Tisagenlecleucel - Uses, Dosage, Side Effects, Interaction

Tisagenlecleucel is a CD19-directed genetically modified autologous T cell immunotherapy or a CAR-T cell therapy for B-cell acute lymphoblastic leukemia. It was granted approval by FDA in August 2017 under the market name Kymriah. Tisagenlecleucel is an immune cellular therapy that involves autologous T cells that are collected from each individual patient and genetically engineered to express a specific protein called a chimeric antigen receptor (CAR) that specifically targets CD19 antigens. Modified T cells are infused back into the patient’s body. These CD19-directed chimeric antigen receptors (CD19 CAR-T cells) direct the T cells to target and kill leukemia cells that express CD19 on the cell surface.

In a multicenter clinical trial involving pediatric and young adult patients with relapsed or refractory B-cell precursor ALL, the overall remission rate within three months of treatment was 83 percent.^[rx]

Mechanism of action

Tisagenlecleucel is a CD19-directed genetically modified autologous T cell immunotherapy that involves genetically modified autologous T cells isolated from each individual patient. The reprogramming of the patient’s T cells uses a lentiviral vector to encode an anti-CD19 chimeric antigen receptor (CAR). The CAR is comprised of a murine single-chain antibody fragment (scFv) specific for CD19, followed by a CD8 hinge and transmembrane region that is fused to the intracellular signaling domains from 4-1BB (CD137) and CD3 zeta.^[rx] These intracellular costimulatory signaling domains increase the expansion, longer-term persistence, and potency of CAR T cells^[rx]; the CD3 zeta component is critical for initiating T-cell activation and antitumor activity, while 4-1BB enhances the expansion and persistence of tisagenlecleucel.^rx] Upon binding to CD19-expressing cells, the CAR transmits a signal to promote T-cell expansion, activation, target cell elimination, and persistence of the tisagenlecleucel cells.^[rx]

Tisagenlecleucel demonstrates efficacy in re-inducing remission in patients with refractory B-cell precursor acute lymphoblastic leukemia. The sole purpose of the therapy is to eliminate CD19-expressing malignant and normal cells with specificity and an increased chance of remission.

Indications

Tisagenlecleucel is indicated for use in individuals aged 25 years and younger with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.
It is also used to treat adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Tisagenlecleucel is also indicated in adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy.^[rx]
For adult patients with relapsed or refractory (r/r) large B-cell lymphoma after 2 or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma (NOTE: This drug not indicated for the treatment of patients with primary central nervous system lymphoma).
Tisagenlecleucel is indicated for the treatment of those under 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse; or adults with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma.^[rx]^[rx]
Refractory Diffuse Large B Cell Lymphoma (DLBCL)
Refractory Follicular Lymphoma
Relapsed Diffuse Large B-cell Lymphoma (DLBCL)
Relapsed Follicular Lymphoma
Refractory B-cell precursor acute lymphoblastic leukemia
Relapsed B cell precursor Acute lymphoblastic leukemia
Tisagenlecleucel is a CAR T cell therapy for relapsed or refractory large B-cell lymphoma and diffuses large B-cell lymphoma.

In May 2022, the indication in the US was updated to include the treatment of adults with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.

Use in Cancer

Tisagenlecleucel is approved to treat:

B-cell acute lymphoblastic leukemia. It is used in children and adults up to 25 years old whose disease is refractory (does not respond to treatment) or has relapsed two or more times.
B-cell non-Hodgkin lymphoma (NHL), including the following types:
- Diffuse large B-cell lymphoma (DLBCL).
- DLBCL in patients who had follicular lymphoma.
- High-grade B-cell lymphoma.
- Follicular lymphoma.¹
It is used in adults whose disease has relapsed or has not gotten better after at least two other types of systemic treatment.

Tisagenlecleucel is only available as part of a special program called Kymriah REMS (Risk Evaluation and Mitigation StrategiesExit Disclaimer).

This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, a confirmatory trial(s) must show that tisagenlecleucel provides a clinical benefit in these patients. Tisagenlecleucel is also being studied in the treatment of other types of cancer.

Contraindications

a bad infection
pregnancy
resolved hepatitis B
reactivation of hepatitis B infection

Dosage

Strength: See Drug Leveling

Acute Lymphoblastic Leukemia

Prior to infusing this drug:

Lymphodepleting chemotherapy: Fludarabine (30 mg/m2 IV daily for 4 days) and cyclophosphamide (500 mg/m2 IV daily for 2 days starting with the first dose of fludarabine); infuse tisagenlecleucel 2 to 14 days after completion of the lymphodepletion chemotherapy.

