Mylotarg in Combination with DA

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Systemic Anti-Cancer Treatment Protocol

Mylotarg® in combination with DA Acute Myeloid Leukaemia (AML)

PROTOCOL REF: MPHAMDAHA

(Version No: 1.1)

Approved for use in: Gemtuzumab Ozogamicin (Mylotarg®) is indicated, in combination with daunorubicin and cytarabine (DA), for the treatment of previously untreated CD33-positive Acute Myeloid Leukaemia (AML) in patients aged 15 years and over when the following conditions are met:  The prescribing consultant is fully aware of the potential for Mylotarg® to induce hepatotoxicity, including veno-occlusive liver disease / sinusoidal obstruction syndrome  The patient does NOT have Acute Promyelocytic Leukaemia (APML)  The patient has previously untreated AML  The patient is aged 15 years or over  The patient starts treatment when they have had cytogenetics performed and confirmed as favourable, intermediate or unknown cytogenetics (that is, because the test was unsuccessful), or when their cytogenetic tests are not available yet.  The patient is fit for intensive induction chemotherapy  Mylotarg® is to be given in combination with daunorubicin and cytarabine  Note this protocol should only be used to treat patients off-trial. Refer to relevant trial protocol for enrolled patients.  Exempt from NHS England treatment break policy

Blueteq registration required for Mylotarg®

Issue Date: 13th March 2020 Page 1 of 14 Protocol reference: MPHAMDAHA Review: March 2023 Author: Niamh McLaughlin Authorised by: Drug & Therapeutics Committee Version No: 1.1

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Dosage: Treatment Drug Dosage Route Frequency course 2 Mylotarg® 3 mg/m /dose IV Days 1,4 and 7 (max 5mg/dose) First 2 Induction Daunorubicin 60 mg/m /day IV Days 1-3 Cytarabine 200 mg/m2/day IV Days 1-7 Mylotarg® should not be administered during second induction Second 2 induction Daunorubicin 35 mg/m /day IV Days 1-2 (if required)* Every 12 hours on days Cytarabine 1000 mg/m2/dose IV 1-3 2 Mylotarg® 3 mg/m /dose IV On day 1 only (max 5mg/dose) Consolidation Daunorubicin 60 mg/m2/day IV On day 1 only course 1** Every 12 hours on days Cytarabine 1000 mg/m2/dose IV 1-4 2 Mylotarg® 3 mg/m /dose IV On day 1 only (max 5mg/dose) Consolidation Daunorubicin 60 mg/m2/day IV Days 1and 2 course 2 Every 12 hours on days Cytarabine 1000 mg/m2/dose IV 1-4

*If residual disease on D14 bone marrow biopsy

**For patients experiencing a complete remission (CR) following induction, defined as fewer than 5% blasts in a normocellular marrow and an absolute neutrophil count (ANC) >1.0 × 109 cells/L with a platelet count of ≥100 × 109/L in the peripheral blood in the absence of transfusion, up to 2 consolidation courses can be given.

Schedule modification for hyperleukocytosis: If leukocyte count ≥30x109/L, cyto-reduction is recommended 48 hours prior to commencing Mylotarg ® in order to reduce the peripheral white cell count. See recommended changes to induction schedule below. Options for cyto-reduction include:

Issue Date: 13th March 2020 Page 2 of 14 Protocol reference: MPHAMDAHA Review: March 2023 Author: Niamh McLaughlin Authorised by: Drug & Therapeutics Committee Version No: 1.1

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 Leukapheresis.  Oral hydroxycarbamide.  Cytarabine +/- hydroxycarbamide

If Cytarabine is used for leukoreduction, (with or without hydroxycarbamide); in patients with previously untreated de novo hyperleukocytic AML, receiving Mylotarg® in combination therapy, apply the following modified schedule for the first induction cycle:

Treatment Drug Dosage Route Frequency course 2 Mylotarg® 3 mg/m /dose IV Days 3,6 and 9 (max 5mg/dose) Daunorubicin 60 mg/m2/day IV Days 3-5 Induction Cytarabine 200 mg/m2/day IV Days 1-7 Hydroxyurea 40-60mg/kg/day PO Day 1

Supportive treatments:

1. Premedication with a corticosteroid, antihistamine, and paracetamol is necessary 1 hour prior to Mylotarg® to help ameliorate infusion-related symptoms 2. Anti-hyperuricaemic treatment as per trust tumour lysis policy 3. Anti-emetics as per Trust chemotherapy-induced nausea and vomiting policy 4. Anti-microbials as per Trust Antimicrobial prophylaxis policy 5. Corticosteroid eye drops QDS for duration of treatment and for five days after (second induction and consolidation cycles only)

Consider avoiding posaconazole and other azoles while on Mylotarg® and for five days after Mylotarg® treatment has finished. AML 19 clinical trial protocol recommends this owing to potential risk of hepatotoxicity, but Mylotarg® SPC makes no reference to this risk, so clinical judgement should be used. Use Caspofungin as an alternative to azole prophylaxis if required.

Issue Date: 13th March 2020 Page 3 of 14 Protocol reference: MPHAMDAHA Review: March 2023 Author: Niamh McLaughlin Authorised by: Drug & Therapeutics Committee Version No: 1.1

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Cautions  Hypotension may occur, therefore it is advisable to withhold anti-hypertensive medications 12hours before and 12 hours after treatment with Mylotarg®  Adverse risk cytogenetics  Moderate/severe hepatic impairment: increased risk of veno-occlusive disease  Concomitant use of cardiotoxic agents  Pregnant/breastfeeding

Extravasation Risk: 1. Daunorubicin- vesicant 2. Cytarabine- non-vesicant 3. Mylotarg®- unknown

Refer to the CCC policy for the ‘Prevention and Management of Extravasation Injuries’

Administration: Do not give other drugs through the same infusion line as Mylotarg®

Day Drug Dosage Route Diluent and Rate

Induction Cycle 1

Diluted in 100ml NaCl 0.9% Hydrocortisone 100mg IV over 30 minutes Chlorphenamine 10mg IV IV Stat Paracetamol 1000mg PO Oral Stat Day 1 In 50ml 0.9% sodium 2 IV chloride over 2 hours, via Mylotarg®* 3mg/m (max 5mg) infusion low-protein binding 0.2 micron filter. Monitor vital signs during Mylotarg® infusion and for 4 hours after

Issue Date: 13th March 2020 Page 4 of 14 Protocol reference: MPHAMDAHA Review: March 2023 Author: Niamh McLaughlin Authorised by: Drug & Therapeutics Committee Version No: 1.1

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In 100ml 0.9% sodium Daunorubicin 60mg/m2 IV chloride given over 30mins In 1000ml 0.9% sodium Cytarabine 200mg/m2 IV chloride given over 22hours In 100ml 0.9% sodium Daunorubicin 60mg/m2 IV chloride given over 30mins Day 2 In 1000ml 0.9% sodium Cytarabine 200mg/m2 IV chloride given over 22hours In 100ml 0.9% sodium Daunorubicin 60mg/m2 IV chloride given over 30mins Day 3 In 1000ml 0.9% sodium Cytarabine 200mg/m2 IV chloride given over 22hours Diluted in 100ml NaCl 0.9% Hydrocortisone 100mg IV over 30 minutes Chlorphenamine 10mg IV IV Stat Paracetamol 1000mg PO Oral Stat In 50ml 0.9% sodium Day 4 2 IV chloride over 2 hours, via Mylotarg®* 3mg/m (max 5mg) infusion low-protein binding 0.2 micron filter. Monitor vital signs during Mylotarg® infusion and for 4 hours after In 1000ml 0.9% sodium Cytarabine 200mg/m2 IV chloride given over 22hours In 1000ml 0.9% sodium Day 5 Cytarabine 200mg/m2 IV chloride given over 22hours In 1000ml 0.9% sodium Day 6 Cytarabine 200mg/m2 IV chloride given over 22hours Diluted in 100ml NaCl 0.9% Hydrocortisone 100mg IV over 30 minutes Chlorphenamine 10mg IV IV Stat Paracetamol 1000mg PO Oral Stat In 50ml 0.9% sodium Day 7 Mylotarg®* 3mg/m2 IV chloride over 2 hours, via (Only for Induction 1) (max 5mg) infusion low-protein binding 0.2 micron filter. Monitor vital signs during Mylotarg® infusion and for 4 hours after In 1000ml 0.9% sodium Cytarabine 200mg/m2 IV chloride given over 22hours

