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Treatment Name: Antithymocyte Globulin (ATG, ATGAM®) + Cyclosporine (Gengraf®, Neoral®) + Eltrombopag (Promacta®)

Antithymocyte Globulin (ATG, ATGAM®) + Cyclosporine (Gengraf®, Neoral®) + Eltrombopag (Promacta®) is a Treatment Regimen for Severe Aplastic Anemia (SAA)

How does cyclosporine + ATG + eltrombopag (Promacta®) work?
In aplastic anemia, it is thought that T-lymphocytes destroy healthy cells within the bone marrow that are required to make white blood cells, red blood cells, and platelets. Both cyclosporine and ATG work by suppressing both the number and function of T-lymphocytes.

Cyclosporine (Gengraf® or Neoral®) inhibits T-lymphocytes (T-cells) in their ability to grow and divide and also blocks the release of a chemical from T-lymphocytes, known as interleukin-2 (IL-2), which can further activate T-cells.

ATGAnti-Thymocyte Globulin (ATGAM®) is a medication made up of antibodies derived from a horse that are specifically designed to reduce the number of lymphocytes responsible for causing bone marrow destruction. A horse is exposed to human thymus lymphocytes, which then makes antibodies against these lymph cells. The antibodies are collected from the horse, purified, and then used to treat humans with overactive lymphocytes thought to cause aplastic anemia. ATG (ATGAM®) may be used for either moderate or severe aplastic anemia (SAA).

Eltrombopag (Promacta®) is designed to increase the number of platelets in your bloodstream by stimulating the cells in your bone marrow that make them.

Goals of therapy:
Cyclosporine + ATG + eltrombopag is given to increase red blood cells, white blood cells, and platelets . If therapy is successful and destruction of healthy bone marrow stops, white blood cells, red blood cells, and platelets grow back. This results in a decrease of symptoms from aplastic anemia such as fatigue, weakness, headaches, shortness of breath, gum bleeding, nose bleeding, bruising, and infection. In addition, red blood cell and platelet transfusions may no longer be required. Although some patients may need to wait longer, the majority of patients have a response within the first 3 months.

In some cases, after therapy with cyclosporine + ATG + eltrombopag a bone marrow transplant may be performed with the goal of cure.

Schedule

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  • ATG intravenous (I.V.) infusion over 4 to 24 hours on Days 1, 2, 3, and 4
    • ATG is often infused using a high-flow vein via a “central catheter” to avoid the risk of vein irritation or blood clot
  • Eltrombopag 150 mg (three 50 mg tablets) by mouth once daily starting on Day 1
    • The dose may need to be lowered for patients less than 12 years old or for East or Southeast Asian patients
    • It is VERY important to take the tablets with water only, or on an empty stomach. Food may decrease the amount absorbed and therefore lessen its effectiveness. Food should be avoided for one hour before and two hours after each dose
  • Cyclosporine (typically 2 to 6 oral capsules) by mouth twice daily starting on Day 1
    • Your dose may need to be changed several times during therapy to achieve the target blood levels of cyclosporine
    • The dose of cyclosporine is based upon “Ideal Body Weight.”
    • In certain instances, dosing based upon “Actual Body Weight” may lead to too much cyclosporine which can increase the risk of kidney and liver problems
    • Cyclosporine is available as several different preparations such as: Gengraf®, Neoral®, or Sandimmune®. Importantly, only “modified” forms of cyclosporine (Gengraf®, Neoral®) should be used. Sandimmune is not modified and should not be used
    • It is generally advisable to take one brand only as switching between preparations may affect blood concentrations and lead to unexpected changes in dosing

Estimated total infusion time for this treatment:

  • As short as 4 hours for each ATG treatment; as long as 24 hours for each treatment
  • Infusion times are based on clinical studies, but may vary depending on doctor preference or patient tolerability. Pre-medications and I.V. fluids, such as hydration, may add more time

ATG can be given in an outpatient infusion center, allowing the person to go home afterwards or it may be given in the hospital. Cyclosporine and eltrombopag are usually taken at home.

Only one treatment (a total of 4 doses) with ATG is usually given. Cyclosporine and eltrombopag are usually taken daily until treatment no longer works, unacceptable side effects occur, or a bone marrow transplant is performed.

Click here for the common cyclosporine + ATG + eltrombopag starting doses.

Side Effects

In a multi-drug regimen, each medication has unique side effects. When these medicines are given together, drug-related side effects reported in clinical studies give the best estimate of what to expect. In clinical studies, the most commonly reported side effects of cyclosporine + ATG + eltrombopag are shown here:

A note about side effect percentages

Importantly, not all people who experience a side effect from ATG (ATGAM®) + Cyclosporine (Gengraf® or Neoral®) + Eltrombopag (Promacta®) will experience it in the same way. It may be mild in some or severe in others, depending upon the individual. Everybody is different. Additionally, side effects may vary over time. For some, side effects may be a reason to delay or switch treatment, reduce the dose, or avoid future treatment with a certain medication altogether.

Side effects may be treatable when they occur or preventable by taking certain medications before they happen. When medications are taken to prevent a problem, this is known as prophylaxis, or "prophy" for short.

After starting treatment with ATG + Cyclosporine + Eltrombopag, be sure to come back and watch all of the side effect videos shown below. Each of these videos contain valuable information about side effect management that will hopefully help you to both feel better and stay out of the hospital.

Side effect videos Side Effect Videos
Neutropenic FeverNeutropenic FeverPainPainBleedingBleedingFatigue Fatigue

Monitoring

How often is monitoring needed?
Labs (blood tests) may be checked before treatment and periodically during treatment. Labs often include: Complete Blood Count (CBC), Comprehensive Metabolic Panel (CMP), magnesium, cyclosporine blood levels, plus any others your doctor may order.

How often is imaging needed?
Imaging may be checked if there are concerns for infection or bleeding. Imaging may include: X-rays, computerized tomography (CT) scans, or magnetic resonance imaging (MRI).

How might blood test results/imaging affect treatment?
Depending upon the results, your doctor may advise to continue cyclosporine + ATG + eltrombopag as planned, reduce the dose of one or more of the treatments, temporarily stop treatment until the side effect goes away, or switch to an alternative therapy.

Cyclosporine trough blood levels are measured periodically (such as weekly for the first month, then every other week) to maintain the cyclosporine level between 200 – 400 ng/mL for the first six months. Afterwards, the dose is typically reduced by 25% every three months over the subsequent 18 months, then discontinued.

ATGAM® prescribing information recommends monitoring for cytomegalovirus (CMV) infection as some studies suggested an increase in the incidence of CMV infection after patients received ATGAM®

ChemoExperts Tips

  • ATG may cause serious allergic reactions. Acetaminophen (Tylenol®) and diphenhydramine (Benadryl®) are given before each ATG infusion to help prevent reactions. If an infusion reaction occurs, the infusion is stopped until symptoms subside, then restarted at a slower infusion rate
  • In some cases, before the ATG infusion a very small dose of ATG is injected under the skin and the area is watched for redness around the injection site. If a skin reaction does not occur, the I.V. dose of ATG is then given. If a skin reaction occur, the infusion of ATG is typically given over a longer period of time or a desensitization to ATG may be performed
  • ATG can potentially cause a condition known as serum sickness. A corticosteroid such as prednisone is typically given during the first 10 days of treatment to help prevent serum sickness. After 10 days, the dose is decreased over time (tapered) and stopped
  • Eltrombopag should be taken at least two hours before or four hours after any medicines (prescription or over-the-counter) or foods such as dairy that contain calcium, magnesium, aluminum, selenium, zinc, or iron. If you are not sure which medicines or foods that may contain these ingredients, ask your pharmacist!
  • If you are taking the liquid suspension eltrombopag, remember to mix it with cool water, not hot water. Take the oral suspension on an empty stomach within 30 minutes of preparing the dose
  • Additional medications that may be prescribed include Bactrim® (Sulfamethoxazole/Trimethoprim; unless you have a sulfa allergy) to prevent Pneumocystis Pneumonia and acyclovir (Zovirax®), valacyclovir (Valtrex®) or famciclovir (Famvir®) to prevent viral infections such as reactivation of herpes simplex virus (HSV) or varicella zoster virus (VZV)
  • Cyclosporine levels are best drawn in the morning right before you take cyclosporine. On days when a cyclosporine level is drawn in the clinic, bring your morning dose with you to your appointment so you can take the dose immediately after the blood level is taken
  • Lemons, limes, and other types of oranges are okay to eat and do not interact with cyclosporine. Try to avoid grapefruit and grapefruit juice, pomegranate, starfruit, and seville oranges (found in marmalade) as they may increase the concentration of cyclosporine in your blood
  • Immunizations should not be given without the approval of the hematologist (blood doctor) treating aplastic anemia. Certain immunizations, such as live vaccines, may lead to the infection that they are meant to prevent due to the immunosuppressant effects of ATG
  • A pharmacist should ALWAYS review your medication list to ensure that drug interactions are prevented or managed appropriately. For example, certain medications may increase or decrease blood levels of cyclosporine and eltrombopag may interact with commonly taken cholesterol medicines known as statins (atorvastatin, pravastatin, simvastatin) and a statin dose reduction may be recommended when starting eltrombopag
  • Clinical trials may exist for aplastic anemia. Ask your doctor if any studies are currently enrolling in your area. If not, go to clinicaltrials.gov to search for other centers offering study medications

Patient Assistance & Co-payment Coverage

Patients under the age of 65 years, or those with private insurance plans:
If you have insurance and are looking for patient assistance or copay assistance for Antithymocyte Globulin (ATG, ATGAM®) + Cyclosporine (Gengraf®, Neoral®) + Eltrombopag (Promacta®), we have provided links that may help.

Visit our Patient Assistance page and click the links to various patient assistance programs for help paying for Antithymocyte Globulin (ATG, ATGAM®) + Cyclosporine (Gengraf®, Neoral®) + Eltrombopag (Promacta®). Depending upon your income, they may be able to help cover the cost of:

  • ATG (Anti-Thymocyte Globulin)
  • Cyclosporine
  • Eltrombo­pag

For Branded medications (may be available for generic medications too), check with the manufacturer to determine if a co-pay card is offered and if it could reduce your monthly copay.

  • If you are uninsured, check with the manufacturer to determine if you are eligible to receive medication at no cost.

Medicare and Medicaid patients (Patients 65 years or older):
The clinic providing treatment will likely pre-authorize medications and immune therapies such as Antithymocyte Globulin (ATG, ATGAM®) + Cyclosporine (Gengraf®, Neoral®) + Eltrombopag (Promacta®) and are the best source to help you understand drug cost.

  • Ask to speak with a patient assistance technician or financial counselor at the clinic or hospital administering this therapy.

Individual Drug Label Information

ATG (Anti-Thymocyte Globulin) (ATGAM®)

  • ATG, also known as ATGAM®, is an intravenous infusion
  • ATGAM may cause serious allergic reactions. A skin test may be done prior to receiving the full dose to see if an allergic reaction develops
  • Although no cases have been reported, transmission of viruses and Creutzfeldt-Jakob disease (CJD) agent is possible after receiving ATG
  • It is not known if ATG is safe in pregnancy and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus
General side effects from ATG (ATGAM®)
  • Fever
  • Chills
  • Skin rash
  • Low platelets [thrombocytopenia]
  • Joint pain
  • Hives
  • Headache
  • Itching
  • Nausea
  • Diarrhea
  • Sore throat
  • Serum sickness
  • Increased infection risk
  • Kidney or liver injury
  • High or low blood pressure
  • Click on the ATG (ATGAM®) package insert below for reported side effects, possible drug interactions, and other ATG prescribing information

Side Effect Videos
Nausea and VomitingNausea and VomitingDiarrheaDiarrheaFatigue Fatigue BleedingBleedingPainPainAnemiaAnemiaNeutropenic FeverNeutropenic Fever

See DailyMed package insert.

Cyclosporine (Gengraf® Neoral®)

  • Is an oral capsule available in 25 mg, 50 mg and 100 mg
  • Modified cyclosporine (Gengraf®, Neoral®) and Non-modified cyclosporine (Sandimmune®) are not equivalent and should not be used interchangeably
  • Each dose of cyclosporine can be taken with or without food
  • If you miss a dose, take the dose as soon as possible unless the next scheduled dose is supposed to be taken in a few hours
  • Cyclosporine should be stored room temperature (68°to 77°F)
  • Dosage adjustments may be required for blood levels of cyclosporine that are too high or too low, liver dysfunction, or drug interactions
  • Cyclosporine may interact with certain antifungal and seizure medications. Ask your doctor or pharmacist to review your medications for any possible interactions
  • Cyclosporine may also interact with grapefruit and grapefruit juice, pomegranate, star fruit, or seville oranges (in marmalade) causing increased blood levels of cyclosporine
  • Avoid eating or drinking these foods during treatment Avoid therapy with St. Johns Wort, carbamazepine, or phenytoin as they will decrease blood levels of cyclosporine
  • Use during pregnancy may cause fetal harm. Cyclosporin should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus
General side effects from cyclosporine (Gengraf®, Neoral®)
  • Kidney injury
  • High blood pressure
  • Decreased blood magnesium
  • Thickening of the gums
  • Joint or muscle pain
  • Muscle tremors
  • Liver injury, increased bilirubin in blood
  • Excessive body hair growth
  • Nausea
  • Diarrhea
  • Click on the cyclosporine (Gengraf®, Neoral®) package insert below for reported side effects, possible drug interactions, and other cyclosporine prescribing information

Side Effect Videos
Nausea and VomitingNausea and VomitingDiarrheaDiarrhea

See DailyMed package insert.

Eltrombo­pag (Promacta®)

  • Eltrombopag is available as an oral tablet available in 12.5 mg, 25 mg, 50 mg, 75 mg, and 100 mg strengths
  • Eltrombopag is also available as a liquid oral suspension
  • The bottle of eltrombopag may contain a little bag that absorbs moisture and keeps the medicine dry. This bag is known as a desiccant pack. If the desiccant pack is in your bottle, do not remove it.
  • Eltrombopag may increase the risk of potentially life-threatening liver damage
  • Eltrombopag should be taken without food, one hour before or 2 hours after a meal. Eltrombopag may be taken with water
  • Food decreases absorption so it is best to take on an empty stomach to avoid a decrease in effectiveness
  • If you miss a dose, wait until the next scheduled eltrombopag dose before taking. Do not take two doses in one day
  • Eltrombopag should be stored at room temperature, between 68°F and 77°F, but may be exposed to as low as 59°F and as high as 86°F. Eltrombopag should be dispensed in the original bottle Dosage adjustments may be required for patients with liver problems. A lower starting dose (example 25 mg) is usually recommended
  • Eltrombopag dosage adjustments may be required for patients of East Asian Ancestry. A lower starting dose (example 12.5 mg) is usually recommended
  • May interact with “statins,” medications taken for HIV, cyclosporine, foods such as dairy products, and over-the-counter antacids or supplements. Talk to your pharmacist for tips on making sure eltrombopag does not interact with your other medicines
  • Eltrombopag may not be safe during pregnancy or breast-feeding. It is not known if eltrombopag is excreted into human breast milk. If you are taking eltrombopag and wish to become pregnant, talk to your doctor or pharmacist about the potential risks and benefits of continuing treatment with eltrombopag 
General side effects from eltrombopag (Promacta)
  • Nausea
  • Headache
  • Diarrhea
  • Upper airway infection, such as sinus infection
  • Vomiting
  • Higher liver enzyme levels in blood (example: ALT or AST)
  • Fatigue
  • Muscle pain
  • Urinary tract infection
  • Sore throat
  • Back pain
  • Rash
  • Cataracts
  • Blood clots
  • Flu-like symptoms (headache, fever, cough, sore throat, body aches)
  • High bilirubin in blood (may cause yellow skin or eyes)
  • Click on the eltrombopag (Promacta®) package insert below for reported side effects, possible drug interactions, and other eltrombopag prescribing information

Side Effect Videos
Nausea and VomitingNausea and VomitingDiarrheaDiarrheaHair LossHair LossFatigue Fatigue BleedingBleedingConstipationConstipationPainPainBlood ClotsBlood Clots

See DailyMed package insert.

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References

1) Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med. 2017;376:1540-1550.

2) Supplement to: Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med. 2017;376:1540-1550.

Created: February 14, 2019 Updated: January 15, 2020

What is Severe Aplastic Anemia (SAA)?

Severe aplastic anemia (SAA) is a rare blood disorder that can be life-threatening if left untreated. SAA is thought to result from certain cells of the immune system inappropriately attacking healthy cells within the bone marrow. This leads to:

  • A low white blood cell count, which increases the risk of infection
  • A low red blood cell count, which decreases the ability to deliver oxygen and may cause fatigue, weakness, and shortness of breath
  • A low platelet count, which increases the risk of bruising and bleeding

The treatment of aplastic anemia may include immunosuppressant agents (shown below) or a stem cell transplant if a stem cell donor can be identified. A matched sibling donor is often thought to be be the best option, if one is available. The goals of these treatments are to restore the healthy bone marrow cells, prevent infection and bleeding, and to stop the need for blood or platelet transfusions.

Common cyclosporine + ATG + eltrombopag starting doses

  • ATG 40 mg/kg intravenous (I.V.) infusion over 4 to 24 hours once daily on Days 1, 2, 3, and 4
  • Usual cyclosporine starting dose: 5 mg/kg by mouth twice daily (Important note: Ideal Body Weight is recommended for dosing cyclosporine)
  • Usual Eltrombopag starting dose: 150 mg (three 50 mg tablets) by mouth once daily starting on Day 1

Note: Individual doses may vary based upon your Doctor's recommendation, or drug availability.

What does Cure mean?

The word “cure” means there are no cancer cells left in the body and cancer will never come back. Depending on the cancer type and stage, this may be the true goal of therapy. However, it is very difficult to prove all cancer cells are gone. Even though images, like X-rays and MRI’s, and blood tests may not show any signs of cancer, there can be a small amount of cancer cells still left in the body. Because of this, the word “remission” is used more often. This means there are no signs or symptoms of cancer. Patients in remission are followed closely for any signs of cancer returning. Sometimes, more chemotherapy may be given while in remission to prevent the cancer from coming back.

Doctors usually do not consider a patient “cured” until the chance of cancer returning is extremely low. If cancer does return, it usually happens within 5 years of having a remission. Because of this, doctors do not consider a patient cured unless the cancer has not come back within 5 years of remission. The five-year cutoff does not apply to all cancers.

What is a CBC?

A Complete Blood Count (CBC) is a frequently ordered blood test that tells clinicians the status of your: 1) White blood cell count, 2) Hemoglobin, and 3) Platelet count at the time the test was taken.

Common uses:
1) White blood cell count (WBC): is used to determine infection risk, or response to chemotherapy. Certain chemotherapy agents may harm our good infection-fighting cells. Sometimes chemotherapy may need to be delayed to allow these cells to recover.

2) Hemoglobin: is used to determine if someone is anemic. Anytime the hemoglobin is below 12 g/dL, the person is said to be anemic. Red blood cell transfusions, and sometimes iron can be given to restore the hemoglobin level, but anemia treatment should always aim at treating the underlying cause or condition.

3) Platelet count: is used to determine if the risk of bleeding is increased or if a platelet transfusion is required to prevent bleeding. Certain medications that increase bleeding risk, such as: aspirin, certain chemotherapy agents, and blood thinners, may need to be stopped temporarily until the platelet count is within a safe range.

What is a CMP?

A Comprehensive Metabolic Panel (CMP) is a frequently ordered blood test that tells clinicians the status of your: 1) Electrolytes & Acid/Base status2) Kidney function, 3) Liver function, 4) Blood sugar, and 5) Calcium at the time the test was taken. It is commonly used to monitor liver and kidney function when beginning new medications such as chemotherapy. A total of 14 tests are run simultaneously and are shown below.

Electrolytes & Acid/Base status:
1) Sodium, 2) Potassium, 3) Carbon dioxide, 4) Chloride

Kidney Function:
5) BUN (blood urea nitrogen), 6) Serum creatinine (Scr)

Liver Function:
7) AST, 8) ALT, 9) Total bilirubin, 10) Alk Phos, 11) Albumin, 12) Total protein

Blood sugar:
13) Serum glucose

Calcium:
14) Serum calcium

What is a Desensitization?

Desensitization is a process that helps the body adjust to a medication to lower the risk of experiencing serious allergic reactions. Typically, the process is done slowly over several hours in a hospital setting. Very small doses of the medication are initially given and the doses are increased over time until the total amount of the medication is received.

What is Serum Sickness?

Serum sickness occurs when the body recognizes medications like ATG as “foreign” proteins and uses the immune system to attack the foreign protein to eliminate it. Symptoms typically start a few days after treatment and can include skin rash, hives, itching, joint pain, fevers, and weakness. In severe cases it can cause low blood pressure, and rarely organ damage.

Cyclosporine Trough Levels

Cyclosporine blood levels are best drawn in the morning right before you take cyclosporine. This is known as a “trough” concentration. On days when a cyclosporine level is drawn in the clinic, it is important to bring your morning dose with you to your appointment so you can take the dose immediately after the cyclosporine blood level is taken

A note about side effect percentages

The number you see next to the percent sign (%) means how many people out of 100 are likely to experience this side effect.

For example, if the side effect is reported to occur in 8% of patients, this means that roughly 8 out of 100 people receiving this treatment will experience this side effect.