Enasidenib - A Targeted Therapy for AML

Overview

Enasidenib is a prescription oral medication used for treating relapsed (recurrent) or refractory stages of acute myeloid leukemia. Acute myeloid leukemia is a cancerous condition of blood and bone marrow (a portion of bone that produces blood cells) with the production of excess immature white blood cells. This also affects normal healthy blood cells, including red blood cells, platelets, and white blood cells. This medication is indicated to treat only relapsed or refractory stages where the disease has recurred or the person showed no improvement with the previous therapies.

Enasidenib is prescribed to treat acute myeloid leukemia with a distinctive mutation of the isocitrate dehydrogenase 2 (IDH2) gene, diagnosed by the Food and Drug Administration (FDA) approved IDH2 test. So, it is an inhibitor of the enzyme called isocitrate dehydrogenase 2. The United States FDA regarded Enasidenib as a first-in-class medication in 2014. This is because this medication shows a new and unique type of mechanism of action for treating the particular condition.

Dosage and Dosage Form:

Enasidenib comes in a tablet form meant to be taken by mouth (orally). This medication is generally available in these strengths:

• 50 mg (milligrams) Tablet: The tablet is pale yellow to yellow colored oval shaped, coated with film. This tablet has the number 50 on either side.

• 100 mg Tablet: The tablet is pale yellow to yellow colored oval shaped, coated with film. This tablet has the number 100 on either side.

For Patients

What Is Acute Myeloid Leukemia?

Acute myeloid leukemia is often referred to as acute myelogenous leukemia, acute myelocytic leukemia, acute non-lymphocytic leukemia, and acute granulocytic leukemia. Acute myeloid leukemia is a form of cancer involving blood and bone marrow (the softener region of specific bones where new blood cells are produced) with immoderate immature white blood cells. This condition rapidly moves into the blood. It can metastasize or spread to various body parts, particularly the spleen, liver, lymph nodes, testicles, and central nervous system comprising the brain and spinal cord. This cancer could progress rapidly with the interference of myeloid cells with the production of normal blood cells (red blood cells, white blood cells, and platelets). The signs and symptoms of acute myeloid leukemia include the following:

• Pale or ‘washed out’ skin.

• Breathlessness.

• Tiredness.

• Frequent infections.

• Unintentional weight loss.

• Night sweats.

• Fever.

• Chills.

• Abnormal and frequent bleeding like nosebleeds or bleeding gums.

• Easy bruising skin.

• Flat red and purple spots on the skin.

• Joint and bone pain.

• Fullness or discomfort of the stomach.

• Swollen glands in the groin, armpit, and neck with soreness.

Stages of Acute Myeloid Leukemia:

Leukemia generally does not form solid tumors. So, the staging of this condition can be different. So, the types or stages of acute myeloid leukemia include the following:

• Untreated.

• Active disease.

• Cancer in remission.

• Measurable residual disease (MRD).

• Relapsed (recurrent) or refractory.

How Serious Is Acute Myeloid Leukemia?

The exact cause of acute myeloid leukemia is still unknown, while the myeloid stem cells produce an excess amount of immature white blood cells than required. As the white blood cells are immature, they do not possess the infection-fighting attributes like the completely developed and matured white blood cells. This results in a substantial decrease in the number of healthy platelets and red blood cells, causing the symptoms of leukemia.

Acute myeloid leukemia is an aggressive and rare form of cancer affecting the blood and bone marrow. So, this condition could turn out to be life-threatening if left untreated. Acute myeloid leukemia generally affects people of age 60 years and older. Nevertheless, it can affect children and younger adults. The recent advancements and treatment options contribute to a longer life with acute myeloid leukemia.

How Does Enasidenib Work?

Enasidenib is a prescription medication that is used for the treatment of people with cancer called acute myeloid leukemia associated with an isocitrate dehydrogenase 2 mutation whose condition has come back or shown no improvement following previous chemotherapies. Enasidenib belongs to a class of medications known as Isocitrate dehydrogenase 2 ( IDH2) inhibitors. So, it works by blocking the action of an enzyme called isocitrate dehydrogenase, which is required by the cancer cells for growth and maturation. As a result, this drug slows down or inhibits the growth of cancer cells, causing acute myeloid leukemia in the body.

What Is the Dosage of Enasidenib?

• Enasidenib is indicated for treating refractory or relapsed (recurrent) acute myeloid leukemia with a mutation in isocitrate dehydrogenase 2 as diagnosed by the FDA-approved kit.

• The recommended dosage of Enasidenib is 100 mg to be taken orally. The dosage is once daily with or without a meal as far as no disease progression and unacceptable toxicity.

• The treatment is generally for greater than six months in people without disease progression and toxicity.

