Aldesleukin

Aldesleukin is a recombinant form of human interleukin-2 (IL-2), a natural lymphokine made by T cells. It is produced by recombinant DNA technology in a strain of Escherichia coli carrying the human IL-2 gene, and its biological activity is comparable to that of human IL-2. In humans and animals it produces several dose-dependent immune effects. In mouse tumour models it reduces tumour growth and spread, but the SmPC states that the precise mechanism by which this immune stimulation produces antitumour activity is not yet known.

Mechanism of Action

• Receptor signalling: aldesleukin binds to the IL-2 receptor and brings together the cytoplasmic domains of its beta and gamma chains. This activates the tyrosine kinase Jak3 and leads to phosphorylation of tyrosine residues on the beta chain; the activated receptor complex recruits signalling proteins and stimulates the growth and differentiation of T cells.
• Immune effects: it enhances lymphocyte proliferation and cytotoxicity, induces lymphokine-activated killer (LAK) and natural killer (NK) cell activity, and induces interferon-gamma production.
• Antitumour activity: shown in mouse tumour models; the mechanism in patients is not established.

Pharmacokinetics

• Absorption: after a short intravenous infusion, plasma concentrations are high and the protein distributes quickly into the extravascular space. After subcutaneous injection, peak levels are reached 2 to 6 hours later and absolute bioavailability is 31 to 47%.
• Distribution: during continuous intravenous infusion at a constant or a decreasing dose, mean tmax was 11 hours and 4.4 hours, and serum concentrations were 3.20 and 1.95 times higher than after subcutaneous injection. Serum concentrations after intravenous administration are proportional to the dose.
• Metabolism and elimination: after an intravenous bolus, serum levels fall in two phases, with an alpha half-life of 13 minutes and a beta half-life of 85 minutes; 87% of the clearance of a bolus occurs in the alpha phase. Mean clearance in cancer patients is 155 to 420 mL/min; in a recent study in patients with metastatic cancer it was 243.2 to 346.3 mL/min, with a terminal half-life of 100.4 to 123.9 minutes. The kidney is the main route: the protein is broken down to amino acids in the cells of the proximal tubules, and little or no active protein appears in the urine.
• Subcutaneous kinetics: a one-compartment model, with an absorption half-life of 45 minutes and an elimination half-life of 3 to 5 hours.
• Special populations: no formal study has compared pharmacokinetics in elderly and younger patients or examined patients with renal or hepatic impairment.

• Metastatic renal adenocarcinoma (renal cell carcinoma): treatment of metastatic renal adenocarcinoma. The posology in the SmPC is for adult patients.
• Risk factors for a lower response: three factors are associated with a lower response rate and shorter median survival, and both fall as the number of factors rises: an ECOG performance status of 1 or more (0 = normal activity; 1 = symptomatic but ambulatory); metastases in more than one organ; and less than 24 months between the initial diagnosis of the primary tumour and the assessment of the patient for treatment. Patients who have all three factors must not be treated.

• Hypersensitivity to the active substance or to any of the excipients.
• General condition: ECOG performance status of 2 or more.
• ECOG performance status of 1 or more together with metastases in more than one organ and less than 24 months between the initial diagnosis of the primary tumour and the assessment for treatment (all three risk factors).
• Significant history or presence of severe heart disease (an exercise stress test is done in doubtful cases).
• Signs of active infection requiring antibiotic treatment.
• PaO2 below 60 mmHg at rest.
• Severe dysfunction of a vital organ.
• Brain metastases or seizure disorder, except brain metastases that have been treated successfully (normal scan, stable neurological state).

The SmPC also recommends not using aldesleukin with: white cells below 4,000/mm³, platelets below 100,000/mm³ or haematocrit below 30%; abnormal serum bilirubin or creatinine; a history of organ allograft; patients likely to need corticosteroid treatment; and pre-existing autoimmune disease.

The frequency and severity of side effects depend on the route, the dose and the schedule. Most are directly related to the product and may disappear within 1 to 2 days of stopping treatment. Among 255 patients with metastatic renal adenocarcinoma given aldesleukin alone, 4% (11 patients) died of treatment-related causes; fewer than 1% of patients treated subcutaneously died of side effects.

