cytarabine effect/toxicity
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

eviQ provides safe and effective instructions on how to administer cancer treatments. However, eviQ does not provide every treatment delivery option, and is unable to provide a comprehensive list of cancer treatment agents and their required IV line giving set/filter. There may be alternative methods of treatment administration, and alternative supportive treatments that are also appropriate. Please refer to the individual product information monographs via the TGA website for further information.

Days 1 to 10

Approximate treatment time: Consider administering as an inpatient during dose escalation of venetoclax with cycle 1.

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

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.

Cytarabine

  • administer via subcutaneous injection
  • localised reactions at the injection site can occur
    • treat with warm compress
  • rotate the injection site each time. 

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

Days 11 to 28

This is an oral treatment

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.

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.
Cytarabine subcutaneous injections
  • Cytarabine subcutaneous injections with written instruction on how to administer.
Antiemetics
  • Antiemetics if required or prescribed. 
Prophylaxis medications
  • Prophylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antifungals, antivirals.
Patient information
  • Ensure patient receives patient information sheet.

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

Immediate (onset hours to days)
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)
Neutropenia

Abnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. 

Read more about immediate management of neutropenic fever
Thrombocytopenia

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

Read more about thrombocytopenia
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
Cytarabine (Ara-C) syndrome

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

Read more about treatment induced diarrhoea
Fatigue

Read more about fatigue
Fever
Oral mucositis

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

Read more about oral mucositis
Respiratory tract infection

Late (onset weeks to months)
Anaemia

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

Read more about anaemia

There are two pivotal publications exploring the utility of low dose cytarabine (LDAC) and venetoclax in combination for acute myeloid leukaemia (AML) in patients not suitable for intensive induction chemotherapy.

Firstly, an international phase Ib/II study evaluating safety and preliminary efficacy of venetoclax with LDAC in older adults (≥60 years) with previously untreated AML and ineligible for intensive chemotherapy (n=82).r Patients were treated with venetoclax 600 mg daily (Day 1 to 28) and LDAC 20 mg/m2 (Day 1 to 10). The study included patients with prior treatment of myelodysplastic syndrome (MDS), including hypomethylating agents (HMA). Key endpoints were tolerability, safety, response rates, duration of response, and overall survival (OS).  Median age was 74 (63 to 90 years), 49% had secondary AML, 29% had prior HMA, and baseline mutations in p53, FLT3, IDH1/2, and NPM1 were detected in 14%, 23%, 25%, and 13% of patients, respectively.

Secondly, an international phase III randomised, double-blind placebo-controlled trial for newly diagnosed patients with AML (age >18 years, median age 76 years) not suitable for intensive induction chemotherapy (VIALE-C).r In this study, 211 patients were randomised 2:1 to venetoclax 600 mg daily (D1-28) plus LDAC 20 mg/m2 (Day 1 to 10) or placebo plus LDAC. The primary endpoint was OS, with key secondary endpoints including, response rate, transfusion independence, and event-free survival (EFS). Similar to the phase Ib/II study, 38% had secondary AML, and 20% had received prior HMA treatment.  Baseline mutations in p53, FLT3, IDH1/2, or NPM1 were detected in 15%, 14%, 16%, and 12% of patients respectively.  Patients were stratified for analysis by baseline intermediate or poor cytogenetic risk, mutations in p53, IDH1/2, FLT3, or NPM1, and other key baseline prognostic factors.

Efficacy

In the phase Ib/II study, the complete remission (CR) plus complete remission with incomplete blood count recover (CRi) rate was 54% with median time to first CR/CRi 1.4 months (range, 0.8 to 14.9 months). Patients with de-novo AML (CR/CRi 71%), intermediate-risk cytogenetics (CR/CRi 63%) and without prior HMA exposure (CR/CRi 62%) had the highest rates of CR/CRi. For patients achieving CR/CRi after venetoclax plus LDAC, the median duration of remission was 8.1 months (95% CI, 5.3 to 14.9 months). The median OS for all patients was 10.1 months (95% CI, 5.7 to 14.2 months). Survival was better for patients achieving CR/CRi, and patients with no response had poor outcomes (Figure 1). Patients without prior HMA exposure had a longer median OS than patients previously treated with HMA (13.5 months vs 4.1 months). Patients with mutations in NPM1 or IDH1/2 had above average CR/CRi rates (89% and 72%, respectively), whereas those with p53 or FLT3 mutations had lower CR/CRi rates (30% and 44%), respectively.r​

