Aldesleukin – Uses, Dosage, Side Effects, Interactions

Aldesleukin is a recombinant analog of interleukin-2 used to induce an adaptive immune response in the treatment of renal cell carcinoma. Aldesleukin, a lymphokine, is produced by recombinant DNA technology using a genetically engineered E. coli strain containing an analog of the human interleukin-2 gene. Genetic engineering techniques were used to modify the human IL-2 gene, and the resulting expression clone encodes a modified human interleukin-2. This recombinant form differs from native interleukin-2 in the following ways: a) Aldesleukin is not glycosylated because it is derived from E. coli; b) the molecule has no N-terminal alanine; the codon for this amino acid was deleted during the genetic engineering procedure; c) the molecule has serine substituted for cysteine at amino acid position 125.

Mechanism of action

Aldesleukin binds to the IL-2 receptor which leads to heterodimerization of the cytoplasmic domains of the IL-2R beta and gamma(c) chains, activation of the tyrosine kinase Jak3, and phosphorylation of tyrosine residues on the IL-2R beta chain. These events led to the creation of an activated receptor complex, in which various cytoplasmic signaling molecules are recruited and become substrates for regulatory enzymes (especially tyrosine kinases) that are associated with the receptor. These events stimulate the growth and differentiation of T cells.

Used to treat renal cell carcinoma, Aldesleukin induces the enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines, the enhancement of lymphocyte cytotoxicity, the induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and the induction of interferon-gamma production. IL-2 is normally produced by the body, secreted by T cells, and stimulates the growth and differentiation of T cell response. It can be used in immunotherapy to treat cancer. It enhances the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor.

Indications

• For treatment of adults with metastatic renal cell carcinoma.
• Metastatic Melanoma
• Metastatic Renal Cell Carcinoma ( mRCC)

Use in Cancer

Aldesleukin is approved to treat adults with:

• Melanoma that has metastasized (spread to other parts of the body).
• Renal cell carcinoma (a type of kidney cancer) has metastasized.

Aldesleukin is also called interleukin-2 (IL-2).

Aldesleukin is also being studied in the treatment of other types of cancer.

Contraindications

The following conditions are contraindicated with this drug. Check with your physician if you have any of the following:

• a bacterial infection
• an infection due to a fungus
• opportunistic fungal infection
• an infection due to a protozoa organism
• spread of cancer to the brain or spinal cord
• untreated decreased level of thyroid hormones
• thyroid gland inflammation
• diabetes
• disease in which the body has an immune response against itself
• confusion
• toxic psychosis
• repeated seizures with unconsciousness between episodes
• myasthenia gravis, a skeletal muscle disorder
• method of removing waste/poison from blood with dialysis
• a heart attack
• angina, a type of chest pain
• bacterial infection of the heart valve
• pericardial tamponade, a disorder of the heart
• supraventricular tachycardia
• rapid ventricular heartbeat
• atrial fibrillation
• slow heartbeat
• abnormal heart rhythm
• capillary leak syndrome, a condition where fluid leaks out of small blood vessels
• low blood pressure
• fluid in the lungs
• lung failure causing loss of breath
• Crohn’s disease
• an ischemic bowel, a condition where the blood flow to the intestine is significantly decreased
• a hole in the intestine
• liver problems
• inflammation of the gallbladder
• bleeding of the stomach or intestines
• glomerulonephritis, a condition that affects the kidneys
• bullous pemphigoid
• scleroderma, hardening and tightening of the skin and connective tissues
• arthritis
• coma
• mental status changes
• seizures
• visible water retention
• decreased urine production
• a patient who is producing milk and breastfeeding
• decreased blood volume
• inflammation of blood vessels that carry blood in the brain
• sepsis
• chronic kidney disease stage 5 (failure)
• kidney disease with likely reduction in kidney function

Dosage

Renal Cell Carcinoma

• 0.037 mg/kg (600,000 IU/kg) every 8 hours via a 15-minute IV infusion for a maximum of 14 doses; the schedule is repeated for another 14 doses after 9 days of rest.
• Maximum Dose: 28 doses per course, as tolerated

Melanoma – Metastatic

• 0.037 mg/kg (600,000 IU/kg) every 8 hours via a 15-minute IV infusion for a maximum of 14 doses; the schedule is repeated for another 14 doses after 9 days of rest.
• Maximum Dose: 28 doses per course, as tolerated

DOSE MODIFICATIONS FOR TOXICITY:

• Decisions to stop, hold, or restart therapy should be made after performing a global patient assessment; dose reductions are not recommended.
• Life-threatening toxicities may be ameliorated with IV dexamethasone, which may also cause this drug to lose its therapeutic effects

RETREATMENT IS CONTRAINDICATED IN PATIENTS WHO HAVE EXPERIENCED THESE TOXICITIES:
CARDIOVASCULAR:

• Sustained ventricular tachycardia (5 beats or greater)
• Cardiac rhythm disturbances not controlled or unresponsive to management
• Chest pain with ECG changes, consistent with angina or myocardial infarction
• Cardiac tamponade

RESPIRATORY:

• Intubation for longer than 72 hours

GENITOURINARY:

• Renal failure requiring dialysis longer than 72 hours

NERVOUS SYSTEM:

• Coma or toxic psychosis lasting longer than 48 hours
• Repetitive or difficult-to-control seizures

GASTROINTESTINAL:

• Bowel ischemia/perforation
• GI bleeding requiring surgery

DOSES SHOULD BE HELD AND RESTARTED ACCORDING TO THE FOLLOWING:
CARDIOVASCULAR:

• Hold dose for atrial fibrillation, supraventricular tachycardia, or bradycardia that requires treatment or is recurrent or persistent; subsequent doses may be given if the patient is asymptomatic with full recovery to normal sinus rhythm.
• Hold dose for systolic BP less than 90 mm Hg with increasing requirements for pressors; subsequent doses may be given if systolic BP is 90 mm Hg or greater and stable or improving requirements for pressors
• Hold dose for any ECG change consistent with MI, ischemia, or myocarditis with or without chest pain, suspicion of cardiac ischemia; subsequent doses may be given if the patient is asymptomatic, MI and myocarditis have been ruled out, clinical suspicion of angina is low; there is no evidence of ventricular hypokinesia

RESPIRATORY:

• Hold dose for O2 saturation less than 90%; subsequent doses may be given if O2 saturation is greater than 90%

NERVOUS SYSTEM:

• Hold dose for mental status changes including moderate confusion or agitation; subsequent doses may be given if mental status changes are completely resolved

BODY AS A WHOLE:

• Hold dose for sepsis syndrome (patient is clinically unstable); subsequent doses may be given if sepsis syndrome has resolved, the patient is clinically stable, and the infection is being treated

GENITOURINARY:

• Hold dose for serum creatinine greater than 4.5 mg/dL or serum creatinine of 4 mg/dL or greater in the presence of severe volume overload, acidosis, or hyperkalemia; subsequent doses may be given if serum creatinine is less than 4 mg/dL and fluid and electrolyte status is stable
• Hold dose for persistent oliguria, urine output of less than 10 mL/hour for 16 to 24 hours with rising serum creatinine; subsequent doses may be given if urine output is greater than 10 mL/hour with a decrease of serum creatinine greater than 1.5 mg/dL or normalization of serum creatinine

HEPATIC:

• Hold dose for signs of hepatic failure including encephalopathy, increasing ascites, liver pain, and hypoglycemia; subsequent doses may be given if all signs of hepatic failure have resolved; discontinue all further treatment for that course; a new course of therapy should be initiated no sooner than 7 weeks after cessation of adverse event and hospital discharge

Side Effects

The Most Common

• nausea
• vomiting
• diarrhea
• loss of appetite
• sores in the mouth and throat
• tiredness
• weakness
• dizziness
• general feeling of being unwell
• pain or redness at the place where the injection was given
• seizures
• chest pain
• extreme worry
• abnormal excitement or agitation
• new or worsening depression
• seeing things or hearing voices that do not exist (hallucinating)
• changes in your vision or speech
• loss of coordination
• decreased alertness
• unusual bruising or bleeding
• extreme sleepiness or tiredness
• difficulty breathing
• wheezing
• stomach pain
• yellowing of the skin or eyes
• decreased urination
• rash
• hives
• itching
• difficulty breathing or swallowing

