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Acute promyelocytic leukaemia APML4 consolidation 2

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

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Drug Dose Route Day
Tretinoin (ATRA) 45 mg/m2 divided in TWO equal doses PO 1 to 7, 15 to 21, 29 to 35
Arsenic trioxide (ATO) 0.15 mg/kg IV infusion 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33

Consolidation 2 therapy may begin 3 to 4 weeks after completion of consolidation 1 therapy.

Duration:
35 days 
Cycles:
1 
Notes:

Arsenic  trioxide is given in 5 day blocks to accommodate administration as an outpatient.

Drug status:

Arsenic trioxide: (PBS authority)

Tretinoin is TGA registered but not PBS listed for this indication

Tretinoin is available as 10 mg capsules

Cost:
~ $10,430 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.

Day 1 to 5
Tretinoin (ATRA) 45 mg/m2 (PO) in TWO equally divided doses daily (round to the nearest 10 mg).
Arsenic trioxide (ATO) 0.15 mg/kg (IV infusion) in 100 mL to 250 mL sodium chloride 0.9% over 2 hours ONCE a day (Mon - Fri every week for 5 weeks)
Day 6 and 7
Tretinoin (ATRA) 45 mg/m2 (PO) in TWO equally divided doses daily (round to the nearest 10 mg).
Day 8 to 12
Arsenic trioxide (ATO) 0.15 mg/kg (IV infusion) in 100 mL to 250 mL sodium chloride 0.9% over 2 hours ONCE a day (Mon - Fri every week for 5 weeks)
Day 15 to 19
Tretinoin (ATRA) 45 mg/m2 (PO) in TWO equally divided doses daily (round to the nearest 10 mg).
Arsenic trioxide (ATO) 0.15 mg/kg (IV infusion) in 100 mL to 250 mL sodium chloride 0.9% over 2 hours ONCE a day (Mon - Fri every week for 5 weeks)
Day 20 and 21
Tretinoin (ATRA) 45 mg/m2 (PO) in TWO equally divided doses daily (round to the nearest 10 mg).
Day 22 to 26
Arsenic trioxide (ATO) 0.15 mg/kg (IV infusion) in 100 mL to 250 mL sodium chloride 0.9% over 2 hours ONCE a day (Mon - Fri every week for 5 weeks)
Day 29 to 33
Tretinoin (ATRA) 45 mg/m2 (PO) in TWO equally divided doses daily (round to the nearest 10 mg).
Arsenic trioxide (ATO) 0.15 mg/kg (IV infusion) in 100 mL to 250 mL sodium chloride 0.9% over 2 hours ONCE a day (Mon - Fri every week for 5 weeks)
Day 34 and 35
Tretinoin (ATRA) 45 mg/m2 (PO) in TWO equally divided doses daily (round to the nearest 10 mg).

Consolidation 2 therapy may begin 3 to 4 weeks after completion of consolidation 1 therapy.

Duration:
35 days 
Cycles:
1 
Drug Dose Route Day
Tretinoin (ATRA) 45 mg/m2 divided in TWO equal doses PO 1 to 7, 15 to 21, 29 to 35
Arsenic trioxide (ATO) 0.15 mg/kg IV infusion 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33

Consolidation 2 therapy may begin 3 to 4 weeks after completion of consolidation 1 therapy.

Duration:
35 days 
Cycles:
1 
Notes:

Arsenic  trioxide is given in 5 day blocks to accommodate administration as an outpatient.

Drug status:

Arsenic trioxide: (PBS authority)

Tretinoin is TGA registered but not PBS listed for this indication

Tretinoin is available as 10 mg capsules

Cost:
~ $10,430 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.