Tisagenlecleucel:
Up to 25 years:

Body weight 50 kg or less: 0.2 to 5 x 10(6) chimeric antigen receptor (CAR)-positive viable T cells per kg of body weight
Body weight above 50 kg: 0.1 to 2.5 x 10(8) CAR-positive viable T cells
Base the dosage on the patient’s weight at the time of leukapheresis.
Administer this drug via IV infusion within 30 minutes of thawing at 10 to 20 mL per minute (adjusted as appropriate for smaller children and smaller volumes); the infusion bag volume ranges from 10 to 50 mL.
Pre-medicate patients with acetaminophen and diphenhydramine or another H1-antihistamine approximately 30 to 60 minutes prior to infusion of this drug; avoid using corticosteroids at any time except in the case of a life-threatening emergency.
For patients up to 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

Lymphoma

Prior to infusing this drug:

Lymphodepleting chemotherapy: Fludarabine (25 mg/m2 IV daily for 3 days) and cyclophosphamide (250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine)
Alternate lymphodepleting chemotherapy: Bendamustine 90 mg/m2 IV daily for 2 days if a patient experienced a previous Grade 4 hemorrhagic cystitis with cyclophosphamide or demonstrates resistance to a previous cyclophosphamide containing regimen; infuse tisagenlecleucel 2 to 11 days after completion of the lymphodepleting chemotherapy.
Lymphodepleting chemotherapy may be omitted if a patient’s white blood cell (WBC) count is less than or equal to 1 x 10(9)/L within 1 week prior to tisagenlecleucel infusion.
Dose: 0.6 to 6 x 10(8) CAR-positive viable T cells

Pediatric Dose

Acute Lymphoblastic Leukemia

Prior to infusing this drug:
Lymphodepleting chemotherapy: Fludarabine (30 mg/m2 IV daily for 4 days) and cyclophosphamide (500 mg/m2 IV daily for 2 days starting with the first dose of fludarabine); infuse tisagenlecleucel 2 to 14 days after completion of the lymphodepletion chemotherapy.

Up to 25 years:

Body weight 50 kg or less: 0.2 to 5 x 10(6) chimeric antigen receptor (CAR)-positive viable T cells per kg of body weight
Body weight above 50 kg: 0.1 to 2.5 x 10(8) CAR-positive viable T cells
Base the dosage on the patient’s weight at the time of leukapheresis.
Administer this drug via IV infusion within 30 minutes of thawing at 10 to 20 mL per minute (adjusted as appropriate for smaller children and smaller volumes); the infusion bag volume ranges from 10 to 50 mL.
Pre-medicate patients with acetaminophen and diphenhydramine or another H1-antihistamine approximately 30 to 60 minutes prior to infusion of this drug; avoid using corticosteroids at any time except in the case of a life-threatening emergency.
For patients up to 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse

Dose Adjustments

MANAGEMENT OF CYTOKINE RELEASE SYNDROME (CRS): Identify CRS based on clinical presentation; evaluate and treat other causes of fever, hypoxia, and hypotension.
If CRS is Suspected, Treat Based on CRS Severity:

Prodromal Syndrome (low-grade fever, fatigue, anorexia): Observe in person; exclude infection; administer antibiotics per local guidelines if neutropenic; provide symptomatic support.
Overt CRS (one or more of the following: high fever, hypoxia, mild hypotension): Administer antipyretics, oxygen, IV fluids, and/or low-dose vasopressors as needed.

Severe or Life-Threatening CRS (one or more of the following: hemodynamic instability despite IV fluids and vasopressor support; worsening respiratory distress including pulmonary infiltrates, increasing oxygen requirement including high-flow oxygen and/or need for mechanical ventilation; rapid clinical deterioration):

Administer high doses or multiple vasopressors, oxygen, mechanical ventilation, and/or other supportive care as needed.
Administer tocilizumab: 12 mg/kg IV over 1 hour (if the patient weighs less than 30 kg) OR 8 mg/kg IV over 1 hour (maximum dose: 800 mg; if the patient weighs 30 kg or greater).

