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Treatment Name: ATRA (Tretinoin) + Arsenic Trioxide (Trisenox®)

ATRA (Tretinoin) + Arsenic Trioxide (Trisenox®) is a Chemotherapy Regimen for Acute Promyelocytic Leukemia (APL)

How does ATRA + Arsenic Trioxide work?
At diagnosis, APL cells are "trapped" in an immature phase of maturation, do not function normally, and can suppress the growth of good cells in the bone marrow. Both of the medications in ATRA + Arsenic Trioxide are designed to reduce the number of APL cells by triggering leukemic promyelocytes to die.

ATRA = All-Trans-Retinoic-Acid = Retinoic Acid = Tretinoin
+
Arsenic Trioxide (Trisenox®)

Goals of therapy:
ATRA + Arsenic Trioxide is given to eliminate leukemic cells for patients with low-to-intermediate risk APL.

ATRA + Arsenic Trioxide is commonly given with the goal of cure.

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Schedule

  • Oral ATRA (Tretinoin) is administered by mouth in two divided doses per day, morning and night, with a large glass of water until hematologic (blood) complete remission is achieved or for a maximum of sixty days
  • Arsenic Trioxide intravenous (I.V.) infusion over two hours once daily, continuing every day until complete remission is achieved or for a maximum of sixty days

Click here for common ATRA plus Arsenic Starting Doses

Supportive Care Medications

  • Prednisone tablets by mouth once daily until end of induction. Prednisone is used to prevent differentiation syndrome
  • If differentiation syndrome is suspected, treatment with ATRA and arsenic are temporarily suspended and prednisone is switched to a more potent steroid known as dexamethasone
  • Hydroxyurea 500 mg capsule by mouth four times daily if the white blood cell count (WBC) rises to a high range [10 – 50 x 109/L]

                OR

  • Hydroxyurea 1,000 mg (two 500 mg capsules) by mouth four times daily if white blood cell count (WBC) rises to a very high level [greater than 50 x 109/L]
  • NOTE: Roughly 47% of patients require treatment with hydroxyurea to decrease the white blood cell count after starting ATRA + Arsenic Trioxide therapy

Hospital stay required

  • ATRA (Tretinoin) + Arsenic Trioxide requires a 32-day stay in a hospital (approximately; range = 22 to 68 days).
  • After the Induction cycle is complete and remission has been obtained, patients receive ATRA + Arsenic consolidation. Consolidation treatment usually begins three to six weeks after induction is complete.
  • Total Duration of therapy (Induction + Consolidation) may last up to nine months, depending upon response, tolerability, and number of cycles prescribed.
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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 with ATRA (Tretinoin) + Arsenic Trioxide are shown here:

  • Liver dysfunction (63%)
  • Heart rhythm abnormalities (16%)
  • Intestinal toxicity (4%)
  • Headache with ATRA use (exact % not reported)
  • Nausea or vomiting (exact % not reported)

Roughly 1% of patients permanently discontinue treatment with ATRA + Arsenic Trioxide due to unacceptable side effects before finishing all recommended cycles.

Side effect videos Side Effect Videos
BleedingBleedingBlood ClotsBlood ClotsNausea and VomitingNausea and VomitingPainPain

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Monitoring

How often is monitoring needed?
Labs (blood tests) will be checked before treatment, and daily or multiple times per day when first diagnosed to assess infection, bleeding risk, and clotting risk. Once stable, labs should still be checked at least twice weekly. Labs often include: Complete Blood Count (CBC), Comprehensive Metabolic Panel (CMP), Lactate dehydrogenase (LDH), magnesium, potassium, phosphorous, alkaline phosphatase (Alk Phos), total bilirubin, uric acid, fibrinogen, D-dimer, plus any others your doctor may order.

Newly diagnosed APL greatly increases the risk of bleeding. It is recommended to maintain the fibrinogen level above 150 mg/dL during induction until the risk of bleeding decreases.

How often is imaging needed?
Imaging may be checked before treatment, and often weekly (or more), until stable. Imaging may include an electrocardiogram, commonly referred to as an ECG, or EKG. ECGs are used to evaluate the QTc interval prior to arsenic therapy and periodically throughout treatment.

How might blood test results/imaging affect treatment?
Depending upon the results, your doctor may advise to continue ATRA or Arsenic Trioxide as planned, or delay or switch therapy.

In 63% of patients, reversible liver abnormalities were noted in blood tests. In all of these patients, liver function returned to normal with temporary discontinuation of either ATRA, Arsenic Trioxide, or both.

If the platelet count drops below 30 thousand in the first ten days, or 20 thousand at any point during induction, a platelet transfusion is usually recommended to prevent bleeding.

A red blood cell transfusion may be given if the hemoglobin drops below 8 g/dL.

If serum bilirubin or alkaline phosphatase (blood tests) increase to greater than five times the upper limit of normal, treatment with Arsenic + ATRA may be temporarily stopped until these tests normalize, and a dose reduction may be necessary.

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ChemoExperts Tips

  • As bleeding may occur as a result of APL, medications used to prevent blood clots (blood thinners) are not routinely recommended with this treatment
  • ATRA (Tretinoin) may cause chapped lips or drying and cracking in the corners of the mouth, known as cheilitis. Frequent lip balm use may help alleviate these symptoms
  • If ATRA (Tretinoin) causes severe headaches, ask your pharmacist to try ordering a different brand (manufacturer) the next time you need a refill
  • A pharmacist should ALWAYS review your medication list to ensure that drug interactions are prevented or managed appropriately
  • Medications that lengthen the time to make the heart beat, such as QT-prolonging medications should be minimized (used less) while receiving arsenic trioxide
  • Clinical trials may exist for APL. 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 ATRA (Tretinoin) + Arsenic Trioxide (Trisenox®), 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 ATRA (Tretinoin) + Arsenic Trioxide (Trisenox®). Depending upon your income, they may be able to help cover the cost of:

  • Tretinoin
  • Arsenic Trioxide

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 ATRA (Tretinoin) + Arsenic Trioxide (Trisenox®) 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.

Emotional Wellness

What is Emotional Wellness?
Emotional wellness is having a positive outlook balanced with a realistic understanding of current life events. This requires both an awareness and acceptance of your emotions. It is with this knowledge that you can develop a plan to take the necessary actions to positively impact your life.

Emotional wellness uses an ongoing process to continually reflect on the stressors of life in a constructive manner to move forward and create happiness.

Because emotional wellness is deeply connected with physical, social, and spiritual wellness, pursuing it often becomes particularly difficult in times of major illness. Despite this difficulty, working toward emotional wellness has been connected to improved treatment outcomes and a higher likelihood of achieving goals of therapy.

Learn more about pursuing emotional wellness while receiving treatment with ATRA (Tretinoin) + Arsenic Trioxide (Trisenox®)

Individual Drug Label Information

Tretinoin (ATRA)

  • Tretinoin is supplied as a 10 mg oral capsule. No other strength currently exists
  • Retinoic acid syndrome (or APL differentiation syndrome) may occur anytime during the first month of treatment with tretinoin. It may occur in as many as 25% of patients. It is characterized by fever, shortness of breath, weight gain, or heart, liver, or kidney problems. It may be life threatening. It is best prevented with steroids such as prednisone but also treated with a more potent steroid known as dexamethasone
  • Tretinoin poses a high risk to a fetus if taken by a pregnant woman, therefore all women should have a pregnancy test before beginning treatment. Women of child-bearing potential should use two reliable forms of contraception while taking tretinoin
  • It is not known if tretinoin is excreted in breast milk, therefore mothers should not nurse while taking this medication
  • May cause the pressure in the head to increase (known as benign intracranial hypertension) leading to headache, visual problems, nausea or vomiting
  • Usually taken without food, with a large glass of water. It should be swallowed whole. Each dose should be taken about 12 hours apart
  • Food may increase absorption of tretinoin so it is best to take on an empty stomach to avoid an increase in side effects
  • If you miss a dose, it is best to call your doctor for instruction, especially if you are unable to take it due to side effects
  • Store at controlled room temperature 68°–77° F
  • Dosage adjustments may be required for liver function
  • May interact with antifungal medications such as fluconazole or voriconazole, or common blood pressure medications known as diltiazem and verapamil.  Your doctor may advise to take a smaller dose of these medications to decrease the risk of side effects
General Tretinoin (ATRA) Side Effects
  • Headache
  • Fever or neutropenic fever
  • Dry skin
  • Bone pain
  • Nausea or vomiting
  • Rash
  • Itching
  • Hair loss
  • Weakness
  • Dizziness
  • Fatigue
  • Cheilitis (cracked corners of mouth)
  • High cholesterol or triglycerides
  • Bleeding, which may be severe
  • Blood clots; can happen in veins or arteries
  • Breathing difficulty (ranges from mild to severe)
  • Liver dysfunction, which often resolves when tretinoin treatment is interrupted or complete
  • Click on the tretinoin (ATRA) package insert below for reported side effects and possible drug interactions

Side Effect Videos
Nausea and VomitingNausea and VomitingHair LossHair LossFatigue Fatigue BleedingBleedingPainPainNeutropenic FeverNeutropenic FeverBlood ClotsBlood Clots

See DailyMed package insert.

Arsenic Trioxide (Trisenox®)

  • Arsenic trioxide is an intravenous infusion typically infused over 1 to 2 hours each day it is given
  • Retinoic acid syndrome (or APL differentiation syndrome) may occur anytime during the first month of treatment with arsenic. It may occur in as many as 25% of patients. It is characterized by fever, shortness of breath, weight gain, or heart, liver, or kidney problems. It may be life threatening. It is best prevented with steroids such as prednisone, but also treated with a more potent steroid known as dexamethasone
  • Can cause heart rhythm problems, which may be fatal. Close monitoring is required to prevent problems. An electrocardiogram (ECG) must be performed to make sure arsenic therapy is safe to begin
  • Dosage adjustments may be required for kidney or liver problems
  • May interact with medications known to interfere with heart rhythm. Ask your pharmacist to double check to see if you are taking any of these types of interacting medicines
General Arsenic Trioxide (Trisenox) Side Effects
  • Nausea or vomiting
  • Fatigue
  • Fever or neutropenic fever
  • Headache
  • Diarrhea
  • Abdominal pain
  • Water retention (edema)
  • High blood sugar
  • Shortness of breath
  • Dry skin
  • Trouble sleeping
  • Cough
  • Muscle or bone pain
  • Itching
  • Headache
  • Dizziness
  • Bleeding, which may be severe
  • Heart rhythm problems. Keeping the potassium and magnesium level in the blood within the normal range is recommended to help prevent this problem
  • If pregnant, arsenic trioxide may cause harm to an unborn baby
  • Click on the arsenic trioxide (Trisenox) package insert below for reported side effects and possible drug interactions

Side Effect Videos
Nausea and VomitingNausea and VomitingDiarrheaDiarrheaFatigue Fatigue BleedingBleedingPainPainNeutropenic FeverNeutropenic FeverBlood ClotsBlood Clots

See DailyMed package insert.

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References

1. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-121.

2. Supplement to: Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-121.

3. Montesinos P, Bergua JM, Vellenga E, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood 2009;113:775-783.

Created: January 17, 2016 Updated: October 15, 2017

What is Acute Promyelocytic Leukemia (APL)?

Acute Promyelocytic Leukemia (APL) is a type of acute leukemia that affects a specific type of white blood cell known as promyelocytes, which are found in the bone marrow. APL is a rare condition. The cause of APL is unknown. It can present as low, intermediate, or high-risk disease. The effectiveness of the treatment may depend upon the risk category (low, intermediate, or high) at diagnosis. APL is highly curable when appropriate treatment is not delayed.

NOTE: Treatment Options listed below are not all-inclusive. Other treatments may be available. ChemoExperts provides drug information and does not recommend any one treatment over another. Only your Doctor can choose which therapy is appropriate for you.

Clinical Studies

If you are interested in reading the clinical trials results, please click on references below:

1. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-121.

2. Supplement to: Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-121.

3. Montesinos P, Bergua JM, Vellenga E, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood 2009;113:775-783.

Differentiation Syndrome

Differentiation syndrome may include a combination of the following signs or symptoms: fever, shortness of breath, water in sac surrounding heart or lungs (pericardial or pleural effusion), kidney dysfunction, low blood pressure, and unexplained weight gain greater than 10 pounds. Prednisone is given each day until the end of induction to prevent differentiation syndrome. Despite prednisone therapy, roughly 19% of patients will still experience differentiation syndrome.

What is QTc interval?

The time it takes your heart to make one beat can be measured using an electrocardiogram (ECG, or EKG) and is reported as the QTc interval. Arsenic is generally safe to give when the QTc: interval for men is less than 450 milliseconds per beat, and for women, less than 460 milliseconds per beat. The QTc interval is prolonged if the heart takes too long to make the next beat, it could lead to a dangerous heartbeat known as an arrhythmia. Certain medications, in addition to arsenic, may prolong the QTc interval. The list includes: ondansetron (Zofran®), levofloxacin or ciprofloxacin antibiotics. Make sure your pharmacist checks all new medications to make sure they do not prolong the QTc interval.

Usual ATRA + Arsenic Starting Doses

  • Oral ATRA (Tretinoin): 45 mg/m2/day (in two divided doses, rounded to 10 mg capsule size). Common doses range between 40 mg (four 10 mg capsules) to 50 mg (five 10 mg capsules) PER DOSE, or 80 mg to 100 mg orally PER DAY. ATRA is taken by mouth morning and night every day until hematologic complete remission is achieved or for a maximum of 60 days
  • Arsenic Trioxide 0.15 mg/kg/day I.V. infusion infused over 2 hours once daily, every day, until hematologic complete remission is achieved or for a maximum of 60 days

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

What is fibrinogen?

Fibrinogen is a clotting factor that gets converted to fibrin and plays a role in the final steps of clot formation. Fibrinogen may be supplemented during treatment in the form of cryoprecipitate, a human-derived product, that is transfused by I.V. infusioin to increase fibrinogen levels and decrease the risk of bleeding.

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 low-to-intermediate risk APL?

Low-to-intermediate risk can be determined by a person's white cell count, reported as:  ≤ 10 x 109 per liter.  Ask your doctor about your white blood cell count and risk level.