Very common (≥1/10): anaemia, thrombocytopenia; hypothyroidism; anorexia; anxiety, confusion, depression, insomnia; dizziness, headache, paraesthesia, somnolence; tachycardia, arrhythmia, chest pain; hypotension; dyspnoea, cough; nausea with or without vomiting, diarrhoea, stomatitis; erythema and rash, exfoliative dermatitis, pruritus, sweating; oliguria, raised blood urea and creatinine; injection-site reactions, pain and inflammation (less frequent with continuous intravenous infusion), fever with or without chills, malaise, asthenia and fatigue, pain, oedema, weight gain, weight loss.

Common (≥1/100 to <1/10): respiratory tract infection, sepsis; leucopenia, coagulopathy including disseminated intravascular coagulation, eosinophilia; hyperthyroidism; acidosis, hyperglycaemia, hypocalcaemia, hypercalcaemia, hyperkalaemia, dehydration, hyponatraemia, hypophosphataemia; irritability, agitation, hallucinations; neuropathy, syncope, speech disorders, loss of taste, lethargy; conjunctivitis; cyanosis, transient ECG changes, myocardial ischaemia, palpitations, cardiovascular disorders including heart failure; phlebitis, hypertension; pulmonary oedema, pleural effusion, hypoxia, haemoptysis, epistaxis, nasal congestion, rhinitis; dysphagia, dyspepsia, constipation, gastrointestinal bleeding (including rectal haemorrhage and haematemesis), ascites, cheilitis, gastritis; raised transaminases, alkaline phosphatase and lactate dehydrogenase, hyperbilirubinaemia, hepatomegaly or hepatosplenomegaly; alopecia, urticaria; myalgia, arthralgia; haematuria, renal failure, anuria; mucosal inflammation, injection-site nodule, hypothermia, flu-like symptoms.

Uncommon (≥1/1,000 to <1/100): neutropenia; hypersensitivity reactions; hypoglycaemia; coma, convulsions, paralysis, myasthenia; myocarditis, cardiomyopathy, cardiac arrest, pericardial effusion; thrombosis, thrombophlebitis, haemorrhage; pancreatitis, intestinal obstruction, gastrointestinal perforation (including necrosis or gangrene); vitiligo, angioedema; myopathy, myositis.

Rare (≥1/10,000 to <1/1,000): agranulocytosis, aplastic anaemia, haemolytic anaemia, febrile neutropenia; anaphylaxis; diabetes mellitus; optic nerve disorder including optic neuritis; ventricular hypokinesia; pulmonary embolism, acute respiratory distress syndrome; activation of quiescent Crohn’s disease; cholecystitis, fatal hepatic failure; vesiculobullous rash, Stevens-Johnson syndrome; injection-site necrosis.

Not known: intracranial or cerebral haemorrhage, stroke, leukoencephalopathy; cardiac tamponade; rhabdomyolysis.

Capillary leak syndrome may be accompanied by cardiac arrhythmias, angina, myocardial infarction, respiratory failure requiring intubation, gastrointestinal bleeding, mesenteric infarction, renal failure, oedema and changes in mental state; it is less frequent and less severe with subcutaneous than with continuous intravenous administration. Rare cases of leukoencephalopathy have been reported in the literature, mostly in patients treated for HIV infection who also had other risk factors.

• Cisplatin, vinblastine and dacarbazine: a fatal tumour lysis syndrome has been reported with concomitant use, so the combination is not recommended.
• Interferon alfa: severe rhabdomyolysis and heart damage (myocardial infarction, myocarditis, ventricular hypokinesia) appear more frequent with intravenous aldesleukin plus interferon alfa. Exacerbation or first onset of autoimmune and inflammatory diseases (IgA glomerulonephritis, severe oculobulbar myasthenia, inflammatory arthritis, thyroiditis, bullous pemphigus, Stevens-Johnson syndrome) has been seen with the combination.
• Glucocorticoids: may reduce the effectiveness of aldesleukin and should be avoided. If life-threatening signs or symptoms appear, dexamethasone can be used until the toxic effects become acceptable.
• Hepatotoxic, nephrotoxic, myelotoxic or cardiotoxic medicines: may worsen aldesleukin toxicity in the same organs. Because aldesleukin reversibly raises transaminases, bilirubin, urea and creatinine, the hepatic metabolism or renal excretion of other medicines may change; use medicines with known kidney or liver toxicity with caution.
• Antihypertensives such as beta-blockers: may increase the blood-pressure-lowering effect, so monitoring is needed.
• Psychotropic and other centrally acting medicines: aldesleukin affects the central nervous system and may modify the response to psychotropic medicines; monitor.
• Contrast media: used after aldesleukin they can bring back the toxicity seen during treatment, mostly within 2 weeks of the last dose but sometimes months later. Contrast media should not be used during the 2 weeks after treatment.
• Sequential high-dose aldesleukin with chemotherapy: hypersensitivity reactions (erythema, itching, hypotension) within hours of chemotherapy have been reported with dacarbazine, cisplatin, tamoxifen and interferon alfa, and some patients needed medical intervention.

