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Treatment Name: HiDAC (High Dose Ara-C) + Midostaurin (Rydapt®)

HiDAC (High Dose Ara-C) + Midostaurin (Rydapt®) is a Chemotherapy Regimen for Acute Myeloid Leukemia (AML)

How does HiDAC plus midostaurin (Rydapt®) work?
High Dose Ara-C, also known as "HiDAC," is designed to kill the remaining cancer cells after induction chemotherapy is completed.

How does midostaurin (Rydapt®) work?
A mutated FLT3 protein, (pronounced “flit three”), is sometimes found in myeloid white blood cells and can cause these cells to divide more rapidly and survive longer, leading to leukemia. Midostaurin is designed to bind to mutated FLT3 (FLT3 stands for Fms-Like Tyrosine kinase 3) on the surface of myeloid leukemia cells. By blocking the function of the abnormally active FLT3 protein, midostaurin slows the production of new leukemia cells and causes some of the leukemia cells to die. Patients without a known FLT3 mutation may not benefit from midostaurin (Rydapt®).

Goals of HiDAC plus midostaurin (Rydapt®) therapy:
HiDAC plus midostaurin is commonly given with the goal of cure or to help keep the leukemia in remission until a bone marrow transplant can be performed.

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Schedule

  • Cytarabine intravenous infusion (I.V.) given over three hours every 12 hours on Days 1, 3, and 5 (six total doses)
  • Midostaurin 50 mg (two 25 mg capsules) by mouth twice daily with food on Days 8 through 21 of each cycle of consolidation (up to four total cycles)
    • Then after 4 cycles of consolidation with cytarabine, midostaurin may be continued (without cytarabine) twice daily every day for up to one year
    • Midostaurin is packaged and supplied as 28-capsule cartons containing seven separate blister pack cards, each containing four capsules

Estimated total infusion time for HiDAC consolidation treatment:

  • Up to three hours for each dose of cytarabine on Days 1, 3, and 5 (the first two doses of cytarabine are given 12 hours apart, followed by a 24-hour break; this is repeated until all six doses are given)
  • 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

HiDAC usually requires a 5-day stay in a hospital; midostaurin is usually taken at home.

HiDAC plus midostaurin is repeated every 28 to 35 days. This is known as one Cycle. Each cycle may be repeated up to 3 to 4 times, depending upon the response to chemotherapy, or if the plan is to proceed with a bone marrow transplant. Duration of HiDAC plus midostaurin therapy may last up to five months, depending upon response, tolerability, and number of cycles prescribed. Midostaurin may then be continued (without cytarabine) for up to twelve additional 28-day cycles for approximately one year, if tolerated.

Click here for the common HiDAC + midostaurin starting doses.

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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 of HiDAC + midostaurin (Rydapt®) are shown here:

  • Neutropenic fever (83%)
  • Nausea (83%)
  • Mouth sores [mucositis] (66%)
  • Vomiting (61%)
  • Headache (46%)
  • Small pinpoint size bleeds under skin [petechiae] (36%)
  • Muscle or bone pain (33%)
  • Nose bleed [epistaxis] (28%)
  • Infection of infusion catheter (24%)
  • Sinus or upper respiratory infection (20%)
  • High blood sugar (20%)
  • Hemorrhoids (15%)
  • Joint pain (14%)
  • Excessive sweating [hyperhidrosis] (14%)
  • Prolonged clotting time [increased bleeding risk] (13%)
  • Kidney injury (12%)
  • Trouble sleeping (12%)
  • High blood pressure (8%)
  • Dry skin (7%)
  • Skin infection (7%)
  • Fungus infection (7%)
  • Weight gain (7%)
  • Fluid collection around lungs (6%)
  • Blood clots (5%)
  • Tremor (4%)
  • Fluid collection around heart (4%)
  • Swollen or puffy eyes (3%)

Cytarabine does NOT usually cause hair loss.

Currently, it has not been reported whether the side effects listed in clinical trials were experienced during the induction phase of treatment when midostaurin is given with “7+3”, or when midostaurin is given with HiDAC.

Roughly 9% of patients discontinued treatment with midostaurin in the clinical study.

Patients should seek medical attention if they develop a new cough, chest pain or discomfort, or shortness of breath as lung problems could occur while taking midostaurin.

