2043-Induction 7-3 (cytarabine And DAUNOrubicin) - EviQ

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Acute myeloid leukaemia induction 7-3 (cytarabine and DAUNOrubicin)

• ID: 2043 v.3
• Endorsed
• Essential Medicine List EML

  All anti-cancer drugs and essential supportive drugs in this protocol are included on the World Health Organisation (WHO) Model List of Essential Medicines (21st List June 2019).

  Select link for more information and access to the full WHO Model List of Essential Medicines.

• Acute myeloid leukaemia induction 7-3 (cytarabine and DAUNOrubicin)

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This protocol replaces a previous version of the AML Induction 7-3 protocol ID 348 (daunorubicin 50mg/m2 dose) which has been discontinued.

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

Link to Australian National AML Clinical Guideline

Related pages:

• Acute myeloid leukaemia induction 7-3 Ida (cytarabine and iDArubicin)
• Acute myeloid leukaemia induction 7-3 high dose DAUNOrubicin (cytarabine and DAUNOrubicin) SUPERSEDED

On this page

• Treatment schedule
• Indications and patient population
• Clinical information
• Dose modifications
• Interactions
• Administration
• Side effects
• Evidence
• References
• Literature search
• History

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Treatment schedule Treatment schedule

• Overview
• Detail

Drug	Dose	Route	Day
DAUNOrubicin	60 mg/m2	IV	1 to 3 *
Cytarabine (Ara-C) **	100 mg/m2	CIV	1 to 7 *

*The days of administration have been aligned with the ELN and NCCN guidelinesrr

**Cytarabine at a dose of 100 – 200 mg/m2 is acceptable and as per clinician discretionrrrr

Cycles: 1 or 2. Usually given once but may be repeated if remission is not achieved Drug status:

Cytarabine is on the PBS general schedule Daunorubicin is TGA registered but not PBS listed for this indication

Cost: ~ $160 per cycle, excluding daunorubicin. "How this cost is calculated"

The cost displayed on the protocol is an estimated cost 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) and are based on the cost of drug as listed for public hospital use (where applicable). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

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.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

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, growth factor support etc.), infusion times, diluents, volumes, routes of administration and specific bag/container if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy. Please refer to the individual product information monographs via the TGA and Australian Injectable Drugs Handbook websites for further information

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.

eviQ acknowledges that non-PVC, DEHP-free and PUR-free infusion bag/container and line selection recommendations are inconsistent across the literature. eviQ is currently reviewing and considering how we update this information in eviQ protocols. Please refer to the Australian Injectable Drugs Handbook (AIDH) summary document Non-PVC and/or DEHP-free IV infusion bags and sets.

Day 1 to 3
DAUNOrubicin	60 mg/m2 (IV)	over 5 to 15 minutes
Cytarabine (Ara-C)	100 mg/m2 (CIV)	in sodium chloride 0.9% over 24 hours as a continuous infusion

Day 4 to 7
Cytarabine (Ara-C)	100 mg/m2 (CIV)	in sodium chloride 0.9% over 24 hours as a continuous infusion

Note: the days of administration have been aligned with the ELN and NCCN guidelinesrr

Cycles: 1 or 2. Usually given once but may be repeated if remission is not achieved

Treatment schedule - Overview

Drug	Dose	Route	Day
DAUNOrubicin	60 mg/m2	IV	1 to 3 *
Cytarabine (Ara-C) **	100 mg/m2	CIV	1 to 7 *

*The days of administration have been aligned with the ELN and NCCN guidelinesrr

**Cytarabine at a dose of 100 – 200 mg/m2 is acceptable and as per clinician discretionrrrr

Cycles: 1 or 2. Usually given once but may be repeated if remission is not achieved Drug status:

Cytarabine is on the PBS general schedule Daunorubicin is TGA registered but not PBS listed for this indication

Cost: ~ $160 per cycle, excluding daunorubicin. "How this cost is calculated"

The cost displayed on the protocol is an estimated cost 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) and are based on the cost of drug as listed for public hospital use (where applicable). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

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.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

