Proleukin (Aldesleukin) is a recombinant interleukin-2 (IL-2)marketed by Novartis for the treatment of metastatic renal cell carcinoma and metastatic melanoma.

IL-2 is a cytokine that is produced by macrophages and lymphocytes. It stimulates the T-lymphocytes and is also called as the T-cell growth factor. Because of the drug targets the T-cells, it is being studied in patients with type 1 diabetes mellitus.

Proleukin/ Aldesleukin Uses:

Aldesleukin (Proleukin) in metastatic melanoma:

• Aldesleukin has been found to have modest efficacy in patients with malignant melanoma.
• Clinical trials using aldesleukin as monotherapy in high doses have demonstrated clinical efficacy of 10 - 31% in patients with metastatic melanoma.
• When combined with Interferon α, the response rate was 18 - 41%.

Aldesleukin in combination with Cyclophosphamide:

• Objective response: 4 - 25%
• Complete response rates: 0 - 5%

Aldesleukin in combination with Decarbazine:

• Objective response: 16 - 26%
• Complete response rates: 2 - 11%

Aldesleukin in combination with Cisplatin:

• Objective response: 17 - 37%
• Complete response rates: 6 - 11%

Aldesleukin in combination with Interferon α and either dacarbazine or cisplatin:

• Objective response: 26 - 54%
• Complete response rates: 4 - 13%

(Ref: Noble S, Goa KL. Aldesleukin (recombinant interleukin-2). BioDrugs. 1997 May 1;7(5):394-422). Other studies using high-dose aldesleukin demonstrated a 16% response with 6% of the patients having a full response while 10% of the patients had a partial response. Patients who had liver metastasis responded less well than metastasis involving other organs.

Proleukin in Renal Cell Carcinoma:

• ALdesleukin has been approved by the FDA since 1992 for the treatment of renal cell carcinoma.
• It has also been used in combination with other drugs including hydroxychloroquine with better clinical response rates.
• It has produced durable response rates in both good and poor-risk patients.

Proleukin/ Aldesleukin Dose in Adults

Proleukin dose in Renal cell carcinoma: 

• 600,000 units/kg intravenously every 8 hours for a maximum of 14 doses.
• The dose should be repeated after nine days for a total of 28 doses per course.
• Retreat if tumor shrinkage is observed (and if no contraindications) at least 7 weeks after the hospital discharge date

or

Unlabeled dosing:

• 720,000 units/kg every 8 hours for up to 12 doses.
• Repeat with a second cycle 10-15 days later

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Proleukin dose in Metastatic Melanoma:

• Single-agent use:
  • 600,000 units/kg intravenously every 8 hours for a maximum of 14 doses
  • The dose should be repeated after nine days for a total of 28 doses per course.
  • Retreat if tumor shrinkage is observed (and if no contraindications) at least 7 weeks after hospital discharge date
• or

Unlabeled dosing:

• 720,000 units/kg every 8 hours for 12-15 doses.
• Repeat with a second cycle ~14 days after the first dose of the initial cycle

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Combination bio-chemotherapy (unlabeled use): 

• 9 million units/m 2 /day continuous infusion over 24 hours for 4 days every 3 weeks for up to 4 cycles

or 

• 9 million units/m 2 /day continuous infusion over 24 hours days 5 to 8, 17 to 20, and 26 to 29 every 42 days for up to 5 cycles

or 

• 9 million units/m 2 /day continuous infusion over 24 hours for 4 days every 3 weeks for 6 cycles

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Note: Premedicate the patient with an antipyretic, an antacid or an H2 receptor blocker to reduce the risk of gastrointestinal bleeding, antiemetics, and antidiarrheals. Continue these medicines for at least 12 hours after the last dose of aldesleukin. Prophylactic antibiotics are also recommended to reduce the risk of opportunistic infections.

Treatment should be withheld (interrupted) rather than reducing the dose in case of toxicity.

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Cardiovascular toxicity:

• Atrial fibrillation, supraventricular tachycardia, or bradycardia that is persistent, recurrent, or requires treatment:

  • Withhold treatment.

  • Treatment may be resumed when asymptomatic and full recovery to normal sinus rhythm.

• Systolic BP less than 90 mm Hg:

  • Withhold treatment.
  • Treatment may be resumed when systolic BP is 90 mm Hg or greater and stable or pressor requirements improve.

