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Treatment Name: Tisagenlecleucel (Kymriah®) CAR T-Cells

Tisagenlecleucel (Kymriah®) CAR T-Cells is an Immunotherapy Regimen for Acute Lymphoid Leukemia (ALL)

How does tisagenlecleucel (Kymriah®) work?
Tisagenlecleucel is a specific type of treatment known as Chimeric Antigen Receptor T-cells (CAR-T). Certain “good” white blood cells, known as T-cells, are removed from the patient’s body using a method called leukapheresis.

It is currently indicated for patients up to 25 years of age with B-Cell Acute Lymphoblastic Leukemia (B-cell ALL) that did not respond to one or more treatments, or leukemia that came back after one or more treatments.

T-cells help to fight infection in your body. However, once the T-cells are collected and sent to a laboratory, they are modified or “reprogrammed” to specifically recognize and destroy cancerous leukemia cells (bad white blood cells). The modified T-cells, now referred to as CAR T-cells, are then infused back into the body where they can attack and kill the leukemia cells.

Goals of therapy:
Tisagenlecleucel (Kymriah®) is given to kill leukemia cells and restore normal healthy bone marrow activity. Tisagenlecleucel is given with the goal of achieving disease remission, and possibly a cure. If remission is achieved, some patients may receive a bone marrow transplant with the goal of cure.

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Schedule

Tisagenlecleucel treatment consists of two steps:

  • A course of chemotherapy is given first to decrease the amount of cancerous white blood cells known as B-lymphocytes, or B-cells, in the body. This makes it easier for the T-cells in tisagenlecleucel to survive and multiply in the body after being infused, and kill the remaining cancerous B-cells
  • Two to fourteen days after the chemotherapy is finished, tisagenlecleucel (Kymriah®) is infused

Step 1: Chemotherapy:

  • Fludarabine intravenous (I.V.) infusion over 30 to 60 minutes on Days 1, 2, 3, and 4
  • Cyclophosphamide I.V. infusion over 30 to 60 minutes on Days 1 and 2 only

Step 2: Tisagenlecleucel (Kymriah®) infusion:

  • Pre-medications may include acetaminophen and diphenhydramine, 30 to 60 minutes before the infusion
  • Tisagenlecleucel (Kymriah®) is administered as an I.V. infusion at a rate of 10 – 20 mL per minute and usually takes less than one hour
  • Corticosteroids such as methylprednisolone or dexamethasone are not recommended as they may interfere with the Kymriah infusion

Estimated total infusion time for Tisagenlecleucel (Kymriah®):

  • Up to two hours for Days 1 and 2 of chemotherapy; up to one hour for Days 3 and 4
  • Preparation and infusion time may take up to three hours or more for tisagenlecleucel
  • 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

Chemotherapy with fludarabine and cyclophosphamide may be given in an outpatient infusion center, allowing the person to go home afterwards, or may be given in a hospital. Once tisagenlecleucel is given, patients are typically required to stay in a hospital for 7 to 10 days (or sometimes longer), depending upon how well the side effects are tolerated. Only one treatment in total with tisagenlecleucel is given.

Only certain healthcare facilities are able to administer tisagenlecleucel due to the expertise and resources needed to give this treatment safely as required by the tisagenlecleucel Risk Evaluation and Mitigation Strategy program (Kymriah® REMS program).

Click here for common fludarabine, cyclophosphamide, and tisagenlecleucel (Kymriah®) starting doses.

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Side Effects

In clinical studies, the most commonly reported side effects of tisagenlecleucel are shown here:

  • Cytokine release syndrome (79%)
  • Low blood immunoglobulins [hypogammaglobulinemia](43%)
  • Infection from unknown cause (41%)
  • Fever (40%)
  • Neutropenic fever (37%)
  • Decreased appetite (37%)
  • Headache (37%)
  • Change in mental status (34%)
  • Bleeding (31%)
  • Low blood pressure (31%)
  • Low blood potassium (27%)
  • Fast heart rate (26%)
  • Nausea and vomiting (26%)
  • Diarrhea (26%)
  • Viral infection (26%)
  • Low oxygen levels in the blood (24%)
  • Fatigue (22%)
  • Kidney injury (22%)
  • High blood pressure (19%)
  • Bacterial infection (19%)
  • Cough (19%)
  • Low blood phosphorous (19%)
  • Constipation (18%)
  • Stomach pain (16%)
  • Fluid in the lungs (16%)
  • Increased rate of breathing (16%)
  • Pain in arms or legs (16%)
  • Muscle pain (15%)
  • Fungal infection (13%)
  • Anxiety (13%)
  • Joint pain (12%)
  • Swelling of the face (10%)
  • Swelling in arms and legs (10%)
  • Chills (10%)
  • Back pain (10%)
  • Fluid accumulation in the sac around the lungs (10%)
  • Nasal congestion (10%)
  • Tumor Lysis Syndrome (6%)
  • Seizure (3%)

A condition known as cytokine release syndrome (CRS) may occur during therapy, most often occurring 3 days after receiving tisagenlecleucel, but may be seen as late as 22 days (or longer) after therapy. Monitoring for CRS should continue for at least four weeks after Kymriah® infusion.

