Asparaginase – Uses, Dosage, Side Effects, Interactions

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 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 ³; 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.^4,8 In addition to asparagine, asparaginase Erwinia chrysanthemi also deaminates glutamine to a lesser extent.¹

Asparaginase Erwinia chrysanthemi is an enzyme that exerts cytotoxic effects on leukemic cells by depleting the source of the amino acid asparagine, which plays a role in the proliferation, protein metabolism, and survival of malignant? cells.⁴

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.
• Spectrila is indicated as a component of antineoplastic combination therapy for the treatment of acute? lymphoblastic leukemia (ALL) in pediatric patients from birth to 18 years and adults.
• Acute? Lymphoblastic Leukemia (ALL)
• Lymphoma, Lymphoblastic

Use in Cancer

Asparaginase erwinia chrysanthemi is approved to be used with other drugs to treat:

• Acute lymphoblastic leukemia. It is a form of asparaginase made from the bacterium Erwinia chrysanthemi. It is used in patients who can no longer take asparaginase made from E. coli.
• Asparaginase is a bacterial? enzyme that is used as an antineoplastic agent, largely in the therapy of acute? lymphocytic leukemia. L-asparaginase has many side effects, one of which is a hepatic injury that is characterized by inhibition of hepatic protein synthesis and steatosis, which can be severe and lead to death from hepatic failure.

Asparaginase erwinia chrysanthemi is also being studied in the treatment of other types of cancer.

Contraindications

• a serious allergic reaction;
• serious pancreas problems;
• a life-threatening blood clot; or
• serious bleeding problems.
• problems with your liver or pancreas;
• bleeding problems;
• a blood clot; or
• insulin? is low or not working well. সহজ বাংলা: রক্তে চিনি বেশি থাকার রোগ।" data-rx-term="diabetes" data-rx-definition="Diabetes is a condition where blood sugar stays too high because insulin is low or not working well. সহজ বাংলা: রক্তে চিনি বেশি থাকার রোগ।">diabetes?.
• Serious allergic reactions to Elspar or other Escherichia coli-derived L-asparaginases
• Serious thrombosis? with prior L-asparaginase therapy
• Pancreatitis with prior L-asparaginase therapy
• Serious hemorrhagic events with prior L-asparaginase therapy

Dosage?

Strengths: 10000 intl units

Acute? Lymphocytic Leukemia

Intradermal Skin Test:

• Because of the occurrence of allergic reactions, an intradermal skin test should be performed prior to the initial administration of asparaginase and when asparaginase is given after an interval of a week or more has elapsed between doses.
• Use approximately two international units for the intradermal skin test. The skin test site should be observed for at least one hour for the appearance of a wheel or allergy?, infection, or inflammation. সহজ বাংলা: চামড়া লাল হয়ে যাওয়া।" data-rx-term="erythema" data-rx-definition="Erythema means skin redness, often from irritation, allergy, infection, or inflammation. সহজ বাংলা: চামড়া লাল হয়ে যাওয়া।">erythema? either of which indicates a positive reaction. An allergic reaction even to the skin test dose in certain sensitized individuals may rarely occur. A negative skin test reaction does not preclude the possibility of the development of an allergic reaction.
• Clinical data are insufficient for a recommendation concerning the use of combination regimens in adults. However, the use of asparaginase as the sole induction agent should be undertaken only in an unusual situation when a combined regimen is inappropriate because of toxicity or other specific patient-related factors, or in cases refractory to other therapy.
• As a sole induction agent: 200 international units/kg/day intravenously for 28 days.
  

  (When complete remissions were obtained with this regimen, they were of short duration, 1 to 3 months.)

Usual Pediatric Dose for Acute? Lymphocytic Leukemia

Intradermal Skin Test:

• Because of the occurrence of allergic reactions, an intradermal skin test should be performed prior to the initial administration of asparaginase and when asparaginase is given after an interval of a week or more has elapsed between doses.
• Use approximately two international units for the intradermal skin test. The skin test site should be observed for at least one hour for the appearance of a wheal or allergy?, infection, or inflammation. সহজ বাংলা: চামড়া লাল হয়ে যাওয়া।" data-rx-term="erythema" data-rx-definition="Erythema means skin redness, often from irritation, allergy, infection, or inflammation. সহজ বাংলা: চামড়া লাল হয়ে যাওয়া।">erythema? either of which indicates a positive reaction. An allergic reaction even to the skin test dose in certain sensitized individuals may rarely occur. A negative skin test reaction does not preclude the possibility of the development of an allergic reaction.