• Any ECG change consistent with MI, ischemia or myocarditis (with or without chest pain), or suspected cardiac ischemia:

  • Withhold treatment.
  • Resume treatment when asymptomatic, myocardial infarction/ myocarditis have been ruled out, suspicion of angina is low, or there is no evidence of ventricular hypokinesia.

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Central Nervous system toxicity: 

• Mental status change, including moderate confusion or agitation:
  • Withhold treatment.
  • Resume treatment when resolved completely.

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Dermatologic toxicity: 

• Bullous dermatitis or marked worsening of pre-existing skin condition:
  • Withhold treatment.
  • Treat with antihistamines or topical products (do not use topical steroids).
  • Resume treatment with the resolution of all signs of bullous dermatitis.

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Gastrointestinal: 

• Stool guaiac repeatedly >3-4+:
  • Withhold treatment
  • Resume treatment with negative stool guaiac.

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Hepatotoxicity: 

• Signs of hepatic failure, encephalopathy, increasing ascites, liver pain, hypoglycemia:
  • Withhold the dose and discontinue treatment for the balance of the cycle.
  • may initiate a new course if indicated only after at least 7 weeks past resolution of all signs of hepatic failure (including hospital discharge).

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Infection: 

• Sepsis syndrome, clinically unstable:
  • Withhold dose.
  • Resume when sepsis syndrome has resolved, the patient is clinically stable, and the infection is under treatment.

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Proleukin dose in Renal toxicity:

• Serum creatinine >4.5 mg/dL (or ≥4 mg/dL with severe volume overload, acidosis or hyperkalemia):

  • Withhold dose.
  • Resume when <4 mg/dL and fluid/electrolyte status is stable.

• Persistent oliguria or urine output <10 mL/hour for 16-24 hours with rising serum creatinine:

  • Withhold dose.
  • Resume when urine output >10 mL/hour with serum creatinine decrease of >1.5 mg/dL or normalization.

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Proleukin dosage in respiratory toxicity: 

Oxygen saturation <90%:

• • Withhold dose;
  • may resume when >90%.

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Retreatment with aldesleukin is contraindicated with the following toxicities: 

• Sustained ventricular tachycardia (≥5 beats),
• uncontrolled or unresponsive cardiac arrhythmias,
• chest pain with ECG changes consistent with angina or MI,
• cardiac tamponade,
• intubation >72 hours,
• renal failure requiring dialysis for >72 hours,
• coma or toxic psychosis lasting >48 hours,
• repetitive or refractory seizures,
• bowel ischemia/perforation, or
• GI bleeding requiring surgery

Proleukin/ Aldesleukin Dose in Children

Proleukin in Acute Myeloid Leukemia (unlabeled dose):

• 9 million international units (9 x 10 6 international units)/m 2 /day continuous infusion over 24 hours daily for 4 days
• Repeat 4 days later with 1.6 million international units (1.6 x 10 6 international units)/m 2 /day continuous infusion over 24 hours daily for 10 days

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Note:

• Premedicate the patient with an antipyretic, an antacid or an H2 receptor blocker to reduce the risk of gastrointestinal bleeding, antiemetics, and antidiarrheals.
• Continue these medicines for at least 12 hours after the last dose of aldesleukin. Prophylactic antibiotics are also recommended to reduce the risk of opportunistic infections.

Pregnancy Risk Factor C

• The data available to pregnant patients is very limited.
• Therefore, it should not be used in pregnancy unless the benefits outweigh any risks. 
• Both male and female contraception is recommended.

Use during Breastfeeding

• It is found in breast milk and therefore breastfeeding is not advised.

Proleukin dose in renal disease:

• No specific recommendations by the manufacturer. Use with caution.

Proleukin dose in liver disease:

Signs of hepatic failure, encephalopathy, increasing ascites, liver pain, hypoglycemia:

• Withhold treatment.
• may initiate a new course if indicated only after at least 7 weeks past resolution of all signs of hepatic failure (including hospital discharge).

Side effects of Proleukin (aldesleukin):

• Bone-marrow toxicity
• CNS toxicity
• Hepatic toxicity
• Renal toxicity
• Thyroid toxicity
• Alopecia
• Extravasation
• Hyperuricaemia
• Nausea
• Oral mucositis
• Thromboembolism
• Tumour lysis syndrome
• Vomiting

The following are contraindications to the use of Proleukin (aldesleukin):

• Hypersensitivity to aldesleukin or any component
• Abnormal thallium stress test or pulmonary function tests;
• Organ allografts (due to increased risk of rejection);
• Retreatment in patients who have experienced:
  • sustained ventricular tachycardia (≥5 beats),
  • cardiac rhythm disturbances not controlled or unresponsive to management,
  • recurrent chest pain with ECG changes (consistent with angina or MI),
  • intubation required >72 hours,
  • cardiac tamponade;
  • renal dysfunction requiring dialysis >72 hours,
  • coma or toxic psychosis lasting >48 hours,
  • repetitive or difficult-to-control seizures,
  • bowel ischemia/perforation, and
  • GI bleeding requiring surgery

Boxed Warnings and caution!