More Common

• fever
• numbness and tingling
• signs of bleeding (e.g., blood in the urine, vomiting blood, nosebleeds, unusual bleeding or bruising)
• signs of breathing problems (e.g., shortness of breath, troubled breathing, wheezing, tightness in the chest, fast or irregular breathing)
• signs of changed mental status (e.g., confusion, irritability, or trouble speaking)
• signs of decreased red blood cell production (e.g., unusual tiredness, pale skin)
• signs of electrolyte imbalance (e.g., muscle pain or cramps, weakness, irregular heartbeat, lack of coordination, thirst, confusion)
• signs of kidney problems, such as a major decrease in urine output
• signs of liver problems (e.g., darkening of urine, pale stools, yellow eyes or skin)
• sores in the mouth and on the lips
• stomach pain
• swelling of the ankles, feet, hands
• symptoms of high blood sugar (e.g., frequent urination, increased thirst, excessive eating, unexplained weight loss, poor wound healing, infections, fruity breath odor)
• symptoms of irregular heartbeat (e.g., chest pain, dizziness, rapid, pounding heartbeat, shortness of breath)
• symptoms of low blood pressure (e.g., fainting, dizziness, lightheadedness, blurred vision, nausea)
• symptoms of low blood sugar (e.g., cold sweat, cool pale skin, headache, fast heartbeat, weakness)
• symptoms of a urinary tract infection (e.g., pain when urinating, urinating more often than usual, low back or flank pain)

Rare

• chest pain
• severe stomach pain
• signs of bleeding in the stomach (e.g., bloody, black, or  tarry stools; spitting up of blood; vomiting blood or material that looks like coffee grounds)
• signs of a heart attack (e.g., chest pain or pressure, pain extending through shoulder and arm, nausea and vomiting, sweating)
• signs of heart complications (e.g., chest pain; changes in heart rhythm; dizziness; swelling in hands, feet, or abdomen)
• signs of infection (e.g., cough or hoarseness, sore throat, chills, fever, swollen or painful glands, unusual tiredness or weakness, painful or difficult urination)
• signs of sepsis (blood infection; e.g., fever; dizziness; chills; very high or very low body temperature; low blood pressure; pounding or rapid heartbeat; rapid, shallow breathing)
• signs of severe skin reaction (e.g., skin blisters, severe rash or itching, pinpoint red spots on the skin, blisters on the skin, white spots on lips or in the mouth)
• swollen or enlarged stomach

Drug Interactions

There may be an interaction between aldesleukin and any of the following:

• 5-ASA medications (e.g., mesalamine, olsalazine, sulfasalazine)
• alcohol
• aliskiren
• alpha-agonists (e.g., clonidine, methyldopa)
• alpha-blockers (e.g., alfuzosin, doxazosin, tamsulosin)
• angiotensin-converting enzyme inhibitors (ACEIs; e.g., captopril, lisinopril, ramipril)
• angiotensin receptor blockers (ARBs; e.g., candesartan, irbesartan, losartan)
• antihistamines (e.g., cetirizine, doxylamine, diphenhydramine, hydroxyzine, loratadine)
• antipsychotics (e.g., chlorpromazine, clozapine, haloperidol, olanzapine, quetiapine, risperidone)
• barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
• BCG vaccine
• beta-blockers (e.g., acebutolol, propranolol, metoprolol)
• brimonidine
• calcium channel blockers (e.g., diltiazem, nifedipine, verapamil)
• cancer medications (e.g., asparaginase, cisplatin, dacarbazine, doxorubicin, interferon-alfa, methotrexate, tamoxifen, vinblastine)
• conivaptan
• corticosteroids (e.g., prednisone, dexamethasone)
• diuretics (e.g., furosemide, hydrochlorothiazide)
• duloxetine
• hydralazine
• levodopa
• muscle relaxants (e.g., baclofen, cyclobenzaprine, methocarbamol, orphenadrine)
• nitrates (e.g., isosorbide dinitrate, nitroglycerin)
• obinutuzumab
• opioid pain relievers (e.g., codeine, fentanyl, oxycodone, morphine)
• pentoxifylline
• phosphodiesterase 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil)
• radiocontrast dye
• tricyclic antidepressants (e.g., clomipramine, desipramine, imipramine)

Pregnancy and Lactation

FDA pregnancy risk category C

Pregnancy

There are no adequate studies on the use of this medication by pregnant women. This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately. Aldesleukin, IL-2 is classified; there are no adequate well-controlled studies of aldesleukin in pregnant women. The effects of aldesleukin therapy on fertility or pregnancy have not been studied, and it is unknown whether aldesleukin can affect reproduction capacity or cause fetal harm. Administration of aldesleukin to fertile persons of either gender not practicing effective contraception is not recommended, and aldesleukin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known if aldesleukin passes into breast milk. If you are breastfeeding and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding. According to the manufacturer, either aldesleukin, IL-2 or breastfeeding should be discontinued because of the potential for serious adverse reactions in nursing infants from aldesleukin exposure. Aldesleukin excretion into human milk is unknown. Consider the benefits of breastfeeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.