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Acute myeloid leukaemia consolidation 5-2 ida (cytarabine and iDArubicin)

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

This protocol is based on limited evidence; please refer to the evidence section of this protocol for more information.

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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.

Day 1 and 2
iDArubicin 12 mg/m2 (IV) over 10 to 15 minutes
Cytarabine (Ara-C) 100 mg/m2 (CIV) in sodium chloride 0.9% over 24 hours as a continuous infusion
Day 3 to 5
Cytarabine (Ara-C) 100 mg/m2 (CIV) in sodium chloride 0.9% over 24 hours as a continuous infusion
Cycles:
1 or 2. First cycle commenced on confirmation of induction remission. A second cycle may be administered after bone marrow recovery.

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.

Day 1 and 2
iDArubicin 12 mg/m2 (IV) over 10 to 15 minutes
Cytarabine (Ara-C) 100 mg/m2 (CIV) in sodium chloride 0.9% over 24 hours as a continuous infusion
Day 3 to 5
Cytarabine (Ara-C) 100 mg/m2 (CIV) in sodium chloride 0.9% over 24 hours as a continuous infusion
Cycles:
1 or 2. First cycle commenced on confirmation of induction remission. A second cycle may be administered after bone marrow recovery.
  • Post remission acute myeloid leukaemia in patients not suitable for consolidation with high dose cytarabine
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

Antiemetic therapy should be administered throughout the duration of the chemotherapy protocol and to cover delayed nausea. The acute and delayed emetic risk of multi-day chemotherapy protocols will overlap depending on the individual drugs and their sequence of administration. More or less antiemetic cover may be required. 

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 or 12.5 mg IV every 6 hours when necessary.

Read more about preventing antineoplastic induced nausea and vomiting
Cumulative lifetime dose of idarubicin

The total cumulative lifetime dose of idarubicin is 160 mg/m2 (for IV) and 400mg/m2 (for oral).

Baseline clinical assessment, 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 anthracycline threshold is reached or if patient displays symptoms of cardiac impairment. 

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 and management of tumour lysis syndrome.
Pneumocystis jiroveci pneumonia (PJP) prophylaxis

­

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

­

Read more about antiviral prophylaxis drugs and doses
Antifungal prophylaxis ­

Read more about antifungal prophylaxis drugs and doses.
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 and LFTs at baseline and prior to each treatment.
Hepatitis B screening and prophylaxis

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

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

Live vaccines, including BCG, MMR, zoster and varicella vaccines, are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease.

Refer to the recommended schedule of vaccination for immunocompromised patients, as outlined in the Australian Immunisation Handbook.
Effects of cancer treatment on fertility

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

Read more about the effect of cancer treatment on fertility
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the antineoplastic regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient​ preferences. Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. 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 (filgrastim, lenograstim, lipegfilgrastim or pegfilgrastim) from Day 6
Renal impairment
No specific dose modifications recommended for cytarabine in renal impairment, but please note an increased risk of neurotoxicity has been associated with high dose cytarabine with creatinine clearance less than 60 mL/min
Hepatic impairment
Hepatic dysfunction
Mild Reduce idarubicin by 25%
Moderate Reduce idarubicin by 50%
Severe Omit idarubicin. 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.

References & Disclaimer

Cytarabine
No specific clinically significant drug-drug interactions
Idarubicin
  Interaction Clinical management
Cardiotoxic drugs (eg. calcium channel blockers, propranolol) Increased risk of idarubicin-induced cardiotoxicity Avoid combination or monitor closely for cardiotoxicity
General
  Interaction Clinical management
Warfarin Antineoplastic agents 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 antineoplastic 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 Antineoplastic agents 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 antineoplastic levels may occur, possibly leading to loss of efficacy or toxicity. Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the antineoplastic therapy.
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia. Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update
Vaccines Diminished response to vaccines and increased risk of infection with live vaccines. Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Days 1 and 2

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.

Prime IV line(s).

Access CVC.

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

Hydration if prescribed.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Idarubicin

Administer idarubicin (vesicant):
  • over 10 to 15 minutes
    • via a minibag OR
    • by IV bolus via a side port of a freely flowing IV infusion
  • ensure vein is patent and monitor for signs of extravasation throughout administration
  • flush with ~150 mL of sodium chloride 0.9%
  • potential for flare reaction during administration of idarubicin (facial flushing and red streaking along the vein) stop infusion exclude extravasation before continuing at a slower rate of infusion.

Although rare, cardiac arrhythmias may occur during or immediately after idarubicin administration. If sudden onset of dyspnoea, palpitations or irregular pulse occurs, stop administration immediately and obtain urgent medical officer review.

Cytarabine 

  • administer via continuous IV infusion over 5 days
  • hang a new bag every 24 hours
  • do not interrupt the infusion of cytarabine.

Observe for symptoms of 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.

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

Days 3 to 5

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.

Hydration if prescribed.

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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Cytarabine 

  • administer via continuous IV infusion over 5 days
  • hang a new bag every 24 hours
  • do not interrupt the infusion of cytarabine.

