Tisagenlecleucel: Drug information

(For additional information see "Tisagenlecleucel: Patient drug information" and see "Tisagenlecleucel: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)

Special Alerts

CAR T Cell Immunotherapies Safety Alert November 2023

The FDA has received reports of T-cell malignancies in patients treated with BCMA-directed or CD19-directed autologous CAR T cell immunotherapies. Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, the FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action.

Further information may be found at https://www.fda.gov/safety/medical-product-safety-information/bcma-directed-or-cd19-directed-autologous-chimeric-antigen-receptor-car-t-cell-immunotherapies-fda.

ALERT: US Boxed Warning

Cytokine release syndrome:

Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving tisagenlecleucel. Do not administer tisagenlecleucel to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.

Neurological toxicities:

Neurological toxicities, which may be severe or life-threatening, can occur following treatment with tisagenlecleucel, including concurrently with CRS. Monitor for neurological events after treatment with tisagenlecleucel. Provide supportive care as needed.

REMS program:

Tisagenlecleucel is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS.

Brand Names: US

Kymriah

Brand Names: Canada

Kymriah

Pharmacologic Category

Antineoplastic Agent, Anti-CD19;
Antineoplastic Agent, CAR-T Immunotherapy;
CAR-T Cell Immunotherapy;
Cellular Immunotherapy, Autologous;
Chimeric Antigen Receptor T-Cell Immunotherapy

Dosing: Adult

Note: For autologous use only; confirm patient identity on each bag prior to infusion. A single dose may be contained in 1 to 3 patient-specific infusion bags; verify the number of bags received for the dose with the certificate of conformance/analysis (cells from all bags must be infused to complete a single dose). The actual number of CAR-positive T cells in tisagenlecleucel are provided in the certificate of analysis. Begin infection prophylaxis (according to local recommendations) prior to initiating tisagenlecleucel. Do not administer tisagenlecleucel to patients with active infection or inflammatory disorders. Delay tisagenlecleucel infusion for unresolved serious adverse reactions from chemotherapy (eg, pulmonary/cardiac reactions or hypotension), or active uncontrolled infection, active graft versus host disease (GVHD), or worsening leukemia burden following lymphodepleting chemotherapy. Ensure that tocilizumab is available (a minimum of 2 doses) on site prior to tisagenlecleucel infusion. Myeloid growth factors, particularly GM-CSF (sargramostim), are not recommended during the first 3 weeks after tisagenlecleucel infusion.

Premedications: Premedicate with acetaminophen and diphenhydramine (or another H₁-antihistamine) ~30 to 60 minutes prior to tisagenlecleucel infusion. Avoid prophylactic use of corticosteroids (may interfere with tisagenlecleucel activity).

Acute lymphoblastic leukemia, relapsed/refractory

Acute lymphoblastic leukemia, relapsed/refractory: Note: A treatment course consists of lymphodepleting chemotherapy (with fludarabine and cyclophosphamide) followed by tisagenlecleucel 2 to 14 days following completion of the fludarabine/cyclophosphamide regimen. Dosing is based on weight reported at the time of leukapheresis.

<25 years and ≤50 kg: IV: 0.2 to 5 × 10⁶ CAR-positive viable T cells per kg body weight.

<25 years and >50 kg: IV: 0.1 to 2.5 × 10⁸ CAR-positive viable T cells.

Diffuse large B-cell lymphoma, relapsed or refractory

Diffuse large B-cell lymphoma, relapsed or refractory: IV: 0.6 to 6 × 10⁸ CAR-positive viable T cells. A treatment course consists of lymphodepleting chemotherapy (with fludarabine and cyclophosphamide or with bendamustine for cyclophosphamide intolerance or resistance to a previous cyclophosphamide-containing regimen) followed by tisagenlecleucel 2 to 11 days following completion of the lymphodepleting regimen; lymphodepleting chemotherapy may be omitted if the patient is experiencing significant cytopenia (eg, if the WBC ≤1,000/mm³) within 1 week prior to tisagenlecleucel infusion.