Figure 1: Overall survival based on response in the phase Ib/II studyr​

© Journal of Clinical Oncology 2019

In the phase III trial, pre-planned analysis at 12 months (Figure 2A) showed 40% (57 of 143) and 31% (21 of 68) of patients remained alive in the venetoclax and placebo arms, respectively. Median OS for patients treated with venetoclax plus LDAC was 7.2 months vs. 4.1 months for the placebo plus LDAC, with a hazard ratio (HR) (venetoclax vs. placebo) of 0.75 (95% CI, 0.52-1.07). Additional follow up at 18 months (Figure 2B) showed majority of patients passed the median OS in both arms (8.4 months for venetoclax plus LDAC vs 4.1 months for placebo plus LDAC). HR between venetoclax vs placebo treatment arms after this additional follow-up was 0.70 (95% CI, 0.50-0.99, p=0.04).r

Figure 2: Overall survival in the phase 3 trialr

© Blood 2020

Post-hoc analysis of variables revealed significant factors associated with response to venetoclax.  CR/CRi and CR was achieved in 48% and 27% of patients receiving venetoclax, compared to 13% and 7% in the placebo arm.  Responses in the venetoclax arm were faster, with higher remission rates accompanied by a longer median EFS (4.7 months vs. 2 months). Rates of transfusion independence were higher for venetoclax-treated patients compared to those receiving LDAC alone (37% vs. 16%). Patient subgroups with NPM1- (median OS not reached) and IDH1/2-mutant AML (median OS 19.4 months) demonstrated promising survival outcomes.r

Toxicity

The most common grade 3 or 4 adverse events (AEs) in the phase Ib/II study were haematological including febrile neutropenia (42%), thrombocytopenia (38%), neutropenia (27%), and anaemia (27%). The most common non-haematological AEs of any grade or cause were nausea (70%), diarrhoea (49%), hypokalaemia (48%), and fatigue (43%).r

The phase III trial demonstrated similar safety outcomes. Median dose intensity was similar in both arms and 99% of patients in both arms experienced ­1 or more AE. The most frequent ≥ grade 3 AEs were febrile neutropenia, neutropenia, thrombocytopenia and anaemia.  The most common non-haematological AEs of any grade were nausea, hypokalaemia, diarrhoea and constipation. Serious adverse events (SAE), of any grade, were reported in 66% (venetoclax arm) and 62% (placebo arm) of patients. There was a higher percentage of ≥ grade 3 bleeding AEs in the venetoclax arm, although the incidence of fatal bleeding was similar in both arms (1.4% vs. 1.5%).  8 patients (6%) in the venetoclax arm developed TLS (4 clinical, 4 laboratory) and 2 of these were SAEs related to TLS despite receiving TLS prophylaxis according to the protocol.r

Treatment emergent AEs by frequencyr

© Blood 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 1

Date Summary of changes
23/10/2020

New protocol presented at the Haematology Reference Committee meeting.
23/03/2021 Protocol approved by Haematology reference committee. For review in 1 year.
17/06/2021 Clinical information updated to aligned with ID 7 and ID 1182.
21/12/2021

Changed antiemetic clinical information block to minimal or low, to align with new categories. See ID 7 Prevention of anti-cancer therapy induced nausea and vomiting (AINV) v5.
14/06/2022

Protocol reviewed at the Haematology Reference Committee meeting on 11 March 2022, with updates to:

  • drug status - venetoclax is TGA approved but not PBS listed for this indication
  • dose modifications - added (e.g. azole antifungals) for strong CYP3A4 inhibitors & changed day 3 venetoclax dose to 50 mg. Minor change to wording for BM assessment at D21 of cycle 1. Changed post-escalation phase from C1 D5 to C1 D4. Added updated data from venetoclax PI to renal impairment
  • administration - added: consider administering as an inpatient during dose escalation of venetoclax with cycle 1
  • evidence - minor update.

Next review in 2 years.
17/10/2022 Updates made to Dose modifications section - Concomitant use with CYP3A4 inhibitor or P-gp inhibitor - Dose titration phase; amended to "Moderate CYP3A4 inhibitor:"

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31 May 2023