Gemtuzumab Ozogamicin

Gemtuzumab ozogamicin is a CD33-directed antibody-drug conjugate. The antibody (gemtuzumab, a humanised IgG4 produced in mammalian NS0 cells) recognises human CD33, a sialic acid-dependent adhesion protein found on myeloid leukaemic blasts and on immature normal cells of the myelomonocytic lineage, but not on normal haematopoietic stem cells. It is covalently linked, through an AcBut (4-(4-acetylphenoxy)butanoic acid) linker, to the semisynthetic cytotoxic natural product N-acetyl gamma calicheamicin.

Mechanism of Action

• Targeting: the antibody binds CD33 on leukaemic cells, and the antibody–CD33 complex is internalised.
• Release: inside the cell the linker is cleaved by hydrolysis, releasing N-acetyl gamma calicheamicin dimethyl hydrazide.
• DNA damage: the activated calicheamicin derivative binds DNA and induces double-stranded DNA breaks, leading to cell-cycle arrest and apoptotic cell death.
• CD33 saturation: in studies of relapsed or refractory AML, near-maximal peripheral CD33 saturation was seen at all dose levels of 2 mg/m² and above, suggesting that a low dose is enough to bind all available CD33 sites.

Pharmacokinetics

• Exposure: after 3 mg/m² (up to one 5 mg vial) on Days 1, 4 and 7 in adults with relapsed or refractory AML, geometric mean AUC and peak concentration were 461,500 pg·h/mL and 11,740 pg/mL for conjugated calicheamicin, and 26,820 ng·h/mL and 585.6 ng/mL for total hP67.6 antibody. Unconjugated calicheamicin could not be reported because it is unstable in plasma.
• Distribution: the released calicheamicin derivative is about 97% bound to human plasma proteins in vitro and is a P-gp substrate in vitro. The total volume of distribution of the antibody is about 20 L.
• Metabolism: the main pathway is expected to be hydrolytic release of the calicheamicin derivative, which is then extensively metabolised, mainly by non-enzymatic reduction of its disulphide moiety. The resulting metabolites are expected to be much less cytotoxic.
• Elimination: gemtuzumab ozogamicin does not undergo renal clearance. See section 5.2 of the SmPC for the elimination parameters.
• Special populations: no dose adjustment in the elderly or in mild to moderate renal impairment. Hepatic impairment is addressed in the dosing rules below.

• Previously untreated, de novo CD33-positive acute myeloid leukaemia (AML): in combination with daunorubicin and cytarabine, for patients aged 15 years and above, except acute promyelocytic leukaemia (APL).
• It is used only in patients eligible for intensive induction chemotherapy.

• Hypersensitivity to gemtuzumab ozogamicin or to any of the excipients.

The profile rests on the combination study ALFA-0701, monotherapy studies (mostly in relapsed AML) and post-marketing experience. In ALFA-0701 the clinically relevant serious reactions were hepatotoxicity including VOD/SOS (3.8%), haemorrhage (9.9%), severe infection (41.2%) and tumour lysis syndrome (1.5%); the most common reactions (above 30%) were haemorrhage and infection. In monotherapy studies, serious reactions also included infusion-related reactions (2.5%), thrombocytopenia (21.7%) and neutropenia (34.3%). The reactions most often leading to permanent discontinuation in the combination study were thrombocytopenia, VOD, haemorrhage and infection.

Very common (≥1/10): infection (including sepsis and bacteraemia, fungal, bacterial, viral, skin, gastrointestinal and respiratory tract infections), febrile neutropenia, thrombocytopenia, neutropenia, anaemia, leukopenia, hyperglycaemia, decreased appetite, headache, tachycardia, haemorrhage (including central nervous system, gastrointestinal, subcutaneous bleeding and epistaxis), hypotension, hypertension, dyspnoea, vomiting, diarrhoea, abdominal pain, nausea, stomatitis, constipation, raised transaminases, hyperbilirubinaemia, rash, pyrexia, oedema, fatigue, chills, raised blood lactate dehydrogenase. In the combination study, laboratory changes were also very common: falls in haemoglobin, platelets, white cells, lymphocytes and neutrophils, raised AST, ALT, alkaline phosphatase and bilirubin, prolonged prothrombin time and activated partial thromboplastin time, and hyperuricaemia.

Common (≥1/100 to <1/10): pancytopenia, lymphopenia, infusion-related reaction, tumour lysis syndrome, ascites, dyspepsia, oesophagitis, veno-occlusive liver disease, hepatomegaly, jaundice, abnormal hepatic function, raised gamma-glutamyltransferase, erythema, pruritus, multi-organ failure, raised blood alkaline phosphatase.

Uncommon (≥1/1,000 to <1/100): hepatic failure and Budd-Chiari syndrome (single cases).

Not known: interstitial pneumonia, neutropenic colitis and haemorrhagic cystitis (some with fatal outcome), and, from post-marketing reports, fungal lung infections (including pulmonary mycosis and Pneumocystis jirovecii pneumonia) and bacterial infections such as Stenotrophomonas infection.

Serious reactions to watch for are hepatotoxicity with VOD/SOS (reported in 4.6% of patients in the combination study, 2 fatal), haemorrhage (fatal intracranial or subdural bleeding in 2.3%), severe infection, infusion-related reactions including anaphylaxis, and tumour lysis syndrome.

• No clinical drug interaction studies have been conducted with gemtuzumab ozogamicin.
• In vitro, the calicheamicin derivative is metabolised mainly by non-enzymatic reduction, so inhibitors or inducers of cytochrome P450 or UGT enzymes are unlikely to change its exposure. It is a P-gp substrate in vitro.
• Population pharmacokinetic analysis predicts no clinically meaningful change in the pharmacokinetics of the antibody or of unconjugated calicheamicin when combined with hydroxycarbamide, daunorubicin and cytarabine.

Mylotarg is given under the supervision of a physician experienced in the use of anticancer medicinal products, in an environment where full resuscitation facilities are immediately available. It is used only in patients eligible for intensive induction chemotherapy. It is reconstituted and diluted before use (see section 6.6 of the SmPC) and infused intravenously over 2 hours with close monitoring of pulse, blood pressure and temperature. It must never be given as an intravenous push or bolus.

Premedication and Prophylaxis

• A corticosteroid, an antihistamine and paracetamol are recommended 1 hour before each dose, to ease infusion-related symptoms.
• Measures against tumour lysis-related hyperuricaemia (hydration, antihyperuricaemic or other agents) should be taken.
• In hyperleukocytic AML (leukocyte count 30,000/mm³ or more), cytoreduction with leukapheresis, oral hydroxycarbamide, or cytarabine with or without hydroxycarbamide is recommended to lower the white cell count 48 hours before Mylotarg. If cytarabine is used for this in previously untreated de novo disease on combination therapy, a modified schedule applies: Mylotarg 3 mg/m² on Days 3, 6 and 9, daunorubicin 60 mg/m²/day on Days 3 to 5, cytarabine 200 mg/m²/day on Days 1 to 7, and hydroxycarbamide on Day 1 as per standard practice.

Recommended Dose

• Induction: Mylotarg 3 mg/m²/dose (up to a maximum of one 5 mg vial) over 2 hours on Days 1, 4 and 7, with daunorubicin 60 mg/m²/day over 30 minutes on Days 1 to 3 and cytarabine 200 mg/m²/day by continuous infusion on Days 1 to 7.
• Second induction, if required: no Mylotarg. Daunorubicin 35 mg/m²/day on Days 1 and 2 and cytarabine 1 g/m² every 12 hours on Days 1 to 3 only.
• Consolidation: for patients in complete remission after induction (fewer than 5% blasts in a normocellular marrow, neutrophils above 1.0 × 10⁹/L and platelets of 100 × 10⁹/L or more without transfusion), up to 2 courses of Mylotarg 3 mg/m² (maximum one 5 mg vial, over 2 hours) on Day 1, with daunorubicin 60 mg/m² for 1 day (first course) or 2 days (second course) and cytarabine 1 g/m² every 12 hours, over 2 hours, on Days 1 to 4.

Dose Modifications

• Persistent thrombocytopenia (platelets below 100,000/mm³ at the planned start of consolidation): postpone consolidation. If platelets reach 100,000/mm³ or more within 14 days, start consolidation as above. If they reach 50,000/mm³ or more but stay below 100,000/mm³ within 14 days, do not give Mylotarg again; consolidation is daunorubicin and cytarabine only. If they stay below 50,000/mm³ for more than 14 days, consolidation is re-evaluated and a bone marrow aspirate performed.
• Persistent neutropenia: if neutrophils do not recover above 500/mm³ within 14 days after the planned start of a consolidation cycle, stop Mylotarg and give no Mylotarg in consolidation.
• VOD/SOS: discontinue Mylotarg.
• Total bilirubin above 2 × ULN and AST and/or ALT above 2.5 × ULN: postpone Mylotarg until bilirubin is 2 × ULN or lower and AST and ALT are 2.5 × ULN or lower before each dose. Consider omitting a scheduled dose if the delay between sequential infusions exceeds 2 days.
• Infusion-related reactions: interrupt the infusion, give appropriate treatment, and resume once symptoms have fully resolved. Consider permanent discontinuation for severe or life-threatening reactions.
• Other severe or life-threatening non-haematological toxicity: delay Mylotarg until it has recovered to mild or less; consider omitting a scheduled dose if the delay exceeds 2 days between sequential infusions.

Special Populations

• Hepatic impairment: no change to the starting dose if total bilirubin is 2 × ULN or lower and AST/ALT 2.5 × ULN or lower; postpone each dose until these limits are met.
• Renal impairment: no adjustment in mild to moderate impairment; not studied in severe impairment.
• Elderly (65 years and older): no dose adjustment.
• Children: safety and efficacy below 15 years of age have not been established; no posology can be recommended.