Follicular lymphoma, relapsed or refractory

Follicular lymphoma, relapsed or refractory: IV: 0.6 to 6 × 10⁸ CAR-positive viable T cells. A treatment course consists of lymphodepleting chemotherapy (with fludarabine and cyclophosphamide or with bendamustine for cyclophosphamide intolerance or resistance to a previous cyclophosphamide-containing regimen) followed by tisagenlecleucel 2 to 6 days following completion of the lymphodepleting regimen; lymphodepleting chemotherapy may be omitted if the patient is experiencing significant cytopenia (eg, if the WBC ≤1,000/mm³) within 1 week prior to tisagenlecleucel infusion.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Adjustment for Toxicity: Adult

Cytokine release syndrome: Note: Evaluate patients immediately at the first sign of cytokine release syndrome (CRS). Identify patients based on clinical presentation. Evaluate and treat other causes of fever, hypoxia, and hypotension. If cytokine release syndrome is suspected, manage according to table; alternative management may be used based on appropriate institutional or academic guidelines. Myeloid growth factors, particularly GM-CSF (sargramostim), are not recommended during the first 3 weeks after tisagenlecleucel infusion or until CRS has resolved.

**Tisagenlecleucel-** **Related CRS Grading and Management**
Cytokine release syndrome grade	Symptomatic treatment	Tocilizumab^a	Corticosteroids
^aAlso see Tocilizumab monograph. ^b Alternate therapy may include (but is not limited to) anakinra, siltuximab, ruxolitinib, cyclophosphamide, IV immune globulin, and antithymocyte globulin. ^cRefer to table below for management of neurologic toxicity.
Grade 1: Mild symptoms requiring symptomatic treatment only (eg, low grade fever, fatigue, anorexia)	Exclude other causes (eg, infection) and treat specific symptoms (eg, with antipyretics, antiemetics, analgesics)	In patients with persistent (>3 days) or refractory fever, consider managing as grade 2 CRS.	n/a
Grade 2: Symptoms require and respond to moderate intervention: oxygen requirement <40% or hypotension responsive to fluids or low dose of one vasopressor or grade 2 organ toxicity^c	Antipyretics, oxygen, IV fluids and/or low dose vasopressors as needed.	Administer tocilizumab 8 mg/kg (maximum dose: 800 mg) IV over 1 hour; if no improvement after the first dose, repeat tocilizumab every 8 hours; (maximum: 3 doses/24 hours; maximum total of 4 doses).	If no improvement within 24 hours of tocilizumab, administer methylprednisolone 2 mg/kg/day IV (or equivalent) until vasopressor and oxygen no longer needed, then taper. If no improvement, manage as appropriate grade below.
Grade 3: Symptoms require and respond to aggressive intervention: oxygen requirement ≥40% or hypotension requiring high dose or multiple vasopressors or grade 3 organ toxicity^c or grade 4 transaminitis	High-flow oxygen, IV fluids, and high-dose or multiple vasopressors Treat other organ toxicities as per institutional guidelines.	Administer tocilizumab as per grade 2. If no improvement, consider alternate therapy^b.	Administer corticosteroids as per grade 2. If no improvement, manage as grade 4.
Grade 4: Life-threatening symptoms: Requiring ventilator support or grade 4 organ toxicity^c (excluding transaminitis)	Mechanical ventilation, IV fluids, and high dose vasopressor(s) Treat other organ toxicities as per institutional guidelines.	Administer tocilizumab as per grade 2. If no improvement, consider alternate therapy^b.	Administer methylprednisolone 1 g IV 1 to 2 times per day for 3 days. If no improvement, consider methylprednisolone 1 g IV 2 to 3 times per day or alternative therapy^b. Continue corticosteroids until improvement to grade 1 and then taper as clinically appropriate.

Neurotoxicity: Note: Monitor for signs/symptoms of neurologic toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS) and other neurotoxicities. Identify patients based on clinical presentation. Evaluate and treat other causes of neurological signs/symptoms. Consider nonsedating seizure prophylaxis (eg, levetiracetam) in patients with increased seizure risk (eg, CNS disease, concerning EEG findings, neoplastic brain lesions, seizure history). If neurological toxicity is suspected, manage according to neurotoxicity table; alternative management may be used based on appropriate institutional, academic, or consensus guidelines.

