Asparaginase Erwinia chrysanthemi 

Asparaginase Erwinia chrysanthemi is an asparaginase-specific enzyme derived from Erwinia chrysanthemi used as an anticancer agent. It works by depleting the stores of an important amino acid called asparagine, which is involved in DNA synthesis and cell survival of malignant? cells, leading to cell death.^[rx] L-asparaginase was first identified in 1963,^[rx] and there are different formulations of L-asparaginase, including Asparaginase Escherichia coli and a pegylated form of this enzyme, Pegaspargase.^[rx] Asparaginase Erwinia chrysanthemi and Asparaginase Escherichia coli differ in their pharmacokinetic and immunogenic profiles;^[rx] thus, those who are allergic to Asparaginase Escherichia coli do not cross-react to Asparaginase Erwinia chrysanthemi.^[rx] Studies show that the substitution of Erwinia asparaginase for E. coli-derived asparaginase following an allergic reaction has been safe and effective.^[rx]

Asparaginase Erwinia chrysanthemi was first approved by the FDA in November 2011 to treat patients with acute lymphoblastic leukemia (ALL) who are allergic to E. coli-derived asparaginase: it has been used as part of multi-agent chemotherapy?.^[rx] In June 2021, the recombinant form of asparaginase Erwinia chrysanthemi was approved by the FDA as a component of a chemotherapy regimen to treat acute lymphoblastic leukemia and lymphoblastic lymphoma in adult and pediatric patients who are allergic to the E. coli-derived asparaginase.^[rx]

Mechanism of action

Asparaginase Erwinia chrysanthemi is a tetrameric enzyme made up of four identical subunits, each having a molecular weight of about 35 kDa. It rapidly and completely catalyzes the deamidation reaction of L-asparagine to aspartic acid and ammonia, resulting in reduced levels of circulating asparagine in the plasma. Asparagine is essential for DNA synthesis, RNA synthesis, protein metabolism, and survival of leukemic cells ^[rx]; however, they lack the asparagine synthetase enzyme and depend on an exogenous source of asparagine. Asparaginase Erwinia chrysanthemi depletes the source of asparagine for leukemic cells, resulting in the death of leukemic cells.^[rx,rx] In addition to asparagine, asparaginase Erwinia chrysanthemi also deaminates glutamine to a lesser extent.^[rx]

Asparaginase Erwinia chrysanthemi is an enzyme that exerts cytotoxic effects on leukemic cells by depleting the source of an amino acid asparagine, which plays a role in the proliferation, protein metabolism, and survival of malignant cells.^[rx]

Indications

• Asparaginase Erwinia chrysanthemi is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma in adults and children who have developed hypersensitivity to E. coli-derived asparaginase.^[rx,rx]
• Indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E. coli-derived asparaginase.
• Spectrila is indicated as a component of antineoplastic combination therapy for the treatment of acute lymphoblastic leukemia (ALL) in paediatric patients from birth to 18 years and adults.
• Acute Lymphoblastic Leukemia (ALL)
• Lymphoma, Lymphoblastic

Contraindications

• History of serious thrombosis? with prior asparaginase therapy.
• History of serious pancreatitis? with prior asparaginase therapy. History of serious hemorrhagic events with prior asparaginase therapy.
• diabetes?
• increased uric acid in the body resulting in kidney? disease
• a type of joint disorder due to excess uric acid in the blood called gout?
• anemia?
• an increased risk of bleeding
• low levels of white blood cells
• obstruction of a blood vessel by a blood clot
• bleeding
• acute inflammation? of the pancreas?
• high amount of bilirubin? in the blood
• high amount of uric acid in the blood
• abnormally high levels of nitrogen-containing compounds in your blood
• abnormal liver? function tests
• pregnancy
• a patient who is producing milk and breastfeeding
• a type of brain disorder called posterior reversible encephalopathy syndrome?

Dosage?

Strengths: 10000 intl units; rywn recombinant 10 mg/0.5 mL

Acute Lymphoblastic Leukemia

To substitute for a dose of pegaspargase:

• 25,000 International Units/m2 intramuscularly three times a week (Monday/Wednesday/Friday) for six doses for each planned dose of pegaspargase.