Hepatotoxicity, Including Veno-occlusive Disease (VOD/SOS)

Hepatotoxicity, including life-threatening and sometimes fatal hepatic failure and VOD/SOS, has been reported. Adult patients who received Mylotarg as monotherapy before or after a haematopoietic stem cell transplant (HSCT), and patients with moderate or severe hepatic impairment, are at increased risk of VOD. Signs and symptoms must be closely monitored: raised ALT, AST, total bilirubin and alkaline phosphatase (checked before each dose), painful hepatomegaly, rapid weight gain and ascites. Monitoring total bilirubin alone may not identify every patient at risk. Liver tests and clinical signs should be monitored more often when tests are abnormal, and closely after HSCT. The ALFA-0701 study recommended an interval of 2 months between the last Mylotarg dose and HSCT. Hepatic toxicity may require a dose interruption or discontinuation; in a patient with VOD/SOS, Mylotarg should be discontinued and the patient treated according to standard medical practice.

Infusion-Related Reactions, Including Anaphylaxis

Infusion-related reactions, including anaphylaxis, have occurred, and fatal infusion reactions have been reported after marketing. Signs include fever and chills and, less often, low blood pressure, rapid heart rate and respiratory symptoms, mostly within the first 24 hours. Premedication is recommended. The infusion should be interrupted at once for severe reactions, especially dyspnoea, bronchospasm or clinically significant hypotension, and the patient monitored until symptoms resolve completely. Discontinuation should be strongly considered if signs of anaphylaxis appear, including severe respiratory symptoms or clinically significant hypotension.

Myelosuppression, Infection and Bleeding

Neutropenia, thrombocytopenia, anaemia, leukopenia, febrile neutropenia, lymphopenia and pancytopenia have been reported, some life-threatening or fatal, with infections and bleeding as complications. Complete blood counts must be checked before each dose, and patients monitored for signs of infection, bleeding or other effects of myelosuppression, with routine clinical and laboratory surveillance during and after treatment. Severe infection, bleeding, severe neutropenia or persistent thrombocytopenia may require a dose delay or permanent discontinuation.

Tumour Lysis Syndrome

Tumour lysis syndrome has been reported, including fatal cases complicated by acute renal failure after marketing. In hyperleukocytic AML, leukoreduction with hydroxycarbamide or leukapheresis should be considered to bring the white cell count below 30,000/mm³ before Mylotarg. Patients should be monitored and treated according to standard practice, with hydration and antihyperuricaemic agents (for example allopurinol or rasburicase) to prevent hyperuricaemia.

AML with Adverse-Risk Cytogenetics

Efficacy was shown in patients with favourable- and intermediate-risk cytogenetics, with uncertainty about the size of the effect in adverse-risk disease. When cytogenetic results become available, it should be considered whether the benefit of continuing Mylotarg still outweighs the risks for the individual patient.

Traceability

For this biological medicinal product, the name and batch number of the product given must be clearly recorded.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should avoid pregnancy during treatment. Women of childbearing potential, or partners of such women, should use 2 methods of effective contraception during treatment and for at least 7 months (women) or 4 months (men) after the last dose.
• Pregnancy: there are no or limited data and animal studies showed reproductive toxicity. Mylotarg must not be used in pregnancy unless the benefit to the mother outweighs the risk to the foetus; patients must be told of the potential hazard.
• Breastfeeding: nothing is known about passage into human milk. Women should not breastfeed during treatment and for at least 1 month after the final dose.
• Fertility: there is no information in patients; non-clinical findings suggest male and female fertility may be compromised. Men and women should seek advice on fertility preservation before treatment.

Sodium

Each dose contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free. As the product may be further prepared with sodium-containing solutions, the total sodium from all sources should be considered.

Effect on Driving

Mylotarg has a moderate influence on the ability to drive and use machines. Fatigue, dizziness and headache may occur, so caution is needed when driving or operating machines.

Store the vials in a refrigerator at 2–8 °C, in the original carton to protect from light. Do not freeze. Keep the cold chain unbroken from supply to the hospital pharmacy. Reconstituted and diluted solutions are protected from light, used immediately and never frozen; the permitted holding times are given under Shelf Life. The vial is amber type 1 glass with a butyl rubber stopper and a crimp seal with a flip-off cap; each carton holds 1 vial of 5 mg.

5 years for the unopened vial. If the reconstituted or diluted solution cannot be used immediately: after reconstitution the original vial may be stored for up to 16 hours at 2–8 °C or up to 3 hours at room temperature (below 30 °C); the diluted solution may be stored for up to 18 hours at 2–8 °C and up to 6 hours at room temperature (below 30 °C). The time at room temperature includes preparation of the diluted solution, equilibration if needed, and administration to the patient. The SmPC gives further detail on handling.

Prescription only (Rx). Mylotarg is subject to restricted medical prescription (Annex II B) and is given under the supervision of a physician experienced in anticancer medicinal products, in a setting with full resuscitation facilities. As an intravenous infusion given in hospital, it is supplied to the hospital that administers it, with cold-chain (2–8 °C) delivery.