346-Acute myeloid leukaemia FLAG (fludarabine cytarabine and filgrastim)

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

Treatment schedule Treatment schedule

Overview
Detail

Drug	Dose	Route	Day
Filgrastim	5 micrograms/kg	Subcut	0 to 5 and continue daily until neutrophil recovery
Fludarabine	30 mg/m²	IV infusion	1 to 5
Cytarabine (Ara-C)	2,000 mg/m² *	IV infusion	1 to 5

* Cytarabine dose may be reduced for older patients; consider 1000 mg/m² if the patient is older than 60 years of age.

Cycles:: 1 or 2. Upon recovery a second cycle may be given (generally only given if the patient has responded to Cycle 1)

Notes:: The scheduling of the drugs in this protocol is important; commence cytarabine administration 4 hours after the start of the fludarabine infusion.^r

Drug status:

Cytarabine is on the PBS general schedule

Filgrastim: (PBS authority)

Cost:: ~ $3,070 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 antineoplastic drugs only (not antiemetics or other supportive medications), 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 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 are not included in protocol cost calculations.

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

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Day 0
Filgrastim	5 micrograms/kg (Subcut)	inject subcutaneously once daily from day 0 and continue until neutrophil recovery. To be given before chemotherapy on days 1 to 5.

Day 1 to 5
Filgrastim	5 micrograms/kg (Subcut)	inject subcutaneously once daily from day 0 and continue until neutrophil recovery. To be given before chemotherapy on days 1 to 5.
Fludarabine	30 mg/m² (IV infusion)	in 100 mL sodium chloride 0.9% over 30 minutes
Cytarabine (Ara-C)	2,000 mg/m² (IV infusion)	in 500 mL sodium chloride 0.9% over 4 hours. Administer 4 hours after commencing the fludarabine infusion.

Note: cytarabine dose may be reduced for older patients; consider 1000 mg/m² if the patient is older than 60 years of age.

Cycles:: 1 or 2. Upon recovery a second cycle may be given (generally only given if the patient has responded to Cycle 1)

Treatment schedule - Overview

Drug	Dose	Route	Day
Filgrastim	5 micrograms/kg	Subcut	0 to 5 and continue daily until neutrophil recovery
Fludarabine	30 mg/m²	IV infusion	1 to 5
Cytarabine (Ara-C)	2,000 mg/m² *	IV infusion	1 to 5

* Cytarabine dose may be reduced for older patients; consider 1000 mg/m² if the patient is older than 60 years of age.

Cycles:: 1 or 2. Upon recovery a second cycle may be given (generally only given if the patient has responded to Cycle 1)

Notes:: The scheduling of the drugs in this protocol is important; commence cytarabine administration 4 hours after the start of the fludarabine infusion.^r

Drug status:

Cytarabine is on the PBS general schedule

Filgrastim: (PBS authority)

Cost:: ~ $3,070 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 antineoplastic drugs only (not antiemetics or other supportive medications), 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 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 are not included in protocol cost calculations.

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

Treatment schedule - Detail

Day 0
Filgrastim	5 micrograms/kg (Subcut)	inject subcutaneously once daily from day 0 and continue until neutrophil recovery. To be given before chemotherapy on days 1 to 5.

Day 1 to 5
Filgrastim	5 micrograms/kg (Subcut)	inject subcutaneously once daily from day 0 and continue until neutrophil recovery. To be given before chemotherapy on days 1 to 5.
Fludarabine	30 mg/m² (IV infusion)	in 100 mL sodium chloride 0.9% over 30 minutes
Cytarabine (Ara-C)	2,000 mg/m² (IV infusion)	in 500 mL sodium chloride 0.9% over 4 hours. Administer 4 hours after commencing the fludarabine infusion.

Note: cytarabine dose may be reduced for older patients; consider 1000 mg/m² if the patient is older than 60 years of age.