Aldesleukin may be used only under the supervision of a qualified physician who is well versed in anticancer chemotherapy. When it is given by continuous intravenous infusion, hospitalisation in a specialised unit with the means of an intensive-care unit is recommended so that clinical and laboratory status can be followed properly. Subcutaneous treatment may be given at home by qualified health professionals. The powder is reconstituted before use (1.2 mL of water for injections gives 18 million IU/mL; preparation is set out in section 6.6 of the SmPC).

Recommended Dose (Adults)

• Continuous intravenous infusion: 18 million IU/m² over 24 hours for 5 days, then 2 to 6 days without aldesleukin, then 5 more days of continuous infusion and 3 weeks without aldesleukin. This is one induction cycle. After the 3 treatment-free weeks of the first cycle, a second induction cycle should be given.
• Maintenance after intravenous induction: if the disease responds or is stable, up to 4 maintenance cycles (18 million IU/m² as a continuous infusion for 5 days), with 4 weeks between cycles.
• Subcutaneous injection: 18 million IU daily for 5 days, then 2 days without aldesleukin. Over the next 3 weeks, 18 million IU on the first 2 days of each week and 9 million IU on days 3, 4 and 5, with no treatment on days 6 and 7. After one week without aldesleukin, the 4-week cycle is repeated. Patients who respond or are stable may continue such cycles as maintenance.

Dose Adjustments

• If the recommended dose is not tolerated, the dose is reduced or treatment interrupted until the signs of intolerance subside. How far dose reduction changes the response rate and median survival is not known.
• The decision to restart takes account of the severity and nature of the toxicity. Side effects can be serious or life-threatening but are treatable, and they usually (though not always) go within 1 to 2 days of stopping.

Supportive Medicines

At the recommended dose, fever and gastrointestinal effects are usual. Paracetamol can be given with aldesleukin to reduce fever, and pethidine can be added for the chills that accompany it. Antiemetics and anti-diarrhoeal medicines treat gastrointestinal effects, and antihistamines can help in some cases of itchy rash.

Special Populations

• Renal or hepatic impairment: no formal study of pharmacokinetics, safety or tolerability; patients with pre-existing impairment need close monitoring.
• Elderly: no formal comparison with younger patients, and few patients aged 65 or over were studied (response rates were similar). Prescribe with caution, because renal and hepatic function may decline with age and older patients may be more sensitive to side effects.
• Children and adolescents: safety and efficacy have not been established.

Capillary Leak Syndrome

Aldesleukin can cause capillary leak syndrome: loss of vascular tone with leakage of plasma proteins and fluid out of the vessels, producing hypotension, fast heart rate and poor organ perfusion. One severe case was fatal. It usually starts within hours of the first dose, with symptoms (hypotension, tachycardia, dyspnoea, pulmonary oedema) reported 2 to 12 hours later. Circulatory and respiratory function must be watched closely, especially with intravenous administration. Hypotension sometimes corrects without treatment; otherwise intravenous fluids are given with care, and refractory cases need low-dose catecholamines, whose prolonged use or higher doses may bring heart-rhythm disorders. The benefit of expanding blood volume must be weighed against the risk of pulmonary oedema, ascites and pleural or pericardial effusion. If these measures fail, aldesleukin is stopped.

Autoimmune Disease

Aldesleukin may worsen existing autoimmune disease with potentially life-threatening complications, and may reactivate quiescent Crohn’s disease. Because patients who develop interleukin-2-related autoimmune problems do not all have a history of them, thyroid function and other possible autoimmune conditions must be monitored closely.