• This long span is considered to allow time for an effective clinical response.

How Effective Is Enasidenib?

Enasidenib is effective in treating adults with recurrent or refractory forms of acute myeloid leukemia, according to clinical research studies. The clinical studies evaluating the effectiveness of Enasidenib say that 50 percent of people with acute myeloid leukemia showed a first response in 1.9 months, and the range was reported as 0.5 to 7.5 months. Moreover, certain controlled studies say that Ernasidenib had an average overall survival time of above 4.5 months longer when compared to those people treated with previous first-line treatments (chemotherapy).

What Are the Things to Inform the Doctor Before the Initiation of Enasidenib Treatment?

• Inform the doctor if one presents an allergic reaction to Enasidenib or any other ingredients of the drug.

• Inform the doctor if one has an allergy to other medications in general.

• Tell the doctor about the prescription and non-prescription medications one takes or plans to take. This includes pharmaceutical drugs, vitamin supplements, nutritional supplements, and herbal products. The doctors might change the dosage of Enasidenib or monitor one conscientiously for side effects.

• Tell the doctor if one is pregnant or has any plans.

• The doctors would advise pregnancy tests before the initiation of Enasidenib therapy.

• Female patients who take Enasidenib medication should consider using effective birth control or contraceptives during Enasidenib treatment for a minimum of two months following the final dose of Enasidenib.

• Male patients having their partners should consider using effective birth control aids or contraceptives for a minimum of two months following the final dosage of Enasidenib.

• Moreover, Enasidenib might influence hormonal contraceptive work, decreasing its efficacy.

• Enasidenib might cause fertility problems in both males and females, affecting the ability to conceive. So, discuss this with the healthcare professionals in case one has any concerns regarding this.

• Inform the doctor if one is breastfeeding currently or plans to do so. Though it is not known whether this medication could pass into the breast milk, the doctors advise not to breastfeed for a minimum of two months following the final dose of Enasidenib.

How Is the Drug Enasidenib Administered?

One should follow the doctor’s advice and the directions on the prescription label conscientiously.

• One should take Enasidenib tablets according to the prescription given by the healthcare provider, considering the duration and frequency.

• Do not take a lower or higher dosage of Enasidenib tablets. In addition, do not take it more often than the doctor’s prescription.

• Enasidenib comes in tablet form, and it is to be taken orally.

• Take the Enasidenib tablet at the same time every day.

• Enasidenib tablets can be administered with or without food.

• Swallow the tablet as a whole.

• One should not chew or split the Enasidenib tablet.

• One can swallow the tablet with eight ounces of water.

Note:

The healthcare providers will perform certain blood tests to assess the blood count before the initiation of Enasidenib therapy and at least at two-week intervals for the first three months during the therapy to monitor the side effects. The doctors might modify the dosage or discontinue the treatment temporarily based on the side effects. Nevertheless, one should not bring Enasidenib therapy to a stop themselves without the consent of the doctor.

What Are the Side Effects of Enasidenib?

Though Enasidenib is a safe and effective drug for the treatment of acute myeloid leukemia, it can cause certain unwanted side effects. The incidence and type of side effects can vary from individual to individual. The common side effects of Enasidenib include the following, which one should consider and report to the healthcare providers if distressing:

• Nausea.

• Vomiting.

• Diarrhea.

• Loss of appetite.

• Jaundice.

The other significant side effects of Enasidenib include the following, and one should reach out to the doctor as early as possible if experiencing any of these:

• Dark-colored urine.

• Jaundice.

• Clay-colored stools.

• Severe vomiting.

• Severe diarrhea.

Serious Side Effects

Enasidenib can induce serious side effects. So, the one encountering any of the following should seek emergency medical care at the earliest.

Allergic Reaction:

An allergic reaction occurs when the person has an allergy to Enasidenib or any other active ingredient of the given formulation. The common associated with an allergic reaction include:

• Hives.

• Rashes.

• Difficulty breathing.

• Swelling of the mouth, throat region, or face.

Differentiation Syndrome:

Enasidenib can lead to a serious condition called differentiation syndrome, affecting healthy blood cells. This can turn out to be fatal if not treated. Differentiation syndrome might result within ten days to five months following the initiation of Enasidenib therapy. The signs and symptoms of differentiation syndrome include:

• Fever.

• Cough.

• Difficulty breathing.

• Rapid weight gain.

• Bone pain and discomfort.

• Swelling of the legs, arms, groin, underarms, and neck.

Tumor Lysis Syndrome:

Tumor lysis syndrome or tumor cell breakdown might occur with Enasidenib therapy. The signs of tumor lysis syndrome include:

• Weakness.

• Tiredness.

• Muscle cramps.

• Nausea.

• Vomiting.

• Diarrhea.