To substitute for a dose of native E. coli asparaginase:

• 25,000 International Units/m2 administered intramuscularly for each scheduled dose of native E. coli asparaginase within a treatment regimen.
• Limit the volume of reconstitution at a single injection site to 2 mL; if reconstituted dose to be administered is greater than 2 mL, use multiple injection sites.
• If a partial vial is used, do not save or reuse the unused drug for later administration. Discard unused portions.

Pediatric Dose for Acute Lymphoblastic Leukemia

To substitute for a dose of pegaspargase:

• 25,000 International Units/m2 intramuscularly three times a week (Monday/Wednesday/Friday) for six doses for each planned dose of pegaspargase.

To substitute for a dose of native E. coli asparaginase:

• 25,000 International Units/m2 administered intramuscularly for each scheduled dose of native E. coli asparaginase within a treatment.
• Limit the volume of reconstitution at a single injection site to 2 mL; if the reconstituted dose to be administered is greater than 2 mL, use multiple injection sites.
• If a partial vial is used, do not save or reuse the unused drug for later administration. Discard unused portions.

Side Effects

The Most Common

• nausea?
• diarrhea?
• constipation?
• muscle or bone pain?
• headache?
• tiredness
• fever?, chills?, cough?, or other signs of infection?
• loss of appetite
• difficulty falling asleep or staying asleep
• swelling of the face, lips, eyes, arms, or legs
• hives
• itching
• rash or redness
• shortness of breath or difficulty breathing
• yellowing of skin or eyes, pain in the upper right part of the stomach, dark-colored urine, or loss of appetite
• unusual bleeding or bruising
• blood in urine
• headache, arm or leg swelling, shortness of breath, and chest pain
• severe abdominal pain, fever, weight loss, nausea, and vomiting

More common

• Agitation
• back pain
• black, tarry stools
• bleeding gums
• bloating
• blood in the urine or stools
• blurred vision
• chest pain
• chills
• coma
• confusion
• constipation
• cough or hoarseness
• difficulty in walking
• dizziness
• drooping eyelids
• drowsiness
• dry mouth
• lightheadedness
• fainting
• fast heartbeat
• fever
• flushed, dry skin
• fruit-like breath odor
• hallucinations
• headache
• increased hunger
• increased menstrual flow or vaginal bleeding
• increased thirst
• increased urination
• indigestion
• irritability
• jaw pain
• lower back or side pain
• mood or mental changes
• nosebleeds
• numbness or tingling in the fingers and toes
• pain in the fingers and toes
• pain in the testicles
• pains in the chest, groin, or legs, especially calves of the legs
• pains in stomach, side, or abdomen, possibly radiating to the back
• painful or difficult urination
• pale skin
• paralysis
• pinpoint red spots on the skin
• prolonged bleeding from cuts
• rapid, shallow breathing
• seizures
• severe headaches of sudden onset
• sleepiness or unusual drowsiness
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• stiff neck
• stomach pain
• sudden loss of coordination
• sudden onset of slurred speech
• sudden vision changes
• sweating
• swollen glands
• trouble breathing
• unexplained weight loss
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting
• yellow eyes or skin

Rare

• Chest tightness
• difficulty swallowing
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• hives, itching, skin rash
• increase in the frequency of seizures
• loss of appetite
• loss of consciousness
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• Diarrhea
• nervousness
• pounding in the ears
• slow or fast heartbeat
• unpleasant breath odor
• vomiting of blood
• Bleeding, blistering,
• burning, coldness,
• discoloration of the skin,
• the feeling of pressure, hives,
• infection, inflammation, itching, lumps,
• numbness, pain, rash, redness, scarring,
• soreness, stinging, swelling, tenderness,
• tingling, ulceration, or warmth at the injection site

Drug Interactions

Pregnancy and Lactation

US FDA pregnancy category: C

Pregnancy

• Use is recommended only if clearly needed and the benefit outweighs the risk. In animal studies, maternal toxicities of decreased body weight and decreased body weight gain and fetal findings of increased incidence of partially undescended thymic tissue, increased post-implantation loss, decreased number of live fetuses, and gross abnormalities were observed. There are no controlled data in human pregnancy. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant the use of the drug in pregnant women despite potential risks.

Lactation

• Use is not recommended and a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.
• Excreted into human milk: Unknown
• Excreted into animal milk: Data not available
• The effects on the nursing infant are unknown.

References