Cycles:: 1 or 2. Upon recovery a second cycle may be given (generally only given if the patient has responded to Cycle 1)

Indications and patient population

Relapsed or refractory acute myeloid leukaemia (predominant use)

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	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
Ocular toxicities	Administer corticosteroid eye drops to minimise corneal toxicity from high dose cytarabine. Commence on the day of first dose of cytarabine and continue for at least 72 hours after completion of final cytarabine dose. Read more about ocular toxicities associated with high dose cytarabine
Cytarabine syndrome	Treatment with cytarabine may cause a "cytarabine syndrome" characterised by flu-like symptoms, skin rash and occasionally chest pain.
Cytarabine induced neurotoxicity	This may occur in patients treated with high dose cytarabine. Assess cerebellar function prior to each cytarabine dose. Read more about neurotoxicity associated with high dose cytarabine and access the cytarabine cerebellar neurotoxicity assessment chart
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 (filgrastim, lipegfilgrastim or pegfilgrastim) is available on the PBS for the primary prevention of neutropenia. Note: lenograstim is available but not PBS reimbursed. Access the PBS website
Irradiated blood components	Irradiation of blood components is recommended. Read more about the indications for the use of irradiated blood components
Blood tests	FBC, EUC, LFTs, LDH 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

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 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.

Renal impairment
Creatinine clearance (mL/min)
30 to 50	Reduce fludarabine by 50%
less than 30	Fludarabine contraindicated

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

Age
Cytarabine dose may be reduced for older patients. Consider reducing dose to 1000 mg/m² if patient is older than 60 years

Interactions

References & Disclaimer

Cytarabine
No specific clinically significant drug-drug interactions

Fludarabine
	Interaction	Clinical management
Dipyridamole	Reduced efficacy of fludarabine possible due to inhibition of adenosine uptake	Avoid combination or monitor for decreased clinical response to fludarabine

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 (e.g. LMWH or unfractionated heparin)
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

Administration

Day 0

Subcutaneous injection

General patient assessment prior to each day of treatment.

Commence corticosteroid eye drops prior to the first dose of cytarabine.

Filgrastim

Inject subcutaneously ONCE daily, starting on day 0 and continuing until neutrophil recovery.

Days 1 to 5

Safe handling and waste management

Safe administration

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.

daily weight
daily urinalysis
strict fluid balance input and output

Hydration if prescribed.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Continue corticosteroid eye drops for 72 hours after the completion of cytarabine.

Filgrastim

Inject subcutaneously ONCE daily, starting on day 0 and continuing until neutrophil recovery.

Chemotherapy - Time out

Fludarabine

administer via IV infusion over 30 minutes
flush with ~ 50 mL of sodium chloride 0.9%

Neurotoxicity of delayed onset (21-60 days post initiation of therapy) characterised by visual disturbances, weakness, loss of hearing and numbness may occur with high doses (> 100 mg/m2 per treatment course); periodic neurologic assessments are recommended.

Administer cytarabine 4 hours AFTER commencing the fludarabine infusion

Cytarabine

Prior to administration:

Ensure corticosteroid eye drops have been administered before starting cytarabine.

Verify that cytarabine neurological assessment has been performed prior to administration of cytarabine:

if the patient scores 0 then administer cytarabine as charted
if the patient scores 1 or above, do not administer the cytarabine and immediately notify medical officer.

Administer cytarabine:

via IV infusion over 4 hours
flush with ~50 mL of sodium chloride 0.9%.

Deaccess CVC.

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

Discharge information

Antiemetics

Antiemetics as prescribed.

Corticosteroid eye drops

Continue corticosteroid eye drops for at least 72 hours after completion of final cytarabine dose.

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.

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)
Ocular toxicities	Reversible corneal toxicity (keratitis), haemorrhagic conjunctivitis, vision loss and other ocular side effects can occur with high dose cytarabine. Corticosteroid eye drops must be administered concurrently with treatment. Read more about ocular toxicities associated with cytarabine
Nausea and vomiting	Read more about prevention of treatment induced nausea and vomiting
Bone pain	Bone pain, usually in the lower back or pelvis, associated with colony stimulating factors (filgrastim, lenograstim, lipegfilgrastim and pegfilgrastim).
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 neutropenia
Thrombocytopenia	A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding. Read more about thrombocytopenia
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.
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
Diarrhoea	Read more about treatment induced diarrhoea
Fatigue	Read more about fatigue
Skin rash	Antineoplastic agents can cause a number of changes in the skin with maculo-papular rash the most common type of drug-induced skin reaction. Read more about skin rash
Photosensitivity	Increased sensitivity to ultraviolet (UV) light resulting in an exaggerated sunburn-like reaction accompanied by stinging sensations and urticaria.