Treatment schedule - Detail

The supportive therapies (e.g. antiemetics, premedications, growth factor support etc.), infusion times, diluents, volumes, routes of administration and specific bag/container if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy. Please refer to the individual product information monographs via the TGA and Australian Injectable Drugs Handbook websites for further information

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.

eviQ acknowledges that non-PVC, DEHP-free and PUR-free infusion bag/container and line selection recommendations are inconsistent across the literature. eviQ is currently reviewing and considering how we update this information in eviQ protocols. Please refer to the Australian Injectable Drugs Handbook (AIDH) summary document Non-PVC and/or DEHP-free IV infusion bags and sets.

Day 1 to 3
DAUNOrubicin	60 mg/m2 (IV)	over 5 to 15 minutes
Cytarabine (Ara-C)	100 mg/m2 (CIV)	in sodium chloride 0.9% over 24 hours as a continuous infusion

Day 4 to 7
Cytarabine (Ara-C)	100 mg/m2 (CIV)	in sodium chloride 0.9% over 24 hours as a continuous infusion

Note: the days of administration have been aligned with the ELN and NCCN guidelinesrr

Cycles: 1 or 2. Usually given once but may be repeated if remission is not achieved

Indications and patient population

• Acute myeloid leukaemia, induction

Clinical information

Venous access	Central venous access device (CVAD) is required to administer this treatment. Read more about central venous access device line selection
Antiemetics for multi-day protocols	Patients being treated with multi-day anticancer protocols should receive antiemetics tailored to the emetogenic risk of the drugs administered each day during treatment and for two days after completion of the anticancer protocol. No standard antiemetic regimen exists for multi-day anticancer protocols. A combination of an NK1 receptor antagonist, 5HT3, and a steroid is available on the PBS for the prevention of nausea and vomiting associated with all moderate to highly emetogenic anti-cancer therapies. 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
Cumulative lifetime dose of anthracyclines	Cumulative doses should take into account all previous anthracyclines received during a patient’s lifetime (i.e. daunorubicin, doxorubicin, epirubicin, idarubicin and mitoxantrone). Criteria for reducing the total anthracycline cumulative lifetime dose include: patient is elderly prior mediastinal radiation hypertensive cardiomegaly concurrent therapy with high dose cyclophosphamide and some other cytotoxic drugs (e.g. bleomycin, dacarbazine, dactinomycin, etoposide, melphalan, mitomycin and vincristine). Baseline clinical assessments include echocardiogram (ECHO) or gated heart pool scan (GHPS) and electrocardiogram (ECG) evaluation. Patients with normal baseline cardiac function (left ventricular ejection fraction (LVEF) > 50%) and low risk patients require LVEF monitoring when greater than 70% of the anthracycline threshold is reached or if the patient displays symptoms of cardiac impairment. Post-treatment cardiac monitoring is recommended for patients who have received high levels of total cumulative doses of anthracyclines at the clinician's discretion. Read more about cardiac toxicity associated with anthracyclines
Cytarabine syndrome	Treatment with cytarabine may cause a "cytarabine syndrome" characterised by flu-like symptoms, skin rash and occasionally chest pain.
Tumour lysis risk	Assess patient for risk of developing tumour lysis syndrome. Read more about prevention of tumour lysis syndrome.
Pneumocystis jirovecii pneumonia (PJP) prophylaxis	­ Read about prophylaxis of pneumocystis jirovecii (carinii) in cancer patients
Antiviral prophylaxis	­ Read more about Herpes simplex virus (HSV) and varicella zoster virus (VZV) prophylaxis in immunocompromised adults
Antifungal prophylaxis	­ Read more about antifungal prophylaxis drugs and doses.
Growth factor support	G-CSF (short or long-acting) is available on the PBS for chemotherapy induced neutropenia depending on clinical indication and/or febrile neutropenia risk. Access the PBS website
Blood tests	FBC, EUC, eGFR and LFTs at baseline and prior to each treatment.
Hepatitis B screening and prophylaxis	Routine screening for HBsAg, anti-HBc and anti-HBs 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 people with cancer who are moderately or severely immunocompromised due to the risk of disseminated disease. Non-live vaccines can be safely administered but response may be suboptimal. For more information about vaccinations for people who are immunocompromised refer to the Australian Immunisation Handbook.
Fertility, pregnancy and lactation	Cancer treatment can have harmful effects on fertility and this should be discussed with all people of reproductive potential prior to commencing treatment. There is a risk of harm to a developing fetus if treatment is given during pregnancy. A pregnancy test should be considered prior to initiating treatment in anyone with the potential to become pregnant. 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 people of reproductive potential. Possibility of infant risk should be discussed with those who are breastfeeding. Refer to the drug product information for further information. Read more about the COSA guidelines for fertility preservation for people with cancer