Supportive care is often recommended for mild CRS symptoms such as low fevers, fatigue, and decreased appetite if any are present.

  • If you experience moderate CRS symptoms such as high fevers, lower than normal blood pressure, or low blood oxygen, you may need oxygen therapy and medications to increase blood pressure
  • If severe or life threatening CRS symptoms are present, you may need an I.V. medication called tocilizumab (Actemra®) to help reverse the cause of CRS
  • In cases of severe CRS that do not respond to the first dose of tocilizumab, high-dose corticosteroids such as methylprednisolone (Solu-Medrol®) and additional doses of tocilizumab, may need to be given

All patients experience low red blood cells, white blood cells, and platelets that may persist up to four weeks or longer after treatment.

Side effect videos Side Effect Videos
AnemiaAnemiaNeutropenic FeverNeutropenic FeverPainPainBleedingBleedingNausea and VomitingNausea and VomitingDiarrheaDiarrheaFatigue Fatigue ConstipationConstipation

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Monitoring

How often is monitoring needed?
Labs (blood tests) may be checked before treatment, then as often as every day after treatment until stable, then periodically as determined by your doctor. Labs often include: Complete Blood Count (CBC), Comprehensive Metabolic Panel (CMP), blood immunoglobulin levels, PT, aPTT, fibrinogen, phosphorous, uric acid, plus any others your doctor may order. If you are a woman of child-bearing potential, a pregnancy test may be recommended. Hepatitis B, Hepatitis C, and human immunodeficiency virus (HIV) screening is also done before starting treatment. Because Tisagenlecleucel (Kymriah®) is made from a lentivirus, some commercial HIV tests may produce a false positive result AFTER receiving tisagenlecleucel.

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

How might blood test results/imaging affect treatment?
Delay of Kymriah may happen if there is an active uncontrolled infection, worsening of leukemia after chemotherapy (fludarabine + cyclophosphamide), unresolved serious reactions from this chemotherapy (example: lung or heart problems), or active graft versus host disease.

Depending upon the results, you may need additional medications or treatments to resolve any side effects that are present or you may need to be monitored more closely for potential side effects that may happen in the future.

A low white blood cell count, platelet count, or red blood cell count/hemoglobin may persist for more than 56 days after the tisagenlecleucel (Kymriah®) infusion, as reported in the clinical studies.

Intravenous immunoglobulin (IVIG) therapy may be recommended if your immunoglobulin levels remain low and you continue to experience severe infections.

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ChemoExperts Tips

  • Premedications such as diphenhydramine (Benadryl®) and acetaminophen (Tylenol®) are given 30 to 60 minutes before infusion to help avoid infusion-related reactions due to the compounds DiMethyl SulfOxide (DMSO) and Dextran 40, in tisagenlecleucel
  • Neurological toxicities such as headache, confusion, anxiety, agitation, tremor, disorientation, or confusion may occur within eight weeks following tisagenlecleucel (Kymriah) therapy. Rarely, patients may experience difficulty speaking or a seizure. When neurological side efffects do occur, roughly 75% of these adverse effects go away within 12 days. Do NOT operate vehicles or machinery during this time as decreased coordination or loss of consciousness may occur
  • Low white blood cells, red blood cells, and platelets may occur during therapy. White blood cell growth factors such as filgrastim (Neupogen®) or pegfilgrastim (Neulasta®) are typically not given during the first three weeks of therapy, but may be given after the first three weeks if needed. Antibiotics, antifungal agents, and antiviral medications are commonly used to treat and prevent infection while white blood cells are low. Be sure to tell your doctor if you experience discomfort anywhere as this may be a symptom of an infection
  • Corticosteroids such as prednisone, methylprednisolone, and dexamethasone should not be used during therapy with tisagenlecleucel unless there is a life-threatening emergency such as severe cytokine release syndrome
  • This therapy may cause low levels of infection fighting proteins in the blood called immunoglobulins. You may need to receive one or more infusions of I.V. immunoglobulins after therapy to keep these at a safe level and to prevent infections
  • DO NOT receive any live vaccines such as the shingles vaccine without talking to your doctor
  • Live vaccines are not recommended anytime 2 weeks prior to tisagenlecleucel (Kymriah) infusion
  • Patients should know that roughly 1 in 10 attempts to prepare the cells after they are removed from your body do not go as planned and a second attempt at manufacturing the cells may be needed. This may delay the Kymriah infusion. During this waiting period, additional chemotherapy may be necessary to treat the leukemia to prevent it from getting worse
  • A pharmacist should ALWAYS review your medication list to ensure that drug interactions are prevented or managed appropriately
  • Clinical trials may exist for ALL. 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 Tisagenlecleucel (Kymriah®) CAR T-Cells, 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 Tisagenlecleucel (Kymriah®) CAR T-Cells. Depending upon your income, they may be able to help cover the cost of:

  • Tisagenlec­leucel
  • Fludarabine
  • Cyclo­phospha­mide

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 Tisagenlecleucel (Kymriah®) CAR T-Cells 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 Tisagenlecleucel (Kymriah®) CAR T-Cells

Individual Drug Label Information

Tisagenlec­leucel (Kymriah®)

  • Is an intravenous infusion that may be colorless or slightly yellow in color
  • Cytokine release syndrome (CRS) may occur during therapy. In severe cases, additional treatments such as tocilizumab (Actemra®) or methylprednisolone (Solu-Medrol®) may be needed to help reverse the cause of CRS
  • Neurological toxicities may occur. Do NOT operate vehicles or machinery during this time as you may experience decreased coordination or loss of consciousness
  • Premedications such as diphenhydramine (Benadryl®) and acetaminophen (Tylenol®) are given 30 to 60 minutes before tisagenlecleucel to help avoid infusion related reactions
  • Secondary malignancies (a new type of cancer) or recurrence of leukemia may develop after treatment with Tisagenlecleucel. If this happens, the Novartis Pharmaceutical Corporation should be contacted at 1-844 -459-6742-4 (1-844-4KYMRIAH). Note: this phone number has 12 digits) 
  • Tisagenlecleucel has the potential to cause fetal toxicity, although it is not known. It is not currently recommend to receive tisagenlecleucel while pregnant or during breastfeeding. Talk with your doctor first before trying to become pregnant or before breastfeeding before you receive tisagenlecleucel treatment 
General side effects from tisagenlecleucel (Kymriah®)
  • Hypersensitivity reactions
  • Low red blood cells, white blood cells, and platelets
  • Infection
  • Decreased ability to make infection-fighting antibodies (hypogammaglobulinemia)
  • Fever
  • Decreased appetite
  • Headache
  • Low blood pressure
  • Nausea and Vomiting
  • Diarrhea
  • Fatigue
  • Constipation
  • Fluid accumulation in arm, legs, face, or lungs
  • Muscle or joint pain
  • Chills 
  • Bleeding
  • Shortness of breath
  • Kidney injury
  • Fast heart rate (tachycardia)
  • Click on the tisagenlecleucel (Kymriah®) package insert below for reported side effects, possible drug interactions, and other tisagenlecleucel prescribing information

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

See DailyMed package insert.

Fludarabine (Fludara®)

  • Fludarabine is an intravenous infusion
  • Dosage adjustments may be required for decreased kidney function
  • Fludarabine can severely suppress bone marrow function resulting in very low white blood cells, low red blood cells, and low platelets
  • There have been reported cases of production of antibodies against red blood cells or platelets causing them to be destroyed. This can result in severe low red blood cell or platelet counts. Patients on fludarabine should be monitored for a condition called “hemolysis” or destruction of blood cells
  • Rare cases of neurological effects such as confusion, irritability, blindness, seizures, coma, or evendeath have occurred
  • Fludarabine should be avoided during pregnancy and breastfeeding
  • Can cause low white blood cells known as “CD4+ T-cells” leading to an increased risk of developing Pneumocystis Pneumonia. Medications that prevent Pneumocystis Pneumonia, such as Bactrim® (sulfamethoxazole/trimethoprim), may be used
General Fludarabine (Fludara) Side Effects
  • Low white and red blood cell count
  • Weakness and fatigue
  • Low platelet cell count 
  • Fever and infections due to low white blood cell count
  • Nausea and vomiting
  • Diarrhea and intestinal bleeding
  • General body pain
  • Mouth sores - stomatitis
  • Decreased appetite
  • Confusion
  • Nerve pain
  • Lung problems: cough, shortness of breath, bleeding in lungs, lung infections
  • Skin rash
  • Heart problems, heart swelling
  • Click on the fludarabine (Fludara) package insert below for reported side effects and possible drug interactions

Side Effect Videos
DiarrheaDiarrheaFatigue Fatigue BleedingBleedingPainPainAnemiaAnemiaNeutropenic FeverNeutropenic Fever

See DailyMed package insert.