Day 1 to 5
Tretinoin (ATRA) 45 mg/m2 (PO) in TWO equally divided doses daily (round to the nearest 10 mg).
Arsenic trioxide (ATO) 0.15 mg/kg (IV infusion) in 100 mL to 250 mL sodium chloride 0.9% over 2 hours ONCE a day (Mon - Fri every week for 5 weeks)
Day 6 and 7
Tretinoin (ATRA) 45 mg/m2 (PO) in TWO equally divided doses daily (round to the nearest 10 mg).
Day 8 to 12
Arsenic trioxide (ATO) 0.15 mg/kg (IV infusion) in 100 mL to 250 mL sodium chloride 0.9% over 2 hours ONCE a day (Mon - Fri every week for 5 weeks)
Day 15 to 19
Tretinoin (ATRA) 45 mg/m2 (PO) in TWO equally divided doses daily (round to the nearest 10 mg).
Arsenic trioxide (ATO) 0.15 mg/kg (IV infusion) in 100 mL to 250 mL sodium chloride 0.9% over 2 hours ONCE a day (Mon - Fri every week for 5 weeks)
Day 20 and 21
Tretinoin (ATRA) 45 mg/m2 (PO) in TWO equally divided doses daily (round to the nearest 10 mg).
Day 22 to 26
Arsenic trioxide (ATO) 0.15 mg/kg (IV infusion) in 100 mL to 250 mL sodium chloride 0.9% over 2 hours ONCE a day (Mon - Fri every week for 5 weeks)
Day 29 to 33
Tretinoin (ATRA) 45 mg/m2 (PO) in TWO equally divided doses daily (round to the nearest 10 mg).
Arsenic trioxide (ATO) 0.15 mg/kg (IV infusion) in 100 mL to 250 mL sodium chloride 0.9% over 2 hours ONCE a day (Mon - Fri every week for 5 weeks)
Day 34 and 35
Tretinoin (ATRA) 45 mg/m2 (PO) in TWO equally divided doses daily (round to the nearest 10 mg).

Consolidation 2 therapy may begin 3 to 4 weeks after completion of consolidation 1 therapy.

Duration:
35 days 
Cycles:
1 
  • Acute promyelocytic leukaemia (APML)
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
Venous access required

IV cannula (IVC) or central venous access device (CVAD) is required to administer this treatment.

Read more about central venous access device line selection
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
Teratogenic effects

Tretinoin can cause severe birth defects or death to an unborn baby. Tretinoin should never be used by women who are pregnant, who could become pregnant whilst taking the drug or could become pregnant within four weeks after stopping the drug. Patients must be advised to use contraception for four weeks before, during and four weeks after stopping tretinoin if there is any chance of pregnancy. Even a single dose taken by a pregnant women, can cause severe birth defects.
Hyperleukocytosis

Treatment related hyperleukocytosis (WBC greater or equal to 100 x10^9/L) develops in approximately 50% of arsenic trioxide treated patients. Peak WBC count occurs at about 20 days post first arsenic trioxide dose and usually resolves at a median of 10.5 days after the peak, despite continuation of arsenic trioxide.

It may be managed with careful observation, checking particularly for emerging APML differentiation syndrome. Hydroxycarbamide (hydroxyurea) has been used to treat marked hyperleukocytosis associated with arsenic trioxide, but its benefit is unclear.
ECG abnormalities

Arsenic trioxide can cause QTc interval prolongation and complete atrioventricular block.
Prior to commencement perform baseline electrocardiogram (ECG), correct pre-existing electrolyte abnormalities, and if possible cease drugs that may prolong the QTc interval.

During treatment it is critical to maintain potassium concentrations above 4 mmol/L and magnesium concentrations above 0.8 mmol/L; continue ECG at least twice weekly or more frequently in unstable patients.

Arsenic trioxide should not be commenced if QTc is greater than 500 msec. If QTc of greater than 500 msec is reached during treatment, consider suspending arsenic trioxide. If syncope or rapid or irregular heartbeat develop, suspend arsenic trioxide treatment until symptoms resolve and QTc falls to below 460 msec.

Read more about drugs that may prolong QTc interval and ECG abnormalities associated with arsenic trioxide
Pseudotumour cerebri

Headaches are common on ATRA therapy, although the possibility of intracranial haemorrhage, particularly during induction always needs to be considered. Pseudotumour cerebri is more common in young patients less than 20, and may be associated with severe headache, nausea and vomiting. It may necessitate temporary discontinuation of ATRA and recommencement at a lower dose.
Peripheral neuropathy

Assess prior to each treatment. If a patient experiences greater than grade 3, a dose reduction or delay of treatment may be required; review by medical officer before commencing treatment.

Read more about peripheral neuropathy

Link to chemotherapy-induced peripheral neuropathy screening tool
Pneumocystis jirovecii pneumonia (PJP) prophylaxis

Depending on dose and duration of steroid therapy, PJP prophylaxis may be appropriate (at clinician's discretion).

Read about prophylaxis of pneumocystis jiroveci (carinii) in cancer patients
Antifungal and antiviral prophylaxis

Antifungal and antiviral prophylaxis should be determined according to individual institutional policy. Note that azole antifungals may contribute to QTc prolongation. 

Read more about antiviral and antifungal prophylaxis
Blood product support

To minimise the risk of cerebral haemorrhage, an aggressive haemostatic support regimen is recommended:

Maintain platelet count of at least 30 x 109/L.

Fresh frozen plasma and/or cryoprecipitate daily as necessary to maintain normal prothrombin time, normal activated partial thromboplastin time, and plasma fibrinogen greater than 1.5 g/L.
Blood tests

FBC, EUC, LFTs, APTT, PT and fibrinogen level at baseline, then throughout treatment as clinically indicated.
Hepatitis B screening and prophylaxis

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

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

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

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

Read more about COVID-19 vaccines and cancer.
Effects of cancer treatment on fertility

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

Read more about the effect of cancer treatment on fertility
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences. Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. 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.
Renal impairment
Safety and efficacy of arsenic trioxide in patients with renal impairment have not been studied. Use with caution in patients with renal failure, as renal excretion is the main route of elimination.
Hepatic impairment
The following dose modifications for hepatic impairment are taken from the ALLG and ANZCHOG APML4 protocol
Grade 1 AST, ALT, GGT greater than ULN to 2.5 x ULN
Bilirubin greater than ULN to 1.5 x ULN		 Continue treatment with arsenic trioxide
Grade 2 AST, ALT, GGT greater than 2.5 x ULN to 5 x ULN
Bilirubin greater than 1.5 x ULN to 3 x ULN		 Continue treatment with arsenic trioxide
Grade 3 AST, ALT, GGT greater than 5 x ULN to 20 x ULN
Bilirubin greater than 3 x ULN to 10 x ULN		 Reduce arsenic trioxide dose to 0.08 mg/kg/day
Grade 4 AST, ALT, GGT greater than 20 x ULN
Bilirubin greater than 10 x ULN		 Stop arsenic trioxide.
Restart at 0.08 mg/kg/day when hepatic function improves to Grade 2.
Consider increasing back to 0.15 mg/kg/day if no deterioration after one week.
QT interval prolongation
If significant QT interval prolongation occurs, arsenic trioxide should be discontinued, together with any other medication known to prolong the QTc interval, and electrolytes should be corrected. The time between discontinuing arsenic trioxide and normalisation of the QTc interval may be several days. Once QTc is normalised, resume arsenic trioxide at 0.075 mg/kg (50%) for the first 7 days, and then if no further prolongation occurs, resume at 0.11 mg/kg for a second week. Thereafter, if no prolongation occurs, resume arsenic trioxide at full dose.
Peripheral neuropathy
Grade 3 to Grade 4 Consider dose reducing or delaying arsenic trioxide

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:  

Arsenic Trioxide (ATO)
  Interaction Clinical management
Drugs that may prolong the QTc interval (e.g. azole antifungals, tricyclic antidepressants, antiarrhythmics etc.) Additive effect with arsenic trioxide; may lead to torsades de pointes and cardiac arrest Avoid combination or minimise additional risk factors (e.g. correct electrolyte imbalances) and monitor ECG for signs of cardiac arrhythmia
Tretinoin (ATRA)
  Interaction Clinical management
Cytochrome p450 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of tretinoin possible due to decreased clearance Avoid combination or monitor for tretinoin toxicity
Cytochrome p450 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of tretinoin possible due to increased clearance Avoid combination or monitor for decreased clinical response to tretinoin
Antifibrinolytic agents (e.g. tranexamic acid and aprotinin) Cases of fatal thrombotic complications have been reported rarely in patients concomitantly treated with tretinoin and antifibrinolytic agents. Avoid combination or closely monitor
Tetracyclines Elevation of intracranial pressure/pseudotumour cerebri may be caused by tetracyclines and retinoids. Patients treated with tretinoin and tetracyclines in combination might be at a greater risk of experiencing this condition. Avoid combination or monitor for elevation of intracranial pressure/pseudotumour cerebri
Vitamin A Combination with vitamin A may cause or exacerbate the symptoms of hypervitaminosis A. Combination is contraindicated
General
  Interaction Clinical management
Warfarin Anti-cancer drugs may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

Interaction with both CYP3A4 and P-gp inhibitors /inducers.

DOAC and anti-cancer drug levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).

Apixaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. If treating VTE, avoid use with strong CYP3A4 and P‑gp inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 and P‑gp  inhibitors.

Dabigatran: avoid combination with strong P‑gp inducers and inhibitors.

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin Anti-cancer drugs can damage the lining of the intestine; affecting the absorption of digoxin. Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics Both altered antiepileptic and anti-cancer drug levels may occur, possibly leading to loss of efficacy or toxicity. Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the anti-cancer therapy.
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia. Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update
Vaccines Diminished response to vaccines and increased risk of infection with live vaccines. Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Days 1 to 7, 15 to 21 and 29 to 35 (PO)

This is an oral treatment

General patient assessment prior to each day of treatment.

Peripheral neuropathy assessment tool.

Any toxicity grade 3 or greater may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Tretinoin (ATRA)

  • administer orally in TWO equal divided doses on days 1 to 7, 15 to 21 and 29 to 35
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • can be taken with or without food
  • protect skin from sunlight

Note: missed doses should not be replaced; if a tablet is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

Notify medical team if the patient reports weight gain, shortness of breath and/or temperature as this may be symptoms of differentiation syndrome.

Read more about APML​ differentiation syndrome

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Days 1 to 5, 8 to 12, 15 to 19, 22 to 26 and 29 to 33 (IV)

Approximate treatment time: 2.5 hours

General patient assessment prior to each day of treatment.

Peripheral neuropathy assessment tool.

Any toxicity grade 3 or greater may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Arsenic trioxide (ATO)

Prior to administration:
  • check BSL as indicated 
  • baseline ECG then at least twice weekly ECG, or more frequently in unstable patients
  • maintain serum potassium above 4 mmol/L and magnesium above 0.8 mmol/L.
Administer arsenic trioxide:
  • via IV infusion over 2 hours
  • flush with 50 mL sodium chloride 0.9%
  • if the patient has a vasomotor reaction (lightheadedness, changes in blood pressure) the time of the arsenic infusion may be extended up to four hours.

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

Discharge information

Tretinoin capsules
  • Tretinoin capsules with written instructions on how to take them
Antiemetics
  • Antiemetics as prescribed.
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)
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Headache
QT prolongation associated with arsenic trioxide

This treatment can cause QTc interval prolongation and complete atrioventricular block. QTc prolongation can lead to ventricular arrhythmias that may be fatal.

Read more about ECG abnormalities related to arsenic trioxide

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
Peripheral neuropathy

Typically symmetrical sensory neuropathy, affecting the fingers and toes, sometimes progressing to the hands and feet.  It is associated with several classes of anti-cancer drugs. These include taxanes, platinum-based compounds, vinca alkaloids and some drugs used to treat multiple myeloma.

Read more about peripheral neuropathy
Thrombocytopenia

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

Read more about thrombocytopenia
Fatigue

Read more about fatigue
Photosensitivity

Increased sensitivity to ultraviolet (UV) light resulting in an exaggerated sunburn-like reaction accompanied by stinging sensations and urticaria.
Abdominal pain

Dull ache, cramping or sharp pains are common with some anti-cancer drugs. These are caused by either increased or decreased gastrointestinal motility and can be associated with diarrhoea or constipation.
Hypomagnesaemia, hypokalaemia, hypocalcaemia

Abnormally low levels of magnesium, potassium and calcium in the blood.
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
Hyperglycaemia

High blood sugar, an excess of glucose in the blood stream.
Skin rash

Anti-cancer drugs 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
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
Hepatotoxicity

Anti-cancer drugs administered either alone or in combination with other drugs and/or radiation may cause direct or indirect hepatotoxicity. Hepatic dysfunction can alter the metabolism of some drugs resulting in systemic toxicity.

Delayed (onset months to years)
Pulmonary toxicity

Pulmonary toxicity may include damage to the lungs, airways, pleura and pulmonary circulation. 

Read more about pulmonary toxicity associated with anti-cancer drugs

Acute promyelocytic leukemia (APML) is a biologically and clinically distinct variant of acute myeloid leukaemia characterised by t(15;17) translocation resulting in a PML-RAR fusion protein. The impaired myeloid differentiation resulting from the translocation may be restored by pharmacologic doses of all-trans-retinoic acid (ATRA).

Arsenic trioxide (ATO) acts synergistically with ATRA to degrade PML-RARA. APML4 was a phase 2 study which aimed to exploit ATO/ATRA synergy in order to minimize exposure to anthracycline (idarubicin) which is only given on days 2,4,6 and 8 of induction along with ATO/ATRA. Two “chemotherapy free” ATO/ATRA-only consolidation cycles were followed by 2 years of oral maintenance (ATRA, weekly methotrexate and 6-mercaptopurine).

Notable inclusion criteria included age >1 year (but no upper limit; age range was 19-73), ECOG performance status 0-3, normal left ventricular ejection fraction and Q-Tc interval <500 milliseconds. Idarubicin dosing was age adjusted. Molecular monitoring of bone marrow was mandated for assessment of treatment efficacy.r

Efficacy

There were 124 evaluable patients with 4 deaths during induction (1 myocardial ischaemia, 2 intracerebral haemorrhage, 1 cerebral oedema), while 2 withdrew from study during induction. The remaining 118/124 (95%) entered haematological complete remission (hCR). 112/118 hCR patients proceeded to consolidation, each of whom attained molecular remission. 2/112 patients relapsed after completion of consolidation, one with initial molecular relapse after 166 days (followed by CNS relapse and death) and one with molecular relapse after 189 (dying from sepsis during salvage therapy).

This equates to a freedom from relapse (FFR) of 97.5% and overall survival (OS) of 93.2%. Age did not correlate with FFR or OS. The failure free survival (FFS) of 88.1% was a composite measure of time from commencement of ATRA therapy to the earliest of treatment failure (failure to achieve molecular CR or withdrawal of protocol therapy for any reason), relapse, or death. The results compared favorably with the group’s prior APML3 study which used ATRA and idarubicin (but no arsenic) in induction and consolidation.r

Comparison of APML4 with APML3 (historic control). (C) FFS.

© Blood 2012

Maintenance therapy in low/intermediate risk patients

A separate cooperative group phase III non-inferiority study (SWOG 0521) was conducted to examine the need for maintenance therapy in patients with low/intermediate risk APML. The primary end point was 3-year disease free survival. The study was closed to new enrolment prematurely (105 patients enrolled of the intended 400) due to slow accrual. However, there were no relapses amongst the randomised patients.r

Further studies in the role of maintenance therapy in patients with low/intermediate risk disease achieving molecular remission post ATRA or ATO containing consolidation regimens, may need to be explored.r 

Toxicity

Most patients received at least 80% of maximum specified dosing of idarubicin, ATRA and ATO. During either of the 2 cycles of consolidation there was no case of differentiation syndrome and there were no deaths. During induction 14% experienced Q-Tc prolongation greater than 500ms, 44% developed grade 3/4 hepatic changes and 76% developed grade 3/4 infections.r

Grade 3/4 differentiation syndrome developed in 14%, with no resulting deaths. During either of the 2 cycles of consolidation there was no case of differentiation syndrome and there were no deaths.

© Blood 2012

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Version 2

Date Summary of changes
20/05/2016 New protocol taken to Reference Committee meeting.
05/10/2016 Approved and published on eviQ.

31/05/2017

Transferred to new eviQ website. Version number change to V.2.
21/09/2018 Protocol reviewed at Haematology Reference Committee meeting. Evidence updated to include paragraph on maintenance therapy in low/intermediate risk patients.Removed ATRA 'with food' from protocol for consistency with patient information. Review in 2 years.
23/10/2020 Protocol reviewed electronically by the Haematology Reference Committee, no changes. Review in 2 years.
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.
24/01/2022 Pulmonary toxicity added to side effects.

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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https://www.eviq.org.au/p/1937

18 May 2022