Dose modifications

Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences. Suggested dose modifications are based on clinical trial findings, product information, 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.

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

Haematological toxicity

Dose reductions for haematological toxicity not usually recommended. Discuss with Haematologist. Consider adding G-CSF from Day 8.

Kidney dosing recommendations

• Suggested dose modifications are based on the International Consensus Guideline on Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).
• Where one or more drugs in a protocol is recommended to be avoided, consider using a clinically appropriate alternative treatment protocol instead.
• Before dose adjusting or omitting a drug, consider treatment intent.
• In kidney replacement therapy consult a multidisciplinary team consisting of oncology/haematology with nephrology and/or clinical pharmacology for the management of dosing.
• For complete information on individual drug recommendations please review the individual drug monograph in the ADDIKD guideline.

eGFR (mL/min/1.73m2)	Cytarabine*	Daunorubicin
≥ 60	Full dose	Full dose
45 - 59	Full dose	Full dose Potential for increased risk of adverse events
30 - 44	Full dose	Full dose Potential for increased risk of adverse events
15 - 29	Full dose	Full dose OR Reduce by 25% in patients with - non-curative treatment intent, and - poor performance status Potential for increased risk of adverse events
< 15 (without kidney replacement therapy)	Full dose	Consult a multidisciplinary team consisting of oncology/haematology with nephrology and/or clinical pharmacology for the management of dosing.
* Cytarabine dose modifications based on low dose cytarabine (< 1000 mg/m2) recommendations

Hepatic impairment
Hepatic dysfunction
Mild	Reduce daunorubicin by 25%
Moderate	Reduce daunorubicin by 50%
Severe	Omit daunorubicin. Consider alternative regimen.

Elevations in liver function tests occur with both standard and high dose cytarabine. Significant liver function abnormalities may require discontinuation or a dose reduction

Interactions

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources:

• MIMS - Interactions Checker (login required)
• Australian Medicines Handbook (AMH) – interactions tab, tables on drugs that may prolong the QT interval, CYP enzymes, P-glycoprotein interactions, and seizure risk (login required)
• Micromedex Drug Interactions (login required)
• Cancer Drug Interactions
• Cytochrome P450 Drug Interactions

For more information see References & Disclaimer.

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

Daunorubicin
Interaction	Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs)	Additive nephrotoxicity	Avoid combination or monitor kidney function closely
Cardiotoxic drugs (eg. calcium channel blockers, propranolol)	Increased risk of daunorubicin-induced cardiotoxicity	Avoid combination or monitor closely for cardiotoxicity

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

Administration

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 or address chemical compatibilities related to IV drug preparation and administration. 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 and Australian Injectable Drugs Handbook websites for further information.

eviQ is currently reviewing and updating the way information is presented in the administration section. This is an extensive and on-going project. If you notice any discrepancies please let us know, via [email protected].

eviQ acknowledges that non-PVC, DEHP-free and PUR-free infusion bag/container and line selection recommendations are inconsistent across the literature. eviQ is reviewing and considering how we update this information in eviQ protocols. Please refer to the Australian Injectables Drugs Handbook (AIDH) summary document Non-PVC and/or DEHP-free IV infusion bags and sets.

1. Days 1 - 3
2. Days 4 - 7
3. Discharge

Days 1 to 3

Safe handling and waste management

Safe administration

Pre treatment assessment

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

Anti-cancer drug patient assessment tool prior to each day of treatment.