• Rapid or slow heart rate.

• The tingling sensation of the hands, feet, or the mouth.

Missed Dose:

If one misses a dosage of Enasidenib tablets or vomits following oral administration, then take the dosage of Enasidenib as soon as possible on the same day. Then, one can continue taking the subsequent dosage on the next day at the regularly scheduled time. Nevertheless, one must consider not taking two tablets at the same time as compensation for a missed Enasidenib dose.

Overdose:

Reach out to the emergency medical team or poison control service at the earliest in the case of an overdose of Enasidenib. Call the emergency services if the individual has difficulty breathing, seizure, or other life-threatening concerns.

Storage:

• Store the Enasidenib tablets at a temperature between 20 and 25 degrees Celsius. Store at excursions within the range of 15 and 30 degrees Celsius.

• One should keep the Enasidenib tablet bottle firmly closed.

• Moreover, store the tablets in the original bottle with a desiccant beaker to protect them from heat, light, and moisture.

For Doctors:

Clinical Data of Enasidenib:

• Drug Name: Enasidenib.

• Other Names: AG-22.

• Drug Class: Isocitrate dehydrogenase-2 (IDH 2) inhibitor.

• Route of Administration: Oral.

• Chemical Formula: C19H17F6N7O

• Molar mass: 473.383 g.mol-1

Indications:

The indication of Enasidenib typically includes treatment of adults with relapsed or refractory forms of acute myeloid leukemia associated with a mutation of isocitrate dehydrogenase 2 (IDH 2).

Associated Conditions:

• Relapsed acute myeloid leukemia.

• Refractory acute myeloid leukemia.

Dosage Modifications:

The following things and dosage modifications are to be considered according to the adverse reactions suspected in the patients when treated with Enasidenib:

1. Differentiation Syndrome:

• Consider administering systemic corticosteroids if there is a suspicion of differentiation syndrome. Also, start with hemp dynamic monitoring.

• Stop Enasidenib therapy if severe pulmonary distress results in requiring ventilator support and intubation. In addition, consider interrupting the treatment of renal dysfunction, which lasts for more than two days, even following the initiation of systemic corticosteroids.

• Resume Enasidenib treatment when the reported signs and symptoms advance to grade two and lower.

2. Noninfectious Leukocytosis:

The white blood cell count (WBC) is greater than 30. 10 9/L in the case of non-infectious leukocytosis.

• Begin hydroxyurea treatment according to the standard institutional guidelines.

• Stop the Enasidenib therapy if the leukocytosis is not improving with hydroxyurea.

• Resume Enasidenib treatment of 100 mg dosage daily when WBC count is lowered to below three.

3. Increased Total Bilirubin Level:

Here, the bilirubin is elevated greater than three times the upper limit of normal (ULN) and persists for more than two weeks without increased transaminase and hepatic disorders.

• Consider reducing the dosage of Enasidenib to 50 mg daily.

• Resume Enasidenib of 100 mg daily when bilirubin drops down to a level less than two times the ULN.

4. Tumor Lysis Syndrome:

The grade three and higher toxicity levels are treated the same as the tumor lysis syndrome.

• Discontinue Enasidenib treatment unless the toxicity amends to grade two and lower.

• Resume the treatment at 50 mg dosage daily, which can be increased to 100 mg dosage daily when the toxicity resolves to grade one and lower.

• Consider termination or discontinuation of the treatment if grade three or higher toxicity recurs.

What Are the Pharmacological Aspects of Enasidenib?

Pharmacodynamics:

The study involving the treatment of Enasidenib for adult patients with refractory or replaced acute myeloid leukemia showed an overall response rate of 40.3 percent. This efficacy was also reported with cellular differentiation and maturation. The study does not show any evidence of aplasia. There were no significant mean changes in the QT corrected for heart rate (QTC) interval following the Enasidenib therapy. Therefore, Enasidenib does not cause QTC prolongation.

Mechanism of Action:

Enasidenib is typically an inhibitor of the enzyme isocitrate dehydrogenase 2 (IDH2). So, this drug targets the mutant isocitrate dehydrogenase 2 variants like R172S, R172K, and R140Q at about 40-fold lower levels compared to the wild enzyme forms in vitro. The inhibition action of the mutant isocitrate dehydrogenase enzyme occurring by Enasidenib results in lowered 2- hydroxyglutarate concentrations and stimulated myeloid differentiation in both in vivo and in vitro, according to the mouse xenograft model studies. Enasidenib lowered the levels of 2-hydroxyglutarate with decreased blast count and raised the percentage of mature myeloid cells, as per the investigation of blood samples of patients with acute myeloid leukemia with isocitrate dehydrogenase 2 mutation.