Side effect videos Side Effect Videos
Neutropenic FeverNeutropenic FeverNausea and VomitingNausea and VomitingPainPainBleedingBleedingBlood ClotsBlood ClotsAnemiaAnemiaFatigue Fatigue

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Monitoring

How often is monitoring needed?
Labs (blood tests) may be checked before treatment, at least weekly during the first four weeks, at least every other week during the next eight weeks, then at least monthly therafter while receiving midostaurin, or at the discretion of your doctor. Labs often include: Complete Blood Count (CBC), Comprehensive Metabolic Panel (CMP), serum lipase, plus any others your doctor may order. Midostaurin may cause high serum sodium levels (found on the CMP test above). Talk with your doctor about ways to decrease your sodium level if it is too high.

How often is imaging needed?
Imaging may be checked if there are concerns for infection or blood clot. Imaging may include: X-rays or computerized tomography (CT) scans. An ECG, or “EKG” may be performed if you are taking other medicines that could lead to a change in heart rhythm.

How might blood test results/imaging affect treatment?
Depending upon the results, your doctor may advise to continue HiDAC + midostaurin as planned, reduce the dose of future treatments, delay the next dose until the side effect goes away, or switch to an alternative therapy.

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ChemoExperts Tips

  • Midostaurin may cause nausea and vomiting. An anti-nausea medication such as ondansetron (Zofran®), prochlorperazine (Compazine®), or promethazine (Phenergan®) can be taken 30 to 60 minutes before each dose of midostaurin
  • Patients should seek medical attention if they develop a new cough, chest pain or discomfort, or shortness of breath as lung problems could occur while taking midostaurin
  • Corticosteroid eye drops, such as prednisolone, are often started before the first dose of cytarabine to prevent eye irritation known as conjunctivitis. Eye drops may be continued at home for up to 72 hours after the last dose of cytarabine
  • Short-term difficulty with writing, walking, or talking may occur but is rare and usually reversible. To prevent these problems, several neurological tests are done before each dose of cytarabine to test for early signs of toxicity. Examples of these tests include: follow an object with your eyes, repeat various phrases, sign your name, or walk a straight line
  • If the leukemia appears to be eliminated, a white blood cell stimulating shot known as filgrastim or pegfilgrastim (Neulasta®) is sometimes given to increase the number of good white blood cells to help avoid infection
  • Antibiotics, antifungal agents, and antiviral medications are commonly used to prevent infection. Be sure to tell your doctor if you experience discomfort anywhere as this may be a clue to an infection
  • Electrocardiograms (ECG, or “EKG”) are checked during therapy to check your heart QTc interval as midostaurin can affect this. Many other medications can also affect the QTc interval so check with your doctor or pharmacist if you are taking any of these medications
  • Lemons, limes, and other types of oranges are okay to eat and do not interact with midostaurin. Try to avoid grapefruit and grapefruit juice, pomegranate, star fruit, and seville oranges (found in marmalade) as they may increase the concentration of midostaurin in your blood leading to a greater risk of side effects
  • A pharmacist should ALWAYS review your medication list to ensure that drug interactions are prevented or managed appropriately. For example, voriconazole (Vfend®) or posaconazole (Noxafil®) are antifungal medicines that may interact with midostaurin. A dose reduction of midostaurin may be required if it is taken with certain antifungal medications
  • Clinical trials may exist for AML. 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 HiDAC (High Dose Ara-C) + Midostaurin (Rydapt®), 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 HiDAC (High Dose Ara-C) + Midostaurin (Rydapt®). Depending upon your income, they may be able to help cover the cost of:

  • Cytarabine
  • Midostaurin

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 HiDAC (High Dose Ara-C) + Midostaurin (Rydapt®) 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 HiDAC (High Dose Ara-C) + Midostaurin (Rydapt®)

Individual Drug Label Information

Cytarabine (Ara-C)

  • Cytarabine is most commonly given as an intravenous infusion but may be given subcutaneously
  • FDA Black-Box Warnings for low white blood cells, low platelets, low red blood cells, nausea, vomiting, diarrhea, mouth sores, liver damage, and abdominal pain
  • Dosage adjustments may be required renal or liver function
  • May cause a series of symptoms known as Cytarabine (Ara-C) Syndrome within 6 to 12 hours after administration. Symptoms may include fever, rash, chest pain, muscle aches, bone pain, tiredness, and inflammation and redness of the eye
General Cytarabine (Ara-C) Side Effects
  • Low red blood cells, white blood cells, or platelets
  • Nausea or vomiting
  • Liver dysfunction
  • Click on the cytarabine (Ara-C) package insert below for reported side effects and possible drug interactions

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

See DailyMed package insert.