Weigh patient.

Strict fluid balance.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Prior to administration

Prime IV line(s).

Access CVAD.

Chemotherapy - Time out

Daunorubicin

Extravasation of a vesicant is a medical emergency.Monitor for signs of extravasation throughout administration.

Administer daunorubicin (vesicant):

• over 5 to 15 minutes
  • via a minibag OR
  • by IV bolus via a side port of a freely flowing IV infusion
• flush with ~150 mL of sodium chloride 0.9%.

Potential adverse events:

• potential for flare reaction during administration of daunorubicin (facial flushing and red streaking along the vein), stop infusion and exclude extravasation before continuing at a slower rate of infusion
• although rare, cardiac arrhythmias may occur during or immediately after daunorubicin administration, if sudden onset of dyspnoea, palpitations or irregular pulse occurs, stop administration immediately and obtain urgent medical officer review.

Cytarabine

Administer cytarabine:

• via continuous IV infusion over 7 days
• hang a new bag every 24 hours
• do not interrupt the infusion of cytarabine.

Potential adverse events:

• cytarabine syndrome:
  • fever, myalgia, bone pain, and/or occasionally rash, chest pain, or conjunctivitis which can occur 6 to 12 hours following drug administration
  • symptoms usually resolve within 24 hours after cytarabine is discontinued
  • corticosteroids may be used for treatment and prophylaxis.

Post administration

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

1. Days 1 - 3
2. Days 4 - 7
3. Discharge

Days 4 to 7

Safe handling and waste management

Safe administration

Pre treatment assessment

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

Anti-cancer drug patient assessment tool prior to each day of treatment.

Weigh patient.

Strict fluid balance.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Prior to administration

Prime IV line(s).

Chemotherapy - Time out

Cytarabine

Administer cytarabine:

• via continuous IV infusion over 7 days
• hang a new bag every 24 hours
• do not interrupt the infusion of cytarabine.

Potential adverse events:

• cytarabine syndrome:
  • fever, myalgia, bone pain, and/or occasionally rash, chest pain, or conjunctivitis which can occur 6 to 12 hours following drug administration
  • symptoms usually resolve within 24 hours after cytarabine is discontinued
  • corticosteroids may be used for treatment and prophylaxis.

Post administration

Deaccess CVAD.

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

1. Days 1 - 3
2. Days 4 - 7
3. Discharge

Discharge information

Discharge medications

Growth factor support - as/if prescribed, and arrangements for administration.

Antiemetics - as/if prescribed.

Prophylaxis medications - as/if prescribed, i.e. antifungals, antivirals, PJP prophylaxis, tumour lysis prophylaxis.

Patient information

Ensure patient receives protocol patient information sheet.

Side effects

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

Immediate (onset hours to days)
Extravasation, tissue or vein injury	The unintentional instillation or leakage of a drug or substance out of a blood vessel into surrounding tissue. This has the potential to cause damage to affected tissue. Read more about extravasation management
Flare reaction	Anthracycline flare reaction is caused by a localised allergic reaction. It is characterised by erythematous vein streaking, urticaria and pruritus which may occur during drug administration and is often associated with too rapid an infusion. Extravasation must be ruled out if flare occurs.
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.
Nausea and vomiting	Read more about prevention of treatment induced nausea and vomiting
Red-orange discolouration of urine	Pink/red/orange discolouration of the urine. This can last for up to 48 hours after some anthracycline drugs.
Taste and smell alteration	Read more about taste and smell changes

Early (onset days to weeks)
Neutropenia	Abnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. Read more about immediate management of neutropenic fever
Thrombocytopenia	A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding. Read more about thrombocytopenia
Anorexia	Loss of appetite accompanied by decreased food intake. Read more about anorexia
Diarrhoea	Read more about treatment induced diarrhoea
Fatigue	Read more about fatigue
Oral mucositis and stomatitis	Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following anti-cancer treatment, 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 and stomatitis
Photosensitivity	Increased sensitivity to ultraviolet (UV) light resulting in an exaggerated sunburn-like reaction accompanied by stinging sensations and urticaria.
Radiation recall	Erythematous or inflammatory skin reaction resembling severe sunburn at sites previously treated with radiation therapy can occur with certain anti-cancer drugs. Symptoms include vesiculation, desquamation and ulceration of the skin. Read more about radiation recall