Absorption:

• The peak plasma concentration of 1.3 mcg/mL is attained within four hours after ingestion of a single (oral) dose of 100 mg Enasidenib.

• The average oral bioavailability is nearly 57 percent following the administration of 100 mg Enasidenib.

• The steady-state plasma levels are attained in about 29 days of one daily dose.

• The median time to (maximum concentration) Cmax is about four hours.

Distribution:

• The average volume of distribution is about 55.8 liters.

• The human plasma protein binding capacity is about 98.5 percent for Enasidenib and 96.6 percent for its metabolite AGI-16903 in vitro.

• The parent drug and its chief metabolite are not considered to be the substrates of OAT 3, OAT 1, OAT 1B1, MRP 2, OCT 2, and OAT 1B3.

• AGI-16903 is regarded as a substrate for both BCRP and P-glycoprotein.

Metabolism:

The metabolism of Enasidenib is N- dealkylation that is typically mediated by multiple cytochromes, including CYP 1A2, CYP2C8, CYP2B6, CYP2C9, CYP2C8, CYP2D6, CYP2C19, and CYP3A4 in addition to Uridine 5-diphospho-glucuronosyltransferase such as UGT1A1, UGT1A4, UGT1A3, UHT1A9, UGT2B15, and UGT2B7 enzymes for the production of AGI-16903. Moreover, AGI-16903 is further metabolized by enzymes such as CYP2C19, CYP1A2, CYP3A4, UGT1A3, and UGT1A9. The parent drug Enasidenib accounts for about 89 percent of the total circulating drug, and its by-product AG1-16903 accounts for ten percent of the total drug circulation.

Elimination:

• The elimination of Enasidenib is about 89 percent of fecal excretion while 11 percent of renal excretion.

• The unchanged drug form in feces and urine constitute 34 percent and 0.4 percent of the total drug, respectively.

Half-Life and Clearance:

• The terminal half-life of Enasidenib is reported as 137 hours.

• Enasidenib shows a mean total clearance of about 0.74 L/hr.

Adverse Effects:

The drug Enasidenib shows adverse events in most cases. The following adverse effects are commonly observed in greater than ten percent:

• Decrease in calcium.

• Increase in total bilirubin.

• Nausea.

• Vomiting.

• Diarrhea.

• Decrease in potassium.

• Decreased appetite.

• Decreased phosphorus.

• Differentiation syndrome.

• Dysgeusia.

• Noninfectious leukocytosis.

In addition, one to ten percent of the cases manifest the following adverse events, in general:

• Tumor lysis syndrome.

• Pulmonary edema.

• Diarrhea.

• Acute respiratory distress syndrome.

What Are the Drug Interactions of Enasidenib?

The effects of Enasidenib on other drugs are discussed below:

• P-Glycoprotein Substrates: Enasidenib is a P-glycoprotein inhibitor. The coadministration of P-glycoprotein substrate and Enasidenib raises the exposure of P-glycoprotein substrates in the system. This results in an increase in the occurrence and severity of the adverse effects of those substrates. A small concentration change might result in severe adverse events for a P-glycoprotein substrate. In that case, reduce or alter the dosage frequency and consider adverse reaction monitoring.

• OATP1B3, OATP1B1, and BCRP Substrates: Enasidenib inhibits the action of OATP1B3, OATP1B1, and BCRP. So, coadministration with Enasidenib raises the exposure of OATP1B3, OATP1B1, and BCRP substrates to a greater extent. This results in an increase in the occurrence and severity of the adverse events associated with such substrates. Discontinue or decrease the dosage of OATP1B3, OATP1B1, and BCRP substrates.

Specific Considerations:

• Lactation: No appropriate data shows the presence of Enasidenib and its metabolite in human milk, its effects on milk production, and its influence on the infant. Advise women not to breastfeed for a minimum of two months following the last dosage of Enasidenib due to its potential for adverse effects.

• Males and Females of Reproductive Ages: The embryo-fetal toxicity studies in females indicate that Enasidenib could harm the fetus when administered to the pregnant woman. So, advise pregnancy tests in women of reproductive potential before the initiation of therapy. Advise the males and females of reproductive potential to consider using effective contraceptives or birth control aids during treatment and for a minimum of two months following the final dosage of Enasidenib. This is because coadministration might affect the efficacy of combined hormonal contraceptives.

• Infertility: According to clinical studies in animals, Enasidenib might impact fertility in males and females of reproductive potential. It is still undetermined whether such effects on fertility can be reversible.

• Pediatric Use: The usage, safety, and efficacy of Enasidenib in the pediatric population have not been determined.

• Geriatric Use: No dosage modification is required for the geriatric population. The clinical studies show no significant differences in the safety and efficacy of Enasidenib in individuals aged 65 years and higher compared to younger patients.