Induction cycle 2 (If required. No Mylotarg®)

In 100ml 0.9% sodium Day 1 Daunorubicin 35mg/m2 IV chloride given over 30mins

Issue Date: 13th March 2020 Page 5 of 14 Protocol reference: MPHAMDAHA Review: March 2023 Author: Niamh McLaughlin Authorised by: Drug & Therapeutics Committee Version No: 1.1

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In 500ml 0.9% sodium 1100 Cytarabine 1000mg/m2 IV chloride given over 2 hours In 500ml 0.9% sodium 2300 Cytarabine 1000mg/m2 IV chloride given over 2 hours In 100ml 0.9% sodium Daunorubicin 35mg/m2 IV chloride given over 30mins In 500ml 0.9% sodium Day 2 1100 Cytarabine 1000mg/m2 IV chloride given over 2 hours In 500ml 0.9% sodium 2300 Cytarabine 1000mg/m2 IV chloride given over 2 hours In 500ml 0.9% sodium 1100 Cytarabine 1000mg/m2 IV chloride given over 2 hours Day 3 In 500ml 0.9% sodium 2300 Cytarabine 1000mg/m2 IV chloride given over 2 hours

Consolidation Cycle 1

In 500ml 0.9% sodium 1100 Cytarabine 1000mg/m2 IV chloride given over 2 hours Day 3 In 500ml 0.9% sodium 2300 Cytarabine 1000mg/m2 IV chloride given over 2 hours In 500ml 0.9% sodium Day 4 1100 Cytarabine 1000mg/m2 IV chloride given over 2 hours

Issue Date: 13th March 2020 Page 6 of 14 Protocol reference: MPHAMDAHA Review: March 2023 Author: Niamh McLaughlin Authorised by: Drug & Therapeutics Committee Version No: 1.1

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In 500ml 0.9% sodium 2300 Cytarabine 1000mg/m2 IV chloride given over 2 hours

Consolidation Cycle 2

Diluted in 100ml NaCl Hydrocortisone 100mg IV 0.9% over 30 minutes Chlorphenamine 10mg IV IV Stat Paracetamol 1000mg PO Oral Stat In 50ml 0.9% sodium 3mg/m2 IV chloride over 2 hours, via Mylotarg®* (max 5mg) infusion low-protein binding 0.2 Day 1 micron filter. Monitor vital signs during Mylotarg® infusion and for 4 hours after In 100ml 0.9% sodium Daunorubicin 60mg/m2 IV chloride given over 30mins In 500ml 0.9% sodium 1100 Cytarabine 1000mg/m2 IV chloride given over 2 hours In 500ml 0.9% sodium 2300 Cytarabine 1000mg/m2 IV chloride given over 2 hours In 100ml 0.9% sodium Daunorubicin 60mg/m2 IV chloride given over 30mins In 500ml 0.9% sodium Day 2 1100 Cytarabine 1000mg/m2 IV chloride given over 2 hours In 500ml 0.9% sodium 2300 Cytarabine 1000mg/m2 IV chloride given over 2 hours In 500ml 0.9% sodium 1100 Cytarabine 1000mg/m2 IV chloride given over 2 hours Day 3 In 500ml 0.9% sodium 2300 Cytarabine 1000mg/m2 IV chloride given over 2 hours In 500ml 0.9% sodium 1100 Cytarabine 1000mg/m2 IV chloride given over 2 hours Day 4 In 500ml 0.9% sodium 2300 Cytarabine 1000mg/m2 IV chloride given over 2 hours *Must be protected from light

Counselling points: Mylotarg® has moderate influence on the ability to drive and use machines. Patients should be advised they may experience fatigue, dizziness and headache during treatment with Mylotarg® (see section 4.8). Therefore, caution should be exercised when driving or operating machines.

Issue Date: 13th March 2020 Page 7 of 14 Protocol reference: MPHAMDAHA Review: March 2023 Author: Niamh McLaughlin Authorised by: Drug & Therapeutics Committee Version No: 1.1

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Contraceptive advise- use at least 2 methods of contraception during treatment with Mylotarg®, and for at least 7 months (females) and 4 months (males) after the last dose.