• Patients with normal thallium stress test results and pulmonary function tests that are negative for thallium should not use this medication.

• U.S. Boxed Warn - Bacterial Infections at Risk

Because of reduced neutrophil function, treatment with Aldesleukin/Proleukin can increase the risk of developing bacterial infections.

Patients receiving aldesleukin therapy should treat bacterial infections before starting treatment.

Before Proleukin therapy, patients should be administered paracetamol (acetaminophen), an antidiarrheal, and an antacid. 

Patients should also be closely monitored for adverse reactions.

Patients with seizure disorders, autoimmune conditions, liver diseases (especially patients taking hepatotoxic drugs), and patients with renal disease (especially patients who are on nephrotoxic medications) should not use Proleukin. Patients are also at risk for graft rejection.

• U.S. Boxed Warn - Follow the instructions of an expert to administer!

Aldesleukin should only be administered by a qualified cancer physician.

• U.S. Boxed Warning – Capillary Leak Syndrome

High-dose Proleukin therapy can cause Capillary leak syndrome.

This is characterized by reduced vascular tone, extravasation fluid from the capillaries, and hypotension, which all occur within two to twelve hours of the treatment. 

Capillary leak syndrome can be fatal. It is important to recognize the condition as soon as possible.

Capillary leak syndrome It may also be associated with angina, cardiac arrhythmias, and myocardial injury.

Patients with normal lungs or cardiac function as determined by formal pulmonary function testing and thallium stress should not be recommended for Proleukin therapy.

You should not withhold treatment for symptoms such as hypoperfusion, altered mental state, decreased urine output, systolic BP 90 mmHg (in adults), and cardiac arrhythmia. 

The majority of CLS patients recover quickly after cessation of treatment.

• U.S. Boxed Warn: Your neurological condition may get worse!

Patients suffering from mild to severe lethargy, somnolence, or aldesleukin should not be given the drug.

Continued administration could cause a coma. Patients with CNS metastasis may experience an increase in their neurological condition. 

It is important to evaluate and treat CNS metastasis before starting treatment.

Monitoring Parameters:

Baseline and periodic monitoring while on Proleukin therapy:

Blood Cp with differential and platelets, serum chemistries including electrolytes, renal and hepatic function tests, and chest x-ray; pulmonary function tests and arterial blood gases (baseline), thallium stress test (prior to treatment)

Monitoring during Proleukin therapy

• Monitor vital signs daily (temperature pulse, blood pressure, respiration rate, and pulse) (if the patient has hypotension, monitor hourly).
• Monitor your weight, fluid intake, and output. A cardiac monitor should be performed on a patient with decreased blood pressure, particularly if it is less than 90 mmHg.
• An ECG should be performed if there is an abnormal rhythm or complexity.
• Patients with hypotension should take their vital signs hourly and have their central venous pressure (CVP), checked. You should monitor for changes in your mental state and signs of infection.

How to administer Proelukin (Aldesleukin)?

Administer as an intravenous infusion over 15 minutes.

Allow the solution to reach room temperature prior to administration.

Flush before and after with D 5 W, particularly if the maintenance intravenous line contains sodium chloride.

Mechanism of Action of Proleukin (Aldesleukin):

Aldesleukin, a human recombinant Interleukin-2 product, promotes the proliferation, differentiation, and recruitment of T cells, B cells, natural killer cells (NK), and thymocytes.

It is cytolytic in a subset of lymphocytes and causes subsequent interactions between the immune and malignant cells.

Proleukin can be used to stimulate lymphokine-activated killer (LAK), and tumor-infiltrating Lymphocytes (TIL), cells.

Proleukin is metabolized by the kidneys to amino acids and is excreted via urine. It has a half-life of 6-13 minutes

International Brand Names of Aldesleukin

• Celeuk
• Interleukina 2
• Interleukina II
• Proleukin

Aldesleukin brand names in Pakistan:

Aldesleukin or Proleukin is currently not available in Pakistan.

It is not available readily in the markets.