Resistant CRS (no clinical improvement in 12 to 18 hours, or worsening at any time despite prior management):

Administer multiple vasopressors, oxygen, mechanical ventilation, and/or other supportive care as needed.
Administer methylprednisolone 2 mg/kg as an initial dose, then 2 mg/kg per day until vasopressors and high-flow oxygen are no longer needed, then taper quickly.
If no response to steroids within 24 hours, repeat the administration of tocilizumab at 12 mg/kg IV over 1 hour (if the patient weighs less than 30 kg) OR 8 mg/kg IV over 1 hour (maximum dose: 800 mg; if the patient weighs 30 kg or greater).
If no response to the second dose of tocilizumab within 24 hours, consider a third dose of tocilizumab or pursue alternative measures for CRS treatment.

Administration Advice:

Delay the infusion of this drug if a patient has unresolved serious adverse reactions (e.g., pulmonary reactions, cardiac reactions, hypotension) from preceding chemotherapies, active uncontrolled infection, active graft versus host disease (GVHD), or worsening of leukemia burden following lymphodepleting chemotherapy.
Do not wash, spin down, and/or re-suspend this drug in new media prior to infusion.
Consult the manufacturer’s product information for additional administration instructions.

Side Effects

The Most Common

constipation
stomach pain
back pain
nasal congestion
decreased appetite
weight loss
unusual bleeding or bruising, blood in urine, red or tarry black bowel movements, vomiting blood or material that looks like coffee grounds
fever, chills, or other signs of infection
weakness, feeling tired, or shortness of breath
decreased urination frequency or amount
swelling of the eyes, face, lips, tongue, throat, arms, hands, feet, ankles, or lower legs
difficulty swallowing
rash
hives
itching

More common

Agitation
back pain
bleeding gums
bloody urine
blue lips, fingernails, or skin
blurred vision
chest pain, discomfort, or tightness
chills
confusion as to time, place, or person
cough
coughing that sometimes produces a pink frothy sputum
coughing up blood
decreased urine output
depression
difficult, fast, noisy breathing
dilated neck veins
dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
drowsiness
dry mouth
fast, pounding, or irregular heartbeat or pulse
fever
general feeling of discomfort or illness
hallucinations
headache
hoarseness
holding false beliefs that cannot be changed by fact
hostility
increase in heart rate
increased blood pressure
increased menstrual flow or vaginal bleeding
increased sweating
irritability
loss of appetite
loss of consciousness
lower back or side pain
mood or mental changes
muscle, joint, or bone pain
nausea
nervousness
nosebleeds
painful or difficult urination
pale skin
pounding in the ears
problems with speech or speaking
prolonged bleeding from cuts
rapid shallow breathing
rapid weight gain
red or black, tarry stools
red or dark brown urine
seeing, hearing, or feeling things that are not there
seizures
shakiness and unsteady walk
slow or fast heartbeat
stiff neck
sunken eyes
swelling of the face, arms, fingers, feet, or lower legs
trembling and shaking of hands
trouble breathing
unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
unusual excitement, nervousness, or restlessness
vomiting
weight gain

Rare

Change in the amount of urine
cloudy urine
headache, sudden or severe
stomach pain
tenderness, pain, swelling, warmth, skin discoloration, and prominent superficial veins over the affected area
Anxiety
decreased appetite
diarrhea
difficulty in moving
joint pain
muscle pain or stiffness
pain in the arms or legs
stuffy nose

Drug Interaction

DRUG	INTERACTION
Articaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Articaine.
Benzocaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Benzocaine.
Benzyl alcohol	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Benzyl alcohol.
Bupivacaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Bupivacaine.
Butacaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Butacaine.
Butamben	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Butamben.
Capsaicin	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Capsaicin.
Chloroprocaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Chloroprocaine.
Cinchocaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Cinchocaine.
Cocaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Cocaine.
Darbepoetin alfa	The risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Tisagenlecleucel.
Diphenhydramine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Diphenhydramine.
Dyclonine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Dyclonine.
Erythropoietin	The risk or severity of Thrombosis can be increased when Erythropoietin is combined with Tisagenlecleucel.
Ethyl chloride	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Ethyl chloride.
Etidocaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Etidocaine.
Levobupivacaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Levobupivacaine.
Lidocaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Lidocaine.
Meloxicam	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Meloxicam.
Mepivacaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Mepivacaine.
Methoxy	The risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta is combined with Tisagenlecleucel.
Oxetacaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Oxetacaine.
Oxybuprocaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Oxybuprocaine.
Peginesatide	The risk or severity of Thrombosis can be increased when Peginesatide is combined with Tisagenlecleucel.
Phenol	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Phenol.
Pramocaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Pramocaine.
Prilocaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Prilocaine.
Procaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Procaine.
Proparacaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Proparacaine.
Propoxycaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Propoxycaine.
Ropivacaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Ropivacaine.
Tetracaine	The risk or severity of methemoglobinemia can be increased when Tisagenlecleucel is combined with Tetracaine.

