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THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST

Systemic Anti Cancer Therapy Protocol

Arsenic Trioxide and ATRA

Acute Promyelocytic Leukaemia (APML)

PROTOCOL REF: MPHAATAHA (Version No: 1.0)

Approved for use in: trioxide is recommended, within its marketing authorisation, as an option for inducing remission and consolidation in acute promyelocytic leukaemia (characterised by the presence of the t[15;17] translocation or the PML/RAR-alpha gene) in adults with:

 untreated, low-to-intermediate risk disease (defined as a white blood cell count of ≤10x109/L), when given with all-trans- (ATRA)

 relapsed or refractory disease, after a and

Blueteq registration required

Dosage - Induction: Drug Dose Route Frequency Tretinoin 45mg/m2/day (in two equally Twice daily for 60 days or (All-Trans- divided doses and rounded to Oral until a complete response – Retinoic- the nearest 10mg capsule) whichever comes first Acid) Arsenic IV 0.3mg/kg Days 1-5 (mon-fri) Trioxide infusion Days 9, 12, 16, 19, 23, 26, Arsenic IV 30, 33, 37, 40, 44, 47, 51 and 0.25mg/kg Trioxide infusion 54 (i.e. twice weekly for seven weeks)

Course length 56 days

Issue Date: 10th July 2020 Page 1 of 13 Protocol reference: MPHAATAHA Review Date: July 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST Dosage – Consolidation (cycles 1-3): Drug Dose Route Frequency Tretinoin 45mg/m2/day (in two equally (All-Trans- Twice daily days 1-14 and divided doses and rounded to Oral Retinoic- 29-42 of cycle the nearest 10mg capsule) Acid) Arsenic IV 0.3mg/kg Days 1-5 (mon-fri) Trioxide infusion Days 9, 12, 16, 19, 23 and 26 Arsenic IV 0.25mg/kg (i.e. twice weekly for three Trioxide infusion weeks

Course length 56 days

Dosage – Consolidation (cycle 4): Drug Dose Route Frequency Tretinoin 45mg/m2/day (in two equally (All-Trans- divided doses and rounded to Oral Twice daily days 1-14 Retinoic- the nearest 10mg capsule) Acid) Arsenic IV 0.3mg/kg Days 1-5 (mon-fri) Trioxide infusion Days 9, 12, 16, 19, 23 and 26 Arsenic IV 0.25mg/kg (i.e. twice weekly for three Trioxide infusion weeks

Course length 28 days

Administration (+/- Counselling Points): can be given over 4 hours if vasomotor reactions are observed. It is recommended that tretinoin be administered with a meal or shortly thereafter. Admission is necessary for induction chemotherapy

Issue Date: 10th July 2020 Page 2 of 13 Protocol reference: MPHAATAHA Review Date: July 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

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Anti-emetic risk (if applicable): Low emetogenic risk.

Supportive treatments: Allopurinol 300mg daily for first month. Consider rasburicase if high risk of tumour lysis syndrome.

Metoclopramide 10mg TDS PRN

Antimicrobial prophylaxis as per local policy (avoid drugs that prolong the QTc interval)

Extravasation risk (if applicable): Arsenic trioxide: non-vesicant Refer to the network guidance for the prevention and management of extravasation

Interactions: Tretinoin Tretinoin is contraindicated with other (i.e. A) because of the risk of symptoms suggestive of for daily doses greater than 10,000 IU. Tretinoin is also contraindicated with : risk of intracranial hypertension (pseudotumor cerebri).

As tretinoin is metabolised by the hepatic P450 system, there is the potential for alteration of parameters in patients administered concomitant medications that are also inducers or inhibitors of this system. Medications that generally induce hepatic P450 enzymes include rifampicin, glucocorticoids, phenobarbital and pentobarbital. Medications that generally inhibit hepatic P450 enzymes include ketoconazole, cimetidine, , verapamil, diltiazem and ciclosporin. There are no data to suggest that co-use with these medications increases or decreases either efficacy or toxicity of tretinoin.

Cases of fatal thrombotic complications have been reported rarely in patients concomitantly treated with tretinoin and antifibrinolytic agents such as tranexamic acid, aminocaproic acid

Issue Date: 10th July 2020 Page 3 of 13 Protocol reference: MPHAATAHA Review Date: July 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST and aprotinin. Therefore, caution should be exercised when administering tretinoin concomitantly with these agents.

Arsenic trioxide No formal assessments of pharmacokinetic interactions between arsenic trioxide and other therapeutic medicinal products have been conducted.

QT/QTc prolongation is expected during treatment with arsenic trioxide, and torsade de pointes and complete heart block have been reported. Patients who are receiving, or who have received, medicinal products known to cause hypokalaemia or hypomagnesaemia, such as diuretics or amphotericin B, may be at higher risk for torsade de pointes. Caution is advised when arsenic trioxide is co-administered with other medicinal products known to cause QT/QTc interval prolongation such as macrolide , the antipsychotic thioridazine, or medicinal products known to cause hypokalaemia or hypomagnesaemia.

Hepatotoxic effects may occur during the treatment with arsenic trioxide, caution is advised when arsenic is co-administered with other medicinal products known to cause hepatotoxic effects.

Treatment schedule: Induction Day Drug Dose Route Diluent and rate 1 to 45mg/m2/day (in 60 two equally With food. divided doses Tretinoin PO Stop once patient is in complete and rounded to remission the nearest 10mg capsule) IV 1 Arsenic trioxide 0.3mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion IV 2 Arsenic trioxide 0.3mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion IV 3 Arsenic trioxide 0.3mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion IV 4 Arsenic trioxide 0.3mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion IV 5 Arsenic trioxide 0.3mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 9 Arsenic trioxide 0.25mg/m2 IV Over 2 hours in 250mls NaCl 0.9%* Issue Date: 10th July 2020 Page 4 of 13 Protocol reference: MPHAATAHA Review Date: July 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST infusion IV 12 Arsenic trioxide 0.25mg/m2 Over 2 hours in 250mls NaCl 0.9%* infusion IV 16 Arsenic trioxide 0.25mg/m2 Over 2 hours in 250mls NaCl 0.9%* infusion IV 19 Arsenic trioxide 0.25mg/m2 Over 2 hours in 250mls NaCl 0.9%* infusion IV 23 Arsenic trioxide 0.25mg/m2 Over 2 hours in 250mls NaCl 0.9%* infusion IV 26 Arsenic trioxide 0.25mg/m2 Over 2 hours in 250mls NaCl 0.9%* infusion IV 30 Arsenic trioxide 0.25mg/m2 Over 2 hours in 250mls NaCl 0.9%* infusion IV 33 Arsenic trioxide 0.25mg/m2 Over 2 hours in 250mls NaCl 0.9%* infusion IV 37 Arsenic trioxide 0.25mg/m2 Over 2 hours in 250mls NaCl 0.9%* infusion IV 40 Arsenic trioxide 0.25mg/m2 Over 2 hours in 250mls NaCl 0.9%* infusion IV 44 Arsenic trioxide 0.25mg/m2 Over 2 hours in 250mls NaCl 0.9%* infusion IV 47 Arsenic trioxide 0.25mg/m2 Over 2 hours in 250mls NaCl 0.9%* infusion IV 51 Arsenic trioxide 0.25mg/m2 Over 2 hours in 250mls NaCl 0.9%* infusion IV 54 Arsenic trioxide 0.25mg/m2 Over 2 hours in 250mls NaCl 0.9%* infusion

Treatment schedule: Consolidation cycles 1-3 Day Drug Dose Route Diluent and rate 1 to 45mg/m2/day (in 14 two equally and divided doses Tretinoin PO With food. 29- and rounded to 42 the nearest 10mg capsule) 1 IV Arsenic trioxide 0.3mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 2 IV Arsenic trioxide 0.3mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 3 IV Arsenic trioxide 0.3mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 4 IV Arsenic trioxide 0.3mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 5 Arsenic trioxide 0.3mg/kg IV Over 2 hours in 250mls NaCl 0.9%*

Issue Date: 10th July 2020 Page 5 of 13 Protocol reference: MPHAATAHA Review Date: July 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST infusion 9 IV Arsenic trioxide 0.25mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 12 IV Arsenic trioxide 0.25mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 16 IV Arsenic trioxide 0.25mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 19 IV Arsenic trioxide 0.25mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 23 IV Arsenic trioxide 0.25mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 26 IV Arsenic trioxide 0.25mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion

Treatment schedule: Consolidation cycle 4 Day Drug Dose Route Diluent and rate 1 to 45mg/m2/day (in 14 two equally divided doses Tretinoin PO With food. and rounded to the nearest 10mg capsule) 1 IV Arsenic trioxide 0.3mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 2 IV Arsenic trioxide 0.3mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 3 IV Arsenic trioxide 0.3mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 4 IV Arsenic trioxide 0.3mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 5 IV Arsenic trioxide 0.3mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 9 IV Arsenic trioxide 0.25mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 12 IV Arsenic trioxide 0.25mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 16 IV Arsenic trioxide 0.25mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 19 IV Arsenic trioxide 0.25mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 23 IV Arsenic trioxide 0.25mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion 26 IV Arsenic trioxide 0.25mg/kg Over 2 hours in 250mls NaCl 0.9%* infusion

Issue Date: 10th July 2020 Page 6 of 13 Protocol reference: MPHAATAHA Review Date: July 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST * NB. Arsenic Trioxide infusion duration may be extended up to 4 hours if vasomotor reactions, e.g. flushing, tachycardia and dizziness, are observe. If patients suffer severe symptoms or hypotension then the infusion should be stopped until recovery and then recommenced at a reduced rate.

Main toxicities:

Thrombocytopenia, neutropenia, anaemia, nausea, vomiting, diarrhoea

Differentiation or ATRA syndrome

This potentially life-threatening complication of ATRA therapy is characterized by fluid retention and features of capillary leak and is most likely related to surface adhesion molecule modulation and cytokine release following induction of differentiation of APL cells. Symptoms and signs include cough, dyspnoea, fever, weight gain, oedema, pleural and pericardial effusions and pulmonary infiltrates differentiation syndrome occurs in up to a third of patients receiving ATRA as single-agent induction therapy and was fatal in approximately 30% in early studies. The syndrome typically develops approximately 10 days after initiation of ATRA, but can appear as early as 2 days and is commonly, but not invariably, associated with a rising peripheral WBC count.

Patients on ATRA should be observed very carefully for symptoms, signs or falling oxygen saturation levels indicative of impending differentiation syndrome. If there are clinical suspicions of this complication;  ATRA should be temporarily discontinued and steroids administered promptly (dexamethasone 10 mg IV BD until disappearance of symptoms and signs, and for a minimum of 3 d), which may prevent progression to the full blown syndrome.  ATRA can then be cautiously re-introduced.

Evidence to date suggests that steroids act by modulating the surface adhesion characteristics of APL blasts, preventing ATRA-induced aggregation that accompanies differentiation. Its occurrence during induction is not a contraindication to use of ATRA later in the patient's treatment course (including management of any relapse). Patients with a relatively high presenting WBC (>10 × 109/l) have in some studies been reported to be at higher risk of differentiation syndrome during induction and some trial groups advocate use of prophylactic steroids as a component of induction therapy. Issue Date: 10th July 2020 Page 7 of 13 Protocol reference: MPHAATAHA Review Date: July 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

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Hepatotoxicity Arsenic and tretinoin have been associated with hepatotoxicity – see below for details. NB toxic effects can be resolved with temporary discontinuation of tretinoin and/or arsenic.

Pseudotumour Cerebri The presence of severe headaches with nausea, vomiting, and visual disorders, generally developing in patients aged < 20 years. It is often necessary to discontinue ATRA temporarily and to administer opiates.

Lipids Up to 60% experience reversible and/or hypertriglyceridemia. Venous and myocardial infarction have been reported in patients ordinarily at low risk for such complications.

QT prolongation Arsenic has been associated with QTc interval prolongation with associated heart block and fatal ventricular arrhythmias. Prior to initiating therapy with arsenic, a 12-lead ECG must be performed and serum electrolytes (potassium, calcium, and magnesium) and creatinine must be assessed; pre-existing electrolyte abnormalities must be corrected and, if possible, medicinal products that are known to prolong the QT interval must be discontinued. Patients with risk factors of QTc prolongation or risk factors of torsade de pointes should be monitored with continuous cardiac monitoring (ECG). For QTc greater than 500 msec, corrective measures must be completed and the QTc reassessed with serial ECGs and, if available, a specialist advice could be sought prior to considering using arsenic. During therapy with arsenic, potassium concentrations must be kept above 4 mmol/l and magnesium concentrations must be kept above 0.74mmol/l. Patients who reach an absolute QT interval value > 500 msec must be reassessed and immediate action must be taken to correct concomitant risk factors, if any, while the risk/benefit of continuing versus suspending arsenic therapy must be considered. If syncope, rapid or irregular heartbeat develops, the patient must be hospitalised and monitored continuously, serum electrolytes must be assessed, arsenic therapy must be temporarily discontinued until the QTc interval regresses to below 460 msec, electrolyte abnormalities are corrected, and the syncope and irregular heartbeat cease. After recovery, treatment should be resumed at 50 % of the preceding daily dose. If

Issue Date: 10th July 2020 Page 8 of 13 Protocol reference: MPHAATAHA Review Date: July 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST QTc prolongation does not recur within 7 days of restarting treatment at the reduced dose, treatment with arsenic can be resumed at 0.11 mg/kg body weight per day for a second week. The daily dose can be escalated back to 100 % of the original dose if no prolongation occurs. There are no data on the effect of arsenic trioxide on the QTc interval during the infusion. Electrocardiograms must be obtained at least twice weekly, and more frequently for clinically unstable patients, during induction and consolidation.

Coagulopathy A major cause of treatment failure is induction death as a result of haemorrhage, which reflects to varying degree DIC excessive fibrinolysis and proteolysis. Patients with higher presenting WBC (i.e. >10 × 109/l) are at highest risk of haemorrhagic death. Patients with very high presenting leucocyte counts should not undergo leucopheresis, which commonly precipitates fatal exacerbation of the coagulopathy.

High rates of induction death have also been observed when low-dose chemotherapy was used to attempt to reduce WBC in the first instance (Vahdat et al, 1994). Haemorrhagic deaths may be reduced by rigorous monitoring of the coagulation profile and administration of appropriate replacement therapy until morphological CR has been attained.

APTT, prothrombin time, thrombin time, fibrinogen level and platelet count should be checked at least twice daily during the early stages of treatment. Coagulation times should be kept within the normal range using FFP or Riaspin as replacement. Fibrinogen levels may be low due to DIC and cryoprecipitate should be given as replacement aiming for a level of approximately 2 g/l. Elevated levels of fibrinogen should be avoided because of the increased risk of thrombosis associated with APL, which may be further exacerbated by ATRA.

The platelet count should ideally be maintained above 50 × 109/l until morphological remission has been confirmed. Clinical studies have not established proven benefit for use of heparin or anti-fibrinolytic agents as a means of decreasing induction death rates in APL and their routine use is not recommended. Indeed, anti-fibrinolytic agents when combined with ATRA could potentially increase the inherent risk of thrombotic complications. Nevertheless, anti-fibrinolytic agents could be contemplated in situations of life-threatening haemorrhage in the presence of normal coagulation assays.

Issue Date: 10th July 2020 Page 9 of 13 Protocol reference: MPHAATAHA Review Date: July 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

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Investigations and treatment plan: Induction

Pre D1 D2 D3 D4 D5 D9 D12 D16 D19 D23 D26 D30 D33 D37 D40 D44 D47 D51 D54 Ongoing

Informed consent x Clinical

Assessment x x x x x x x x x x SACT Assessment (including performance status x x x x x x x x x x x x x x x x x x x and toxicity assessment) Hepatitis B core antibody and surface antigens & x Hep C & HIV 1+2, CMV, VZV PML-RARA screen x Daily until Clotting screen + haematological fibrinogen x x x x x x x x x x x x x x x x x x x x remission FBC x x x x x x x x x x x x x x x x x x x x Glucose x x x x x x x x x x x x x x x x X U&E & LFTs &

Magnesium x x x x x x x x x x x x x x x x x CrCl (Cockcroft and Gault) x Repeat once Bone Marrow haematological Biopsy x remission achieved ECHO x More often in ECG x x x x x x x x x x x x x x x x x unstable patients

Issue Date: 10th July 2020 Page 10 of 13 Protocol reference: MPHAATAHA Review Date: July 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

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Weight x x x x x x x x x x x x x x x x x x Height x

Investigations and treatment plan: Consolidation

Pre D1 D2 D3 D4 D5 D9 D12 D16 D19 D23 D26 D30 D33 D37 D40 D44 D47 D51 D54 Ongoing Senior medical review before Clinical cycle starts Assessment x x x x x x x x thereafter CNS once weekly SACT Assessment (including performance status x x x x x x x x x x x Every cycle and toxicity assessment) Clotting screen +

Fibrinogen x FBC x x x x x x x x x x x x Glucose x x x x x x x x x U&E & LFTs &

Magnesium x x x x x x x x x x x x CrCl (Cockcroft and Gault) x Bone Marrow Between days 44- Biopsy 54 ECG x x x x x x x x Weight x

Issue Date: 10th July 2020 Page 11 of 13 Protocol reference: MPHAATAHA Review Date: July 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

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Dose Modifications and Toxicity Management: Haematological toxicity: Induction should start regardless of cytopenias.

For subsequent cycles proceed if- ANC ≥ 1.5 x 109/L Plt ≥ 100 x 109/L

These haematological guidelines assume that patients are well with good performance status, that other acute toxicities have resolved and the patient has not had a previous episode of neutropenic sepsis.

Dosing in renal and hepatic impairment: Tretinoin

CrCl (ml/min) Dose of tretinoin <50ml/min 25mg/m2 daily

Liver Dysfunction Hepatic insufficiency 25mg/m2 daily

Arsenic

CrCl (ml/min) Dose of arsenic <30ml/min Consider 50% dose reduction

Liver dysfunction - prior to treatment Hepatotoxicity is a known side effect of arsenic therefore caution is required if arsenic is started in anyone with known hepatic impairment.

Liver Dysfunction Dose of arsenic Childs Pugh C Consider 50% dose reduction

Arrhythmias: If syncope, rapid or irregular heartbeat develops, the patient must be hospitalised and monitored continuously, serum electrolytes must be assessed, arsenic therapy must be temporarily discontinued until the QTc interval regresses to below 460 msec, electrolyte abnormalities are corrected, and the syncope and irregular heartbeat cease. After

Issue Date: 10th July 2020 Page 12 of 13 Protocol reference: MPHAATAHA Review Date: July 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

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recovery, treatment should be resumed at 50 % of the preceding daily dose. If QTc prolongation does not recur within 7 days of restarting treatment at the reduced dose, treatment with arsenic can be resumed at 0.11 mg/kg body weight per day for a second week. The daily dose can be escalated back to 100 % of the original dose if no prolongation occurs.

References: 1. Summary of Product Characteristics for Arsenic (Teva Pharma B.V.), viewed January 2020 (available at https://www.medicines.org.uk/emc 2. Summary of Product Characteristics for Tretinoin (Cheplapharm Arzneimittel GmbH), viewed January 2020 (available at https://www.medicines.org.uk/emc) 3. Krens S D, Lassche, Jansman G F G A, et al. Dose recommendations for anticancer drugs in patients with renal or hepatic impairment. Lancet Oncol 2019; 20: e201–08. 4. Thames Valley Strategic Clinical Network. ATRA and Arsenic Protocol. October 2019.

Issue Date: 10th July 2020 Page 13 of 13 Protocol reference: MPHAATAHA Review Date: July 2023 Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0