Recommended Induction Regimens:

Combination regimens recommended for acute? lymphocytic leukemia:

Regimen I

• Prednisone 40 mg/m2 per day orally in three divided doses for 15 days, followed by tapering of the dosage? as follows: 20 mg/square meter for 2 days, 10 mg/square meter for 2 days, 5 mg/square meter for 2 days, 2.5 mg/square meter for 2 days and then discontinue.
• Vincristine sulfate 2 mg/m2 intravenously once weekly on days 1, 8, and 15 of the treatment period. The maximum single dose should not exceed 2 mg.
• Asparaginase 1,000 international units/kg/day intravenously for ten successive days beginning on day 22 of the treatment period.

Regimen II

• Prednisone 40 mg/m2 per day orally in three divided doses for 28 days (the total daily dose should be to the nearest 2.5 mg), following which the dosage? of prednisone should be discontinued gradually over a 14-day period.
• Vincristine sulfate 1.5 mg/m2 intravenously weekly for four doses, on days 1, 8, 15, and 22 of the treatment period. The maximum single dose should not exceed 2 mg.
• Asparaginase 6,000 international units/m2 intramuscularly on days 4, 7, 10, 13, 16, 19, 22, 25, and 28 of the treatment period. When remission? is obtained with either of the above regimens, appropriate maintenance therapy must be instituted. asparaginase should not be used as part of a maintenance regimen. The above regimens do not preclude a need for special therapy directed toward the prevention of central nervous system leukemia.
• Use of asparaginase as the sole induction agent should be undertaken only in an unusual situation when a combined regimen is inappropriate because of toxicity or other specific patient-related factors, or in some cases refractory to other therapy.
• As a sole induction agent: 200 international units/kg/day intravenously for 28 days.
  

  (When complete remissions were obtained with this regimen, they were of short duration, 1 to 3 months.

Side Effects

The Most Common

• Signs of an allergic reaction, like rash?; hives; itching; red, swollen, blistered, or peeling skin with or without fever?; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling? of the mouth, face, lips, tongue, or throat.
• Signs of a pancreas problem (pancreatitis) like very bad stomach pain?, very bad back pain?, or very bad upset stomach or throwing up.
• Signs of high blood sugar like confusion, feeling sleepy, thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain?, light-colored stools, throwing up, or yellow skin or eyes.
• Signs of bleeding like throwing up or coughing up blood; vomit that looks like coffee grounds; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a cause or that get bigger; or bleeding you cannot stop.
• Signs of infection? like fever?, chills, very bad sore throat, ear or sinus pain?, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Feeling very tired or weak.
• Very bad dizziness or passing out.
• A very bad and sometimes deadly brain problem called posterior reversible encephalopathy syndrome (PRES) has happened with asparaginase. Call your doctor right away if you have signs like feeling confused, lowered alertness, change in eyesight, loss of eyesight, seizures, or very bad headache

More Common

• nausea
• vomiting
• fever
• hives
• rash
• itching
• difficulty breathing or swallowing
• ongoing pain that begins in the stomach area, but may spread to the back
• extreme thirst
• frequent urination
• extreme hunger
• weakness
• blurred vision
• headache
• arm or leg swelling
• shortness of breath
• chest pain
• unusual bleeding
• yellowing of the skin or eyes
• pain in the upper right part of the stomach
• dark colored urine
• loss of appetite
• lack of energy
• seizure

Rare

• easy bruising or bleeding (nosebleeds, bleeding gums);
• any bleeding that will not stop;
• blisters or ulcers in your mouth, red or swollen gums, trouble swallowing;
• signs of liver or pancreas problems–severe stomach pain (that may spread to your back), nausea or vomiting, jaundice (yellowing of the skin or eyes);
• signs of a blood clot–sudden numbness or weakness (especially on one side of the body), severe headache, chest pain, feeling short of breath, pain or swelling in an arm or leg;
• low white blood cell counts–fever, mouth sores, skin sores, sore throat, cough; or
• high blood sugar–increased thirst, increased urination, dry mouth, fruity breath odor.

Drug Interactions

Pregnancy and Lactation

Pregnancy Category C

Pregnancy

In mice and rats Elspar has been shown to retard the weight gain of mothers and fetuses when given in doses of more than 1000 International Units/kg (approximately equivalent to the recommended human dose, when adjusted for total body surface area). Resorptions, gross abnormalities, and skeletal abnormalities were observed. The intravenous administration of 50 or 100 International Units/kg (approximately equivalent to 10 to 20% of the recommended human dose, when adjusted for total body surface area) to pregnant rabbits on days 8 and 9 of gestation resulted in dose-dependent embryotoxicity and gross abnormalities. There are no adequate and well-controlled studies on pregnant women. Elspar should be given to a pregnant woman only if clearly needed.

Lactation

It is not known whether Elspar is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ELSPAR, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

References