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

There are no available data on KYMRIAH use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with KYMRIAH to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known if KYMRIAH has the potential to be transferred to the fetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia. Therefore, KYMRIAH is not recommended for women who are pregnant, and pregnancy after KYMRIAH administration should be discussed with the treating physician. Report pregnancies to Novartis Pharmaceuticals Corporation at 1-888-669-6682. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically
recognized pregnancies are 2% to 4% and 15% to 20%, respectively.

Lactation

There is no information regarding the presence of KYMRIAH in human milk, the effect on the breastfed infant, or the effects on milk production. A risk to the breastfed infant cannot be excluded. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KYMRIAH and any potential adverse effects on the breastfed infant from KYMRIAH or from the underlying maternal condition.

Why is this medication prescribed?

Tisagenlecleucel injection is used to treat certain acute lymphoblastic leukemia (ALL; also called acute lymphoblastic leukemia and acute lymphatic leukemia; a type of cancer that begins in the white blood cells) in people 25 years of age or younger that has returned or is unresponsive to other treatment(s). It is also used to treat a certain type of non-Hodgkin’s lymphoma (a type of cancer that begins in a type of white blood cells that normally fights infection) and follicular lymphoma (FL; slow-growing cancer that begins in the white blood cells) in adults that has returned or is unresponsive after treatment with at least two other medications. Tisagenlecleucel injection is in a class of medications called autologous cellular immunotherapy, a type of medication prepared using cells from the patient’s own blood. It works by causing the body’s immune system (a group of cells, tissues, and organs that protects the body from attack by bacteria, viruses, cancer cells, and other substances that cause disease) to fight the cancer cells.

How should this medicine be used?

Tisagenlecleucel injection comes as a suspension (liquid) to be injected intravenously (into a vein) by a doctor or nurse in a doctor’s office or infusion center. It is usually given over a period of up to 60 minutes as a one-time dose. Before you receive your tisagenlecleucel dose, your doctor or nurse will administer other chemotherapy medications to prepare your body for tisagenlecleucel.

About 3 to 4 weeks before your dose of tisagenlecleucel injection is to be given, a sample of your white blood cells will be taken at a cell collection center using a procedure called leukapheresis (a process that removes white blood cells from the body). This procedure will take about 3 to 6 hours and may need to be repeated. Because this medication is made from your own cells, it must be given only to you. It is important to be on time and to not miss your scheduled cell collection appointment(s) or to receive your treatment dose. You should plan to stay within 2 hours of the location where you received your tisagenlecleucel treatment for at least 4 weeks after your dose. Your healthcare provider will check to see if your treatment is working and monitor you for any possible side effects. Talk to your doctor about how to prepare for leukapheresis and what to expect during and after the procedure.

Other uses for this medicine

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before receiving tisagenlecleucel injection

tell your doctor and pharmacist if you are allergic to tisagenlecleucel, any other medications, dimethyl sulfoxide (DMSO), dextran 40, or any other ingredients in tisagenlecleucel injection. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: steroids such as dexamethasone, methylprednisolone (Medrol), prednisolone, and prednisone (Rayos). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
tell your doctor if you have ever had reactions from previous chemotherapy treatments such as breathing problems or irregular heartbeat. Also, tell your doctor if you have or have ever had hepatitis B or C (a virus that infects the liver and may cause severe liver damage), human immunodeficiency virus (HIV), lung, kidney, heart, or liver disease.
tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. You will need to have a pregnancy test before you start tisagenlecleucel treatment. If you become pregnant while receiving tisagenlecleucel injection, call your doctor immediately. Tisagenlecleucel injection may cause fetal harm.
you should know that tisagenlecleucel injection may make you drowsy and cause confusion, weakness, dizziness, and seizures. Do not drive a car or operate machinery for at least 8 weeks after your tisagenlecleucel dose.
do not donate blood, organs, tissues, sperm, or cells for transplantation after you receive tisagenlecleucel injection.
check with your doctor to see if you need to receive any vaccinations. Do not have any vaccinations without talking to your doctor for at least 6 weeks before starting chemotherapy, during your tisagenlecleucel treatment, and until your doctor tells you that your immune system has recovered.