Central Nervous System

Treatment must be interrupted if severe lethargy or somnolence occurs, because continuing may lead to coma. Aldesleukin can worsen symptoms of unrecognised or untreated brain metastases, so every patient needs a proper assessment and treatment of brain metastases first. Psychiatric disturbances (irritability, confusion, depression) can occur; they are usually reversible but may last several days. Aldesleukin can change the effect of psychotropic medicines.

Kidney and Liver Function

Aldesleukin causes reversible rises in liver transaminases, bilirubin, urea and creatinine and can alter the hepatic metabolism or renal excretion of other medicines. Medicines with known kidney or liver toxicity are used with caution, and patients with pre-existing impairment are monitored closely.

Infections

Any existing bacterial infection must be treated before starting, because it can increase toxicity. Aldesleukin can increase the frequency or severity of bacterial infections (sepsis, bacterial endocarditis, septic thrombophlebitis, peritonitis, pneumonia), mainly after intravenous use; the organisms are Staphylococcus aureus or S. epidermidis and, at times, Escherichia coli. Catheter-related local infections are more frequent with continuous intravenous infusion, and preventive antibiotics are essential in patients with central catheters. Subcutaneous injection often causes inflammatory reactions at the injection site, sometimes with necrosis; changing injection sites over the body reduces them.

Serous Effusions and Glucose Metabolism

Aldesleukin may worsen serous effusions, which should be treated before starting, particularly where worsening could cause major organ failure (for example pericardial effusion). It may also disturb glucose metabolism, so blood glucose is monitored, especially in patients with diabetes.

Monitoring Before and During Treatment

• Before treatment and periodically: a standard blood count with differential and platelet count (anaemia and thrombocytopenia may occur), blood chemistry including fluid-electrolyte balance, glucose and kidney and liver function tests, in addition to the usual tests for metastatic renal adenocarcinoma.
• Before treatment: chest X-ray, ECG (with an exercise test if needed) and arterial blood gases. Abnormalities or signs of cardiac ischaemia need further tests to exclude significant coronary artery disease.
• During intravenous treatment: regular blood pressure and pulse, other organ function including mental state and urine output, with more frequent measurements if blood pressure falls. Hypovolaemia is assessed by central venous pressure.
• Respiratory signs: patients with rales, a faster breathing rate or dyspnoea need lung function monitoring, including pulse oximetry and arterial blood gases.

Pregnancy, Breastfeeding and Fertility

• Contraception: men and women of childbearing potential must use effective contraception during treatment.
• Pregnancy: there are no data in pregnant women, and animal reproduction studies are insufficient. In rats aldesleukin caused maternal toxicity and embryo lethality. It must not be used in pregnancy unless the expected benefit to the mother justifies the potential risk to the foetus.
• Breastfeeding: nothing is known about excretion into human milk. Because of the unknown risk of serious side effects in the newborn, breastfeeding is not allowed during treatment.

Sodium

Each mL contains less than 23 mg of sodium, so the product is considered essentially sodium-free.

Effect on Driving

Aldesleukin can affect the central nervous system. Hallucinations, somnolence, syncope and convulsions may occur and impair the ability to drive or use machines. Patients must not drive or use machines until these effects have gone.

Store in a refrigerator at 2–8 °C. Do not freeze. Keep in the original package to protect from light. Aldesleukin is a cold-chain product: keep it at 2–8 °C during transport and storage. After reconstitution as instructed, physico-chemical stability in use was shown for 48 hours at 2–30 °C (refrigerated or at room temperature). From a microbiological point of view the reconstituted product should be used immediately; if it is not, storage times and conditions are the responsibility of the user and should normally not exceed 24 hours at 2–8 °C, unless reconstitution took place under controlled and validated aseptic conditions. Presentation: single-use 5 mL clear type I glass vial with a synthetic rubber stopper, in boxes of 1 or 10 vials; not all presentations may be marketed.

45 months unopened. After reconstitution the SmPC gives 24 hours (section 6.3) and states that the diluted solution must be used within 48 hours of reconstitution, including the infusion time; see Storage Conditions for the conditions.

Prescription only (Rx), for use under the supervision of a qualified physician experienced in anticancer chemotherapy. Aldesleukin is given by health professionals: the continuous intravenous infusion is given in hospital, preferably in a specialised unit with intensive-care facilities, and the subcutaneous course can be given at home by qualified health professionals. It is supplied to the hospital or clinic that administers it, under cold-chain conditions (2–8 °C).