Cyclo­phospha­mide (Cytoxan®)

  • Cyclophosphamide is administered as an intravenous (I.V.) infusion
  • May decrease the ability to become pregnant. Fertility preservation is recommended in couples wishing to become pregnant.
  • A smaller dosage may be required for patients receiving hemodialysis
  • Has been linked to the development of other cancers in a small number of people
General Cyclophosphamide (Cytoxan) Side Effects
  • Low white blood cell count which can increase the risk of infection
  • Nausea or vomiting, which can be acute (first 24 hours) or delayed (Days 2 – 5)
  • Hair loss, which is usually reversible
  • Click on the cyclophosphamide (Cytoxan) package insert below for reported side effects and potential drug Interactions

Side Effect Videos
Nausea and VomitingNausea and VomitingHair LossHair LossNeutropenic FeverNeutropenic Fever

See DailyMed package insert.

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References

1) Tisagenlecleucel (Kymriah®) package insert.

Created: October 20, 2017 Updated: October 20, 2017

What is Acute Lymphoid Leukemia (ALL)?

Acute Lymphoid Leukemia (ALL), also known as acute lymphoblastic leukemia, is a disease of the lymphoid cells found in the bone marrow. Lymphoid cells are responsible for developing into cells of the immune system called B-cells, T-cells, or Natural Killer cells. In ALL, immature lymphoid 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 ALL include fatigue, infection, and bruising or bleeding. ALL is the most common cancer diagnosed in children, but is rare in adults. Most cases of ALL are considered "de novo" meaning that the cause is unknown; however, some cases can be linked to certain genetic syndromes. There is no staging system for ALL. Chromosomes 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 your therapy.

What is Leukapheresis?

Leukapheresis is a procedure where blood is taken out of circulation (out of your vein via an intravenous catherter) and then spun through an apheresis machine. The apheresis machine removes only white blood cells and the remainder of the blood is returned back to the patient. The procedure usually takes 3 to 6 hours to complete and may need to be repeated if not enough cells are collected during the session.

After leukapheresis is complete, it may take 3 to 4 weeks to prepare the cells, or in some cases even longer.

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 the Kymriah® REMS program?

Kymriah® REMS program:

  • Requires that healthcare facilities enroll and comply with the REMS program
  • Facilities must have immediate, on-site access to at least 2 doses of tocilizumab per person to treat CRS if it occurs within 2 hours of the infusion
  • REMS program also requires that healthcare providers are trained in the management of both CRS, and neurological toxicities
  • More information can be found at: www.kymriah-rems.com

Common fludarabine, cyclophosphamide, and tisagenlecleucel (Kymriah®) starting doses

Chemotherapy:

  • Fludarabine 30 mg/m2 intravenous (I.V.) infusion over 30 minutes on Days 1, 2, 3, and 4
  • Cyclophosphamide 500 mg/m2 I.V. infusion over 30 to 60 minutes on Days 1 and 2 only

Tisagenlecleucel Kymriah®:

  • Tisagenlecleucel is administered as an I.V. infusion at a rate of 10 – 20 mL per minute 2 to 14 days after completing fludarabine + cyclophosphamide chemotherapy
  • For patients above 50 kg: 0.1 to 2.5 x 108 CAR-positive viable T cells total (non weight-based)
  • For patients 50 kg or less: 0.2 to 5.0 x 106 CAR-positive viable T cells per kg body weight (weight-based)

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

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 Cytokine Release Syndrome (CRS)?

Cytokine release syndrome (CRS) can occur while receiving therapies that enhance or alter the immune system. When cells of the immune system become active, they release small proteins called cytokines that can result in high fever, difficulty breathing, low blood oxygen levels, shaking or chills, nausea, vomiting, diarrhea, muscle or joint pain, very low blood pressure, lightheadedness or dizziness.

It is important to know that symptoms can change quickly. Patients MUST contact their doctor IMMEDIATELY if any signs or symptoms of CRS are experienced to determine the safest way to treat CRS:

  • If the risk of CRS is high, patients may need to be monitored in the hospital for signs and symptoms of CRS and treated accordingly