**Tisagenlecleucel-Related Neurotoxicity (ICANS) Grading and Management**
ICANS grade	No concurrent CRS	Concurrent CRS
^a ICE (immune effector cell-associated encephalopathy) assessment tool: Orientation (oriented to year, month, city, hospital = 4 points) Naming (ability to name 3 objects, [eg, point to clock, pen, button = 3 points]) Follows commands (eg, “show me 2 fingers” or “close your eyes and stick out your tongue” = 1 point) Writing (ability to write a standard sentence = 1 point) Attention (count backwards from 100 by ten = 1 point) A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, but a patient with an ICE score of 0 may be classified as grade 4 ICANS if unarousable. ^b Alternate therapy may include (but is not limited to) anakinra, siltuximab, ruxolitinib, cyclophosphamide, antithymocyte globulin, or intrathecal hydrocortisone plus methotrexate.
Grade 1: ICE score^a: 7 to 9 with no depressed level of consciousness	Offer supportive care with IV hydration and aspiration precautions.	At any grade CRS, administer tocilizumab per previous table for management of grade 2 CRS. Use caution with repeated tocilizumab doses in patients with ICANS. Consider adding corticosteroid therapy after first tocilizumab dose.
Grade 2: ICE score^a: 3 to 6 and/or mild somnolence awaking to voice	Offer supportive care with IV hydration and aspiration precautions. Consider dexamethasone 10 mg IV every 6 to 12 hours or methylprednisolone 1 mg/kg IV every 12 hours until resolved to ≤ grade 1. If improving, taper corticosteroids.	At any grade CRS, administer tocilizumab per previous table for management of grade 2 CRS. If refractory past the first dose of tocilizumab, administer dexamethasone 10 mg IV every 6 to 12 hours or methylprednisolone equivalent (1 mg/kg IV every 12 hours), until improves to ≤ grade 1, then taper corticosteroids.
Grade 3: ICE score^a: 0 to 2 and/or depressed level of consciousness awakening only to tactile stimulus and/or any clinical seizure focal or generalized that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention and/or focal or local edema on neuroimaging	Administer dexamethasone 10 mg IV every 6 to 12 hours or methylprednisolone equivalent (1 mg/kg IV every 12 hours).	At any grade CRS, administer tocilizumab per previous table for management of grade 2 CRS. Administer dexamethasone 10 mg IV every 6 to 12 hours or methylprednisolone equivalent (1 mg/kg IV every 12 hours). Continue corticosteroids until improves to ≤ grade 1, then taper corticosteroids. If no improvement, manage as grade 4.
Grade 4: ICE score^a: 0 (patient is unarousable and unable to perform ICE) and/or stupor or coma and/or life-threatening prolonged seizure >5 minutes) or repetitive clinical or electrical seizures without return to baseline in between and/or diffuse cerebral edema on neuroimaging, decerebrate or decorticate posturing or papilledema, cranial nerve VI palsy, or Cushing triad.	Consider mechanical ventilation for airway protection. Administer high-dose methylprednisolone 1 g IV 1 to 2 times per day for 3 days. If no improvement, consider methylprednisolone 1 g IV 2 to 3 times per day or alternative therapy^b. Continue corticosteroids until improvement to grade 1 and then taper as clinically appropriate. Treat seizures, status epilepticus, and cerebral edema as per institutional guidelines.	At any grade CRS, administer tocilizumab per previous table for management of grade 2 CRS. Administer methylprednisolone 1 g IV 1 to 2 times per day for 3 days. If no improvement, consider methylprednisolone 1 g IV 2 to 3 times per day or alternative therapy^b. Continue corticosteroids until improvement to grade 1 and then taper as clinically appropriate. Treat seizures, status epilepticus, and cerebral edema as per institutional guidelines.

Other adverse reactions:

Hemophagocytic lymphohistiocytosis/macrophage activation syndrome: Manage per institutional standards.

Hypogammaglobulinemia: Manage with IV immune globulin replacement and with infection precautions and antibiotic and/or antiviral prophylaxis as indicated.

Neutropenic fever: Evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as clinically indicated.