Midostaurin (Rydapt®)

  • Is an oral 25 mg capsule
  • May cause serious lung injury. Notify your doctor if you experience any new shortness of breath, wheezing, or cough
  • Is usually taken with food, swallowed whole, and should not be opened or crushed
  • If you miss a dose, skip the missed dose and take then next dose as scheduled. DO NOT take two doses to make up for the missed dose
  • Should be stored at 68 - 77°F (room temperature). Do not remove capsules from package until immediately prior to taking your dose
  • Dosage adjustments may be required for low blood counts (red blood cells, white blood cells or platelets) or other serious side effects. Doses are typically not adjusted for low blood counts when being used to treat leukemia
  • May interact with certain antifungal and seizure medications. Ask your doctor or pharmacist to review your medications for any possible interactions
  • May interact with grapefruit and grapefruit juice, pomegranate, star fruit, or seville oranges (in marmalade) causing increased blood levels of midostaurin. This could increase your risk of experiencing side effects. Avoid eating or drinking these foods during treatment 
  • Avoid therapy with St. Johns Wort, carbamazepine, phenytoin, or enzalutamide as they will decrease blood levels of midostaurin. This could decrease the effectiveness
  • May cause fetal harm. Males and females of reproductive potential should use contraception during treatment and for 4 months after the last dose
General side effects from midostaurin (Rydapt®)
  • Neutropenic fever
  • Low red blood cells, white blood cells, or platelets
  • Mouth sores (mucositis)
  • Bruising or bleeding
  • High blood sugar
  • Infection
  • Abdominal pain
  • Constipation or diarrhea
  • Nausea and vomiting
  • Headache
  • Abnormal heart rhythm
  • Muscle and joint pain
  • Excessive sweating
  • Infections 
  • Kidney injury
  • Trouble sleeping
  • Fluid collection around lungs or heart
  • Click on the midostaurin (Rydapt®) package insert below for reported side effects, possible drug interactions, and other midostaurin prescribing information

Side Effect Videos
Nausea and VomitingNausea and VomitingDiarrheaDiarrheaBleedingBleedingConstipationConstipationPainPainAnemiaAnemiaNeutropenic FeverNeutropenic FeverBlood ClotsBlood Clots

See DailyMed package insert.

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References

1) Stone RM, Mandrekar S, Sanford BL, et al. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). Blood. 2015;126:6.

Created: May 3, 2017 Updated: June 26, 2017

What is Acute Myeloid Leukemia (AML)?

A disease of the myeloid cells found in the bone marrow. Myeloid cells are responsible for developing into mature white blood cells, red blood cells, and platelets. In AML, immature myeloid cells know as “blasts” replicate at a very fast rate. Sometimes blasts crowd out the normal cells in the bone marrow so that red blood cells or platelets are unable to develop. Common symptoms of this include fatigue, difficulty exercising, or easy bruising or bleeding.

Most cases of AML are considered “de novo” meaning that the cause is unknown. However, there are a few known risk factors for AML, such as exposure to radiation, various environmental toxins, and certain chemotherapy agents. There is no staging system for AML. Chromosomes (strands of DNA) are often analyzed to determine which mutations in the chromosomes exist. The effectiveness of the treatment may depend upon the specific chromosome mutations that are present.

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.

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.

Common HiDAC + midostaurin starting doses

  • Cytarabine 3,000 mg/m2 intravenous infusion, usually given over three hours every 12 hours on Days 1, 3, and 5 (six doses total)
  • Midostaurin 50 mg (two 25 mg capsules) by mouth twice daily with food on Days 8 through 21 of each cycle of consolidation (up to 4 total cycles)
    • After four cycles of consolidation with cytarabine, midostaurin may be continued (without cytarabine) for up to 12 additional 28-day cycles - approximately one year
    • Midostaurin is packaged and supplied as 28-capsule cartons containing 7 separate blister pack cards, each containing four capsules

Clinical Studies

1) Stone RM, Mandrekar S, Sanford BL, et al. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). Blood. 2015;126:6.

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 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. Midostaurin 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, and could lead to a dangerous heartbeat known as an arrhythmia.

Certain medications, in addition to midostaurin, 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.