Observe for symptoms of 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.

Deaccess CVC.

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

Discharge information

Antiemetics
  • Antiemetics as prescribed.
Growth factor support
  • Arrangements for administration if 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)
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
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
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.
Taste and smell alteration

Read more about taste and smell changes
Red-orange discolouration of urine

Pink/red/orange discolouration of the urine. This can last for up to 48 hours after some anthracycline drugs.

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 neutropenia
Thrombocytopenia

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

Read more about thrombocytopenia
Oral mucositis

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

Read more about oral mucositis
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Fatigue

Read more about fatigue
Diarrhoea

Read more about treatment induced diarrhoea
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 radiotherapy can occur with certain antineoplastic 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
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 antineoplastic agents 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 and Efficacy

This regimen has a very limited role in the treatment of acute myeloid leukaemia (AML), probably only in patients over the age of 60 or patients in whom there is a contraindication to high dose cytarabine regimens (e.g. previous significant cerebellar toxicity).

The pivotal CALGB trial of Mayer et alr in patients up to the age of 60 compared 100 mg/m2, 400 mg/m2 and 3 g/m2 doses of cytarabine in consolidation and showed a statistically significant chance of complete remission at 4 years for the 3 g/m2 dosing (Q12H days 1,3,5 IVI 3 hours) compared to the lower doses of cytarabine. Current best practice would be to consolidate with high dose cytarabine containing regimens in the patient population up to the age of 60.r

The optimal management of patients age greater than 60 is not clear however consolidation with an anthracycline and conventional dose cytarabine appear a reasonable option, at least up to the age of 74.r Wiernik et alr included adults of all ages and randomized to two consolidation cycles with standard dose cytarabine (100 mg/m2 D1-5) plus daunorubicin (45 mg/m2) or idarubicin (13 mg/m2) (both for 2 days) and showed a significant survival benefit of idarubicin over daunorubicin. The idarubicin 12 mg/m2 corresponds to the dose used by Berman et al4 in a randomized trial of daunorubicin (50 mg/m2) versus idarubicin (12 mg/m2), showing a survival superiority of idarubicin in patients up to the age of 60.

In summary, the main place of this regimen is in consolidation chemotherapy (typically two cycles) in patients over the age of 60. It usually should not be used in the younger patient population where more intensive consolidation regimens are indicated in most cases. Randomised trial data comparing this regimen to other consolidation strategies is limited.

A search of the literature found limited evidence to support the use of cytarabine and idarubicin 5-2 in the consolidation treatment of AML. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the study by Wiernik et al3 and Berman et al.r

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Randomised trials Wiernik et al. 1992 Yes No Idarubicin 13 mg/m2 days 1-2 and cytarabine 100 mg/m2 days 1-5 for 2 cycles
Berman et al. 1991 Yes No Idarubicin 12 mg/m2 days 1-2 and cytarabine 200 mg/m2 days 1-4 for 2 cycles
Observational studies N/A N/A N/A -
Case series N/A N/A N/A -
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN Mar 2014 Yes N/A -
BCCA N/A N/A N/A -
ESMO 2013 N/A N/A -

Toxicity

There was an increased incidence of dysphagia occurring in 15% of patients receiving idarubicin versus 0% in patients receiving daunorubicin but otherwise toxicity was similar in both groups during consolidation therapy in the Wiernik study.r There was an increased incidence of diarrhoea, hyperbilirubinaemia, elevation of transaminases, alkaline phosphatase and urea, infections and more prolonged myelosuppression in idarubicin arm compared to daunorubicin arm in consolidation therapy in the Vogler study.

Haematological toxicity during consolidation therapy:r

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Version 4

Date Summary of changes
09/09/2008 Addition of information to improve comprehensiveness - including additional drug interactions, clinical considerations (management of tumour lysis syndrome and PCP prophylaxis recommendations).
10/03/2010 Reviewed and transferred to eviQ.
22/10/2010

Full protocol review at Haematology Reference Committee meeting:
- indication updated to include 'where high dose cytarabine is not appropriate'; age cut off removed
- renal and hepatic dose modification recommendations for cytarabine included
11/04/2012

New format to allow for export of protocol information.
Protocol version number changed to V.2.
Additional Clinical Information, Key Prescribing table and Key Administration table combined into new section titled Clinical Considerations.
Drug specific information placed behind the drug name link.
27/06/2014 Full protocol review post Haematology Reference Committee meeting:
- Change the 'AML 5-2 modified' to 'AML 5-2 ida' in the title, review of the evidence but no changes to drug schema.
- Added link to ALLG and ANZCTR with statement 'Patients with AML should be considered for inclusion into clinical trials'. Next review in 2 years
03/02/2016 Standard review, updated drug costs, review again in 5 years.

31/05/2017

Transferred to new eviQ website. Version number change to V.4.
10/10/2019 Clinical information updated with PBS expanded indications for G-CSF. 

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. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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First approved:
Last reviewed:
Review due:

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/342

19 Oct 2019