Late (onset weeks to months)
Anaemia	Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. Read more about anaemia
Alopecia	Hair loss may occur from all parts of the body. Patients can also experience mild to moderate discomfort of the hair follicles, and rarely pain as the hair is falling out. Read more about alopecia and scalp cooling (where applicable for intermittent treatment protocols)
Cognitive changes (chemo fog)	Changes in cognition characterised by memory loss, forgetfulness and feeling vague. This is also referred to as 'chemo brain' or 'chemo fog'. Read more about cognitive changes (chemo fog)

Delayed (onset months to years)

Cardiotoxicity

Anthracyclines are the most frequently implicated anti-cancer drugs associated with cardiotoxicity, which typically manifests as a reduction in left ventricular ejection fraction (LVEF), cardiomyopathy, or symptomatic CHF. Anthracycline induced cardiotoxicity has been categorised into acute, early-onset chronic progressive and late-onset chronic progressive and is usually not reversible. The risk of clinical cardiotoxicity increases with a number of risk factors including higher total cumulative doses. Read more about cardiac toxicity associated with anthracyclines

Evidence

eviQ is currently updating the way information is presented in the evidence section to improve usability, consistency and facilitate easier update and maintenance. An updated evidence template is being implemented in a staged approach, first across new protocols, then existing protocols as they are reviewed. Find out more

Modifying the anthracycline dose in acute myeloid leukaemia (AML) may improve complete remission (CR) rates and reduce relapse, hence improving overall survival (OS). Escalation of the daunorubicin dose to 90 mg/m2/day has been shown to improve OS and remission rates when compared to a daunorubicin dose of 45 mg/m2/day in some patients.rrr

Only one randomised clinical trial has compared daunorubicin dose in AML induction (90 mg/m2 vs 60 mg/m2) with no evidence of overall benefit seen with the 90 mg/m2 dose.r A new re-analysis suggests that the higher dose may be superior for patients with FLT-3 ITD mutations.

Efficacy

Escalation of the daunorubicin to 90 mg/m2/day has been shown to improve OS and remission rates when compared to daunorubicin dose of 45 mg/m2/day, which had previously been the conventional dose for induction therapy in AML. This has been demonstrated in three randomised trials, two enrolling younger patients (<60 years) and the other patients over 60.

The first study treated 813 patients >60 years (range 60-83) with daunorubicin 90 mg/m2 or 45 mg/m2 for 3 days in addition to cytarabine 200 mg/m2 continuous intravenous infusion for 7 days.r A higher response rate was reported in the 90 mg/m2 group when compared to the 45 mg/m2 group with CR rates 64% vs. 54% (p= 0.002), without additional toxicity. However, there was no significant difference in OS between the two groups except in patients 60-65 years.

In the second trial, 657 enrolled patients, escalation of the daunorubicin dose to 90 mg/m2/day for 3 days in combination with cytarabine 100 mg/m2/day continuous infusion for 7 days resulted in increased complete response (CR) rates (70.6% vs 57.3%, p<0.001) and median OS compared to 45 mg/m2/day (23.7 vs 15.7 months, p=0.003).r There was no major increase in toxicity- in particular, the rate of death during induction was 5.5% and 4.5% for the high-dose and standard-dose daunorubicin groups, respectively (p=0.60). Initial analysis appeared to limit the benefit of high-dose daunorubicin to younger (age <50 years) and those with favourable or intermediate risk cytogenetics. Longer follow up indicates the benefit of the higher anthracycline dose to potentially extend to patients with unfavourable cytogenetics (adjusted hazard ratio 0.66, p=0.04) and those with FLT3-ITD (HR 0.61, p=0.009).r Superior outcomes in younger patients using high-dose daunorubicin has been confirmed in a contemporaneous randomised trial of 383 patients from Korea.r