Drug Interactions: Mylotarg®: The concomitant use of hepatotoxic drugs should be risk assessed on a patient by patient basis (e.g. azole antifungals) Based on population pharmacokinetic (PK) analyses, the combination of Mylotarg® with Daunorubicin and Cytarabine is not predicted to cause clinically meaningful changes in the PK of these agents.

Daunorubicin: Concomitant use with cardiotoxic agents is not recommended

Cytarabine: May reduce steady state concentrations of digoxin- monitoring of digoxin levels recommended

Methotrexate: Intravenous cytarabine given concomitantly with intrathecal methotrexate may increase the risk of severe neurological adverse reactions such as headache, paralysis, coma and stroke like episodes

Issue Date: 13th March 2020 Page 8 of 14 Protocol reference: MPHAMDAHA Review: March 2023 Author: Niamh McLaughlin Authorised by: Drug & Therapeutics Committee Version No: 1.1

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Investigations and Treatment plan:

Induction Induction Induction Induction Induction Consolidation Consolidation Pre Cycle 1, Cycle 1, Cycle 1, Cycle 1, Ongoing Cycle 2 cycle 1 cycle 2 D1 D4 D7 D14 (if required) Clinical Assessment X X X X X Every cycle SACT Assessment, X including toxicities and X X X Every cycle

performance status FBC X X X X X Every cycle U&E, LFT, bone profile X X X X X Every cycle Glucose (and HbA1c if X X X X X Every cycle indicated) CrCl X X X X X Every cycle Repeat as Uric Acid X clinically indicated Repeat as LDH X clinically indicated Hepatitis B sAg and core Antibody and X hepatitis C antibody, HIV 1+2 Informed Consent X Weight recorded X X X X X Every cycle Height X

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Pregnancy test X If applicable Continuous monitoring Temperature, X X X X X required if on respiratory rate, pulse mylotarg and for four hours after Bone marrow biopsy X X

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Dose Modifications and Toxicity Management: Haematological toxicity

Induction cycle(s) to be completed regardless of neutrophil and platelet counts.

Proceed with consolidation cycle(s) if all apply:-

ANC ≥ 1.0 x 109/L Platelets ≥ 100 x 109/L

If these parameters are not met- see below:

Mylotarg®

Haematological Toxicity Dose Modification  Postpone start of consolidation course.

 If platelet count recovers to ≥ 100 x 109/L within 14 days following the planned start date of the consolidation course: initiate consolidation therapy

 If platelet count recovers to between 50-100 x 109/L and within 14 days following the planned start date of Persistent the consolidation course: Mylotarg® should not be re- thrombocytopenia introduced and consolidation therapy should consist of Platelets <100 x 109/L DA only.

 If platelet count recovery remains < 50 x 109/L for greater than 14 days, takes longer than 14 days, or if platelet count does not recover to ≥ 50 x 109/L consolidation therapy should be re-evaluated and a bone marrow should be performed to re-assess the patients' status.

If neutrophil count does not recover to greater than 5 x 109/L within 14 days following the planned start date of Persistent neutropenia the consolidation cycle (14 days after haematologic ANC ≤ 1.0 x 109/L recovery following previous cycle), discontinue Mylotarg® (do not administer Mylotarg® in the consolidation cycles).

Issue Date: 13th March 2020 Page 11 of 14 Protocol reference: MPHAMDAHA Review: March 2023 Author: Niamh McLaughlin Authorised by: Drug & Therapeutics Committee Version No: 1.1

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Non-haematological toxicity

Renal Daunorubicin:

Creatinine clearance (ml/min) Daunorubicin dosing >50 100% 30-50 75% <30 50% Hemodialysis 50%

Cytarabine:

No dose reductions are necessary for Induction cycle 1

Dose reductions for cycles 2-4

Creatinine clearance (ml/min) Cytarabine dosing >60 100%

30-60 75%

<30 Not recommended

50% dose

Haemodialysis Start HD 4-5hrs after cytarabine

administration

Mylotarg®:

No dose adjustment required in patients with mild to moderate renal impairment. Mylotarg® has not been studied in patients with severe renal impairment. Mylotarg® does not undergo renal clearance and the pharmacokinetics in patients with severe renal impairment is unknown. Dosing in renal impairment would be a clinical decision.

