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Treatment Name: 7 + 3 (Cytarabine + Daunorubicin) plus Midostaurin (Rydapt®)

7 + 3 (Cytarabine + Daunorubicin) plus Midostaurin (Rydapt®) is a Chemotherapy Regimen for Acute Myeloid Leukemia (AML)

How does 7+3 plus midostaurin (Rydapt®) work?
Both medications in “7+3” are designed to rapidly kill cancer cells in the blood stream and bone marrow.
“7” – refers to Cytarabine given daily for 7 days
“3” – refers to Daunorubicin given daily for 3 days

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 7+3 plus midostaurin (Rydapt®) therapy:
7+3 + midostaurin is given to eliminate leukemia cells from the body and to decrease symptoms from AML, such as bleeding, bruising, and recurrent infections. 7+3 + midostaurin is commonly given with the goal of cure.

Schedule

  • Daunorubicin intravenous infusion given over 10 to 15 minutes once daily on Days 1, 2, and 3
  • Cytarabine is given as a 24-hour continuous intravenous infusion on Days 1, 2, 3, 4, 5, 6, and 7
  • Usual midostaurin starting dose: 50 mg (two 25 mg capsules) by mouth twice daily approximately 12 hours apart with food on Days 8 through 21 (14 days total)

Typically, cytarabine and daunorubicin are both started on the same day. Daunorubicin ends when the third dose is given on Day 3. Cytarabine is infused continuously for 168 hours (Days 1 – 7)

Estimated total infusion time for 7+3 plus midostaurin:

  • 168 hours (Days 1 – 7)
  • Infusion times are based on clinical studies, but may vary depending on doctor preference or patient tolerability. Pre-medications and intravenous (I.V.) fluids, such as hydration, may add more time

Hospital stay required
7 + 3 plus midostaurin is known as induction chemotherapy and requires a 19 to 28-day stay in a hospital (or sometimes longer), depending upon how well the side effects are tolerated and whether remission is achieved. A bone marrow biopsy is often performed between Day 14 and Day 21 to check to see if the leukemia is gone. If no leukemia is detected, patients usually go home once their white blood cell count returns to the normal range. Again, this may take 3, 4, or even 5 weeks.

Once induction therapy is complete, patients go on to get consolidation chemotherapy with HiDAC (High-Dose Ara-C) or IDAC (Intermediate-Dose Ara-C) along with midostaurin. If the bone marrow biopsy obtained between Day 14 and Day 21 shows leukemia, another induction cycle of chemotherapy is usually recommended. This is then referred to as re-induction. A second course of treatment with 7 + 3 plus midostaurin may be recommended. However, if re-induction chemotherapy is recommended, it may be different than 7+3 plus midostaurin induction therapy depending upon doctor preference and may have different side effects.

Approximately 25% of patients in the 7 plus 3 plus midostaurin clinical study required a second induction regimen

Click here for common 7+3 + midostaurin induction chemotherapy 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 7+3 plus 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%)

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

NOTE: 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 VomitingBleedingBleedingHair LossHair LossPainPainBlood ClotsBlood ClotsAnemiaAnemiaFatigue Fatigue DiarrheaDiarrheaConstipationConstipation

Monitoring

How often is monitoring needed?
Labs (blood tests) may be checked before treatment, then daily or every other day for the first few weeks while in the hospital. Labs often include: Complete Blood Count (CBC), Comprehensive Metabolic Panel (CMP), lactate dehydrogenase (LDH), serum lipase, calcium, magnesium, phosphorous, and uric acid, plus any others your doctor may order.

NOTE: It is recommended that women of child-bearing potential take a pregnancy test within the 7 days before starting midostaurin to verify pregnancy status

How often is imaging needed?
Imaging may be checked if there are concerns for lung problems, infection, a blood clot, or bleeding. Imaging may include: X-rays, computerized tomography (CT) scans, or magnestic resonance imaging (MRI). 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 7+3 plus 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.

ChemoExperts Tips

  • Midostaurin may cause nausea and vomiting. An anti-nausea medication such as ondansetron (Zofran®), prochlorperazine (Compazine®), or promethazine (Phenergan®) should be taken at least 30 minutes before each dose of midostaurin
  • 7 + 3 plus midostaurin induction chemotherapy requires a long stay in the hospital. Try to be as active as possible by taking walks in the hallway or using an exercise bicycle in the room, if available. This will hopefully speed time to recovery
  • 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
  • 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
  • It is recommended that women of child-bearing potential take a pregnancy test within the 7 days before starting midostaurin to verify pregnancy status
  • Electrocardiograms (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, starfruit, 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 7 + 3 (Cytarabine + Daunorubicin) plus 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 7 + 3 (Cytarabine + Daunorubicin) plus Midostaurin (Rydapt®). Depending upon your income, they may be able to help cover the cost of:

  • Cytarabine
  • Daunorubicin
  • 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 7 + 3 (Cytarabine + Daunorubicin) plus 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 7 + 3 (Cytarabine + Daunorubicin) plus 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.

Daunorubicin

  • ​Daunorubicin is administered as an intravenous infusion and is red in color
  • Is may be given as a slow intravenous push over 5 – 10 minutes, or as a longer infusion over several hours
  • Can affect heart function. A heart study (echocardiogram) may be required before receiving the first dose
  • Dosage may be reduced in patients with poor liver function
  • Has been linked to the development of other cancers in a small number of people (1.5% chance at 10 years)
General Daunorubicin Side Effects
  • Increases your risk of bleeding.  It is normal to receive red blood cell & platelet transfusions if receiving daunorubicin
  • May cause nausea, vomiting, diarrhea, and mouth sores (stomatitis)
  • Leakage into skin or surrounding muscle may cause severe irritation (extravasation)
  • May temporarily turn urine orange
  • Causes hair loss, This is usually temporary and reversible
  • May increase the risk of infection due to decrease white blood cell count (neutropenia). It is normal to receive I.V. antibiotics after daunorubicin is infused
  • Click on the daunorubicin package insert below for reported side effects and potential drug Interactions

Side Effect Videos
Nausea and VomitingNausea and VomitingDiarrheaDiarrheaHair LossHair LossFatigue 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: April 28, 2017 Updated: June 21, 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.

What is Induction Chemotherapy?

An intensive cycle of chemotherapy that requires hospitalization. Induction chemotherapy often requires intense monitoring by hospital staff to ensure that infections are treated and blood or platelet transfusions are given when needed. The goal of induction chemotherapy is to achieve a complete remission, meaning no leukemia cells are detectable.

Common 7+3 + midostaurin induction chemotherapy starting doses

  • Daunorubicin 60 mg/m2 intravenous infusion given over 10 to 15 minutes once daily on Days 1, 2, and 3
  • Cytarabine 200 mg/m2 continuous intravenous infusion on Days 1, 2, 3, 4, 5, 6, and 7 (168 hour infusion)
  • Usual midostaurin starting dose: 50 mg (two 25 mg capsules) by mouth twice daily with food on Days 8 through 21

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

Exercise Bicycle

What if a bicycle is not available? Some hospitals allow family members to purchase an exercise bicycle and bring it in fully assembled. Ask your nurse if this may be an option!

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.