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
Pulmonary toxicity	Pulmonary toxicity may include damage to the lungs, airways, pleura and pulmonary circulation. Read more about pulmonary toxicity associated with antineoplastic drugs
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)

Evidence

Cytarabine is one of the most effective drugs used for treatment of acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). The administration of fludarabine prior to high dose cytarabine has been shown to increase intracellular accumulation of the active metabolite, ara-CTP,^r providing the rationale for the FLAG protocols. Estey and colleagues were the first to report the use of FLAG for treatment of newly diagnosed AML and MDS patients.^r Most of the evidence for the FLAG protocol comes from case series with only one randomised trial testing the effect of adding fludarabine to high dose cytarabine and G-CSF. Ossenkoppele and colleagues enrolled previously untreated patients with high risk MDS or elderly AML and showed that response did not improve significantly with the addition of fludarabine however toxicity was increased.^r

G-CSF is included in the protocol to speed neutrophil recovery post-chemotherapy. It has also been hypothesised that giving G-CSF the day prior to chemotherapy increases the number of leukaemic cells in cycle at the time of cytotoxic administration and hence increases cell kill.^r ^r The in vivo importance of this effect is debated, with some studies showing a benefit to concurrent vs sequential G-CSF^r whilst others show no benefit.^r

Efficacy

Currently, FLAG and FLAG-Ida protocols are used most commonly as salvage therapy for relapsed and refractory AML patients. There have been several studies of FLAG in this setting with reported complete response (CR) rates generally in the 50-60% range (see table below). Only the CR rates, not disease-free or overall survival, are summarised here because consolidation treatments vary significantly. In general, if induction with FLAG results in a CR, at least one further course of FLAG is recommended, followed by allogeneic transplantation if possible. Although CR rates are good, remission durations are usually short without further treatment.

Reference	n=	Age* (years)	CR (%)	TRM (%)	Comments
Visani et al 1994^r	28	-	58	7	- relapsed/refractory AML
Clavio et al 1996^r	51	64	59	10	- high risk AML: MDS-AML (22), relapsed/refractory (17), poor risk (12)
Huhmann et al 1996^r	22	46	50	5	- relapsed/refractory AML
Nokes et al 1997^r	31	-	66	13	- relapsed/refractory AML (19/4) & MDS (8)
Montillo et al 1998^r	38	41	55	10	- relapsed/refractory AML
Carella et al 2001^r	41	52	56	7	- relapsed/refractory AML
Jackson et al 2001^r	21 44	48 47	81 30	18	- Group 1 = late relapse (>6 months) AML - Group 2 = early relapse or refractory AML
Thomas et al 2003^r	177	49-56	19-35	9-19	- 3 different FLAG variations, used sequentially in relapsed AML patients
Lee et al 2009^r	61	33	48	11	- relapsed/refractory AML

* Median age in years; CR = complete remission; TRM = treatment related mortality; AML = acute myeloid leukaemia; MDS = myelodysplastic syndrome

Toxicity

In general, FLAG is well tolerated with severe myelosuppression being the major toxicity, occurring in nearly all patients. The median time to neutrophil recovery (>0.5 x 10⁹/L) ranges from 19 to 21 days and median time to platelet count >20 x 10⁹/L is 20 to 23 days.^r ^r ^r ^r ^r Neutropenic fever is common and reported infection rates range from 26% to 84%.^r ^r ^r ^r ^r Rates of fungal infection, when reported, are 7 to 10%.^r ^r ^r Non-haematologic toxicities are generally mild and include gastrointestinal toxicity, alopecia, and liver function test abnormalities. Treatment related mortality averages approximately 10% in relapsed and refractory AML patients (see table above).

References References

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History

Version 5

Date	Summary of changes
12/04/2007	Minor editing
12/06/2008	Review, clarification of dose modifications and addition of extra information to increase the comprehensiveness of the protocol
24/03/2010	Review, new dose modifications and transferred to eviQ
17/09/2010	Full protocol review at Haematology Reference Committee meeting. Evidence section updated.
21/11/2011	New format to allow for export of protocol information Protocol version number changed to V.2 Antiemetics and premedications added to the treatment schedule 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	Protocol reviewed by email survey. Added link to ALLG and ANZCTR with statement 'Patients with AML should be considered for inclusion into clinical trials'. Changed the wording in the drug schema for filgrastim to read '0 and continue until neutrophil recovery' (as per the 2010 Reference Committee meeting minutes). Next review in 2 years.
02/02/2016	Standard review, no changes
31/05/2017	Transferred to new eviQ website. Version number changed to V.4.
14/12/2017	The days on which filgrastim is administered was adjusted in the overview and detail treatment schedules to mention days 1 to 5. Version number increased to V.5.

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:: 15 July 2005
Last reviewed:: 14 December 2017
Review due:: 3 February 2021

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/346

20 Feb 2019