Hepatic Daunorubicin:

Bilirubin (µmol/L) Daunorubicin Dose <20 100% 20-50 75% >50 50%

Cytarabine:

Cytarabine Dose Mild to moderate No dose reduction 25-50% original dose and titrate Severe as tolerated

Mylotarg®:

Issue Date: 13th March 2020 Page 12 of 14 Protocol reference: MPHAMDAHA Review: March 2023 Author: Niamh McLaughlin Authorised by: Drug & Therapeutics Committee Version No: 1.1

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Use with caution-may increase risk of veno-occlusive disease.

Liver Impairment: Mylotarg® Dose Postpone Mylotarg® until recovery of total bilirubin to ≤ 2 × ULN and AST and ALT to ≤ Bilirubin >2 x ULN and 2.5 × ULN prior to each dose. AST and/or ALT >2.5 x Consider omitting scheduled dose if delayed ULN more than 2 days between sequential infusions. Note that significantly impaired hepatic function might be a sign of disease progression and require cessation or change of treatment. Hepatotoxicity, including life-threatening, and sometimes fatal hepatic failure and VOD/SOS have been reported in patients treated with Mylotarg®

Always discuss deteriorating organ function with consultant

Drug Specific Management Veno-occlusive Note Mylotarg® frequently causes a transient elevation of liver disease (VOD) function around 8-10 days following infusion. This usually settles within 2-3 days and is not usually indicative of VOD.

Signs and symptoms include: Hyperbilirubinaema, ascites, weight gain (fluid retention) and hepatomegaly.

Send for urgent doppler ultrasound of liver to assess hepatic blood flow

IV Defibrotide should be considered for a minimum of 7 days (6.25mg/kg every 6 hours- i.e. total 25mg/kg/day) If Defibrotide is required, contact your pharmacist immediately for further advice.

Infusion-related Signs and symptoms of infusion related reactions may include reactions fever and chills, and less frequently hypotension, tachycardia, and respiratory symptoms that may occur during the first 24 hours after administration. Infusion of Mylotarg® should be performed under close clinical monitoring, including pulse, blood pressure, and temperature. Premedication with a corticosteroid, antihistamine and acetaminophen (or paracetamol) is recommended 1 hour prior to Mylotarg® dosing. Infusion should be interrupted immediately for patients who develop evidence of severe reactions, especially dyspnoea, bronchospasm, or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinuation of treatment should be strongly considered for patients who develop signs

Issue Date: 13th March 2020 Page 13 of 14 Protocol reference: MPHAMDAHA Review: March 2023 Author: Niamh McLaughlin Authorised by: Drug & Therapeutics Committee Version No: 1.1

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or symptoms of anaphylaxis, including severe respiratory symptoms or clinically significant hypotension

Tumour Lysis See trust protocol Syndrome (TLS)

Other reported Fever, chills, nausea, vomiting, headache, dyspnoea, adverse reactions hypotension, hypertension, hyperglycaemia, infection, bleeding, mucositis, rash, cutaneous herpes simplex, early mortality, abdominal pain, asthenia, back pain, pain, sepsis, tachycardia, anorexia, constipation, diarrhoea, abnormal LFTs, stomatitis, hypokalemia, raised LDH, peripheral oedema, anxiety, depression, dizziness, insomnia, cough, epistaxis, pharyngitis, pneumonia, local reaction.

References:  NICETA545. Gemtuzumab ozogamicin for untreated acute myeloid leukaemia. 2018  NCRI (2016) Adults with Acute Myeloid Leukaemia or High-Risk Myelodysplastic Syndrome (AML19), Version 5.0.  Pfizer Japan (2019) Mylotarg® Injection 5mg Summary of Product Characteristic, Version 7.  Krens SD et al. Dose recommendations for anticancer drugs in patients with hepatic or renal impairment. Lancet Oncol 2019; 20: e201-208  Richardson PG, Murakami C, Jin Z et al. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood 2002;100:4337-4343.  Richardson PG, Elias AD, Krishnan A et al. Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood 1998;92:737-744.  Chopra R, Eaton JD, Grassi A et al. Defibrotide for the treatment of hepatic veno- occlusive disease: results of the European compassionate-use study. British Journal of Haematology 2000;111:1122-1129.

Issue Date: 13th March 2020 Page 14 of 14 Protocol reference: MPHAMDAHA Review: March 2023 Author: Niamh McLaughlin Authorised by: Drug & Therapeutics Committee Version No: 1.1