Although doses of daunorubicin higher than 45 mg/m2 improve outcomes, particularly in younger patients with AML, it is unknown whether a dose of 90 mg/m2 daunorubicin is required or, alternatively if 60 mg/m2 may provide the same benefit. The UK NCRI AML17 trial was a randomised trial comparing daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction.r 1206 patients (mostly under 60 years) were randomised to receive daunorubicin on days 1, 3, and 5 at a dose of 90 mg/m2 or 60 mg/m2 with cytarabine 100 mg/m2 every 12 hours on days 1 to 10 inclusive. A second course was given to patients with favourable or intermediate-risk disease, consisting of daunorubicin 50 mg/m2 on days 1, 3 and 5 with cytarabine 100 mg/m2 every 12 hours on days 1 to 8 inclusive. High-risk patients were randomised to receive either FLAG-Ida or clofarabine with 3 doses of daunorubicin 50 mg/m2.

No difference was seen in achievement of CR according to daunorubicin dose, with rates of 75% and 73% in the 60 mg/m2 and 90 mg/m2 groups, respectively (p=0.6). Day 30 mortality was similar in the two dose groups, but at day 60, there were increased deaths in the 90 mg/m2 group (10% vs 5%, p=0.001). Grade 3 or 4 gastrointestinal toxicity was also higher in the 90 mg/m2 cohort. Time to count recovery (neutrophils and platelets) and cardiac toxicity were not different between dose groups. Two-year OS was 60% in the 60 mg/m2 group compared to 59% in the 90 mg/m2 group (p=0.15), relapse-free survival (RFS) was also similar (48% vs 51%). Exploratory analysis did not reveal any subgroups benefiting from the higher dose of daunorubicin.

A subsequent re-analysis after extended follow up (median 28 months) now indicates that patients with FLT-3 ITD mutations experience improved RFS (45% vs 33%, p=0.02) and OS (54% vs 34%, p=0.03) if they receive 90 mg/m2 daunorubicin in induction rather than 60 mg/m2.r This appears to be independent of NPM1 mutation status. Outcomes remain unchanged for all other subgroups.

Figure 1: Effect of daunorubicin dose on survival according to cytogenetic riskr

© Blood 2015

Figure 2: Effect of daunorubicin dose according to FLT-3 ITD status r

© Blood 2016

Toxicity

​Table 1: Non-haematologic toxicity of 60 mg/m2 vs 90 mg/m2 daunorubicinr

© Blood 2015

References References

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Literature search

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History

Version 3

Date	Summary of changes
26/10/2023	Protocol updated with ADDIKD guideline recommendations. New kidney dosing recommendation table added to dose modification section. PDF of previous protocol. Version number changed to V.3.
09/02/2024	Drug cost updated to exclude daunorubicin, not available on PBS.

Version 2

Date	Summary of changes
26/05/2017	Discussion held at the eviQ Haematology Reference Committee meeting (20/05/2016) regarding the updated daunorubicin dose of between 60 to 90 mg/m2 for Acute Myeloid Leukaemia induction recommended in local and international (ELN and NCCN) guidelines. Consensus decision to increase daunorubicin dose to 60 mg/m2. This protocol replaces a previous version ID 348 AML Induction 7-3 protocol (daunorubicin 50 mg/m2 dose) which has been discontinued. New protocol ID 2043 Acute Myeloid Leukaemia Induction 7-3 (Cytarabine and DAUNOrubicin) with updated daunorubicin 60 mg/m2 dose approved and published on eviQ.
31/05/2017	Transferred to new eviQ website. Version number change to V.2.
01/04/2019	Note added underneath the treatment schedule 'Cytarabine at a dose of 100 – 200 mg/m2 is acceptable and as per clinician discretion'.
10/10/2019	Clinical information updated with PBS expanded indications for G-CSF.
11/03/2022	Reviewed by Haematology Reference Committee with no significant changes, review in 4 years.

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

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First approved: 25 May 2017 Last reviewed: 11 March 2022 Review due: 30 June 2026

The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/2043

21 Jan 2026

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