Dosing: Pediatric

(For additional information see "Tisagenlecleucel: Pediatric drug information")

Note: For autologous use only; confirm patient identity prior to prescribing. A single dose may be contained in 1 to 3 patient-specific infusion bags; verify the number of bags received for the dose with the certificate of conformance/analysis (cells from all bags must be infused to complete a single dose). The actual number of chimeric antigen receptor (CAR)–positive T cells in tisagenlecleucel are provided in the certificate of analysis. Begin infection prophylaxis (according to local recommendations) prior to initiating tisagenlecleucel. Do not administer tisagenlecleucel to patients with active infection or inflammatory disorders. Delay tisagenlecleucel infusion for unresolved serious adverse reactions from chemotherapy (eg, pulmonary/cardiac reactions, hypotension), or active uncontrolled infection, active graft versus host disease (GVHD), or worsening leukemia burden following lymphodepleting chemotherapy. Ensure that tocilizumab is available (a minimum of 2 doses) on site prior to tisagenlecleucel infusion. Myeloid growth factors, particularly granulocyte-macrophage colony-stimulating factor (GM-CSF) (sargramostim), are not recommended during the first 3 weeks after tisagenlecleucel infusion.

Acute lymphoblastic leukemia, relapsed/refractory

Acute lymphoblastic leukemia, relapsed/refractory: Tisagenlecleucel is administered 2 to 14 days after completion of a lymphodepleting chemotherapy course of fludarabine and cyclophosphamide. Note: Delay tisagenlecleucel infusion for unresolved serious adverse reactions from chemotherapy (eg, pulmonary/cardiac reactions or hypotension), active uncontrolled infection, active GVHD, or increasing leukemia burden following lymphodepleting chemotherapy.

Children and Adolescents weighing ≤50 kg: Weight-directed dose: IV: 0.2 to 5 x 10 ⁶ CAR-positive viable T cells per kg body weight.

Children and Adolescents weighing >50 kg: Fixed dose: IV: 0.1 to 2.5 x 10 ⁸ CAR-positive viable T cells.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing adjustment for toxicity: Children and Adolescents:

Cytokine release syndrome:

Note: Evaluate patients immediately at the first sign of cytokine release syndrome (CRS). Identify patients based on clinical presentation. Evaluate and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to institutional policy, expert recommendations, and/or manufacturer recommendations (see following table) (EBMT/JACIE/EHA [Hayden 2022]; EBMT/JACIE [Yakoub-Agha 2020], manufacturer's labeling).

**Tisagenlecleucel-** **Related Cytokine Release Syndrome (CRS) Grading and Management^a**
CRS grade	Symptomatic treatment	Tocilizumab^b	Corticosteroids
^aRefer to institutional policy for specific guidance on management of CRS. ^b Also see Tocilizumab monograph. ^c Alternate therapy may include anti-cytokine and anti-T cell therapy such as (but not limited to) anakinra, ruxolitinib, cyclophosphamide, IV immune globulin, and antithymocyte globulin. ^d EBMT/JACIE/EHA [Hayden 2022]; EBMT/JACIE [Yakoub-Agha 2020]; Mahadeo 2019 ^e Refer to table below for management of neurologic toxicity.
Grade 1: Mild symptoms requiring symptomatic treatment only (eg, low grade fever, fatigue, anorexia)	Exclude other causes (eg, infection) and treat specific symptoms (eg, with antipyretics, antiemetics, or analgesics)	In patients with persistent (>3 days) or refractory fever, consider managing as grade 2 CRS.	n/a
Grade 2: Symptoms require and respond to moderate intervention: Oxygen requirement <40%, hypotension responsive to fluids or low dose of one vasopressor, or grade 2 organ toxicity	Antipyretics, oxygen, IV fluids, and/or low dose vasopressors as needed.	Administer tocilizumab; may repeat doses if no improvement.	If no improvement within 24 hours of tocilizumab, administer methylprednisolone 2 mg/kg/day IV or equivalent until vasopressor and oxygen no longer needed, then taper. If continued deterioration, manage as appropriate grade below.
Grade 3: Symptoms require and respond to aggressive intervention: Oxygen requirement ≥40%, hypotension requiring high dose or multiple vasopressors, grade 3 organ toxicity^e, or grade 4 transaminitis	High-flow oxygen, IV fluids, and high-dose or multiple vasopressors Treat other organ toxicities as per institutional guidelines.	Administer tocilizumab as per grade 2. If no improvement, consider alternate therapy^c.	Per the manufacturer, administer corticosteroids as per grade 2; however, EBMT/JACIE/EHA^d suggest doubling of dexamethasone dose. If no improvement, manage as grade 4.
Grade 4: Life-threatening symptoms: Requiring ventilator support or grade 4 organ toxicity^e (excluding transaminitis)	Mechanical ventilation, IV fluids, and high dose vasopressor(s) Treat other organ toxicities as per institutional guidelines.	Administer tocilizumab as per grade 2. If no improvement, consider alternate therapy^c.	Administer high-dose corticosteroids followed by a rapid taper as clinically appropriate^d (eg, in adults, methylprednisolone 1,000 mg IV 1 to 2 times per day for 3 days); if no improvement administer 2 to 3 times daily or administer alternative therapy^c.

Neurotoxicity:

Note: Monitor for signs/symptoms of neurologic toxicities, including immune effector cell–associated neurotoxicity syndrome (ICANS) and other neurotoxicities. Identify patients based on clinical presentation. Evaluate and treat other causes of neurological signs/symptoms. Consider nonsedating seizure prophylaxis (eg, levetiracetam) in patients with increased seizure risk (eg, CNS disease, concerning EEG findings, neoplastic brain lesions, seizure history). If neurological toxicity is suspected, manage according to institutional policy, expert recommendations, or manufacturer recommendations (see following table) (EBMT/JACIE/EHA [Hayden 2022]; EBMT/JACIE [Yakoub-Agha 2020], Lee 2014; manufacturer's labeling)

**Tisagenlecleucel-Related Immune Effector Cell–Associated Neurotoxicity Syndrome (ICANS) Grading and Management**
ICANS grade	No concurrent CRS	Concurrent CRS
^a ICE assessment tool: Orientation (oriented to year, month, city, and hospital = 4 points) Naming (ability to name 3 objects [eg, point to clock, pen, button = 3 points]) Follows commands (eg, "show me 2 fingers," "close your eyes and stick out your tongue" = 1 point) Writing (ability to write a standard sentence = 1 point) Attention (count backwards from 100 by ten = 1 point) A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, but a patient with an ICE score of 0 may be classified as grade 4 ICANS if unarousable. ^b Alternate therapy may include (but is not limited to) anakinra, ruxolitinib, cyclophosphamide, antithymocyte globulin, or intrathecal hydrocortisone plus methotrexate.
Grade 1: ICE score^a: 7 to 9 with no depressed level of consciousness	Offer supportive care with IV hydration and aspiration precautions.	At any grade CRS, administer tocilizumab (see dosing recommendations in previous table for management of grade 2 CRS). Use caution with repeated tocilizumab doses in patients with ICANS. Consider adding corticosteroid therapy after first tocilizumab dose.
Grade 2: ICE score^a: 3 to 6 and/or mild somnolence awaking to voice	Offer supportive care with IV hydration and aspiration precautions. Consider dexamethasone 0.5 mg/kg/dose (maximum dose: 10 mg/dose) IV every 6 to 12 hours or methylprednisolone 1 mg/kg/dose IV every 12 hours until resolved to ≤ grade 1. If improving, taper corticosteroids (EBMT/JACIE/EHA [Hayden 2022]; EBMT/JACIE [Yakoub-Agha 2020]; manufacturer's labeling).	At any grade CRS, administer tocilizumab ± corticosteroid (see dosing recommendations in previous table for management of grade 2 CRS). The corticosteroid is added if refractory to tocilizumab past the first dose.
Grade 3: ICE score^a: 0 to 2 and/or depressed level of consciousness awakening only to tactile stimulus; any clinical seizure, focal or generalized, that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention; and/or focal or local edema on neuroimaging	Administer dexamethasone 0.5 mg/kg/dose (maximum dose: 10 mg/dose) IV every 6 to 12 hours or methylprednisolone equivalent (eg, 1 mg/kg/dose IV every 12 hours) (EBMT/JACIE/EHA [Hayden 2022]; EBMT/JACIE [Yakoub-Agha 2020]; manufacturer's labeling).	At any grade CRS, administer tocilizumab and corticosteroid (see dosing recommendations in previous table for management of grade 2 CRS).
Grade 4: ICE score^a: 0 (patient is unarousable and unable to perform ICE), stupor or coma, life-threatening prolonged seizure >5 minutes or repetitive clinical or electrical seizures without return to baseline in between, diffuse cerebral edema on neuroimaging, decerebrate or decorticate posturing, papilledema, cranial nerve VI palsy, or Cushing triad.	Consider mechanical ventilation for airway protection. Administer high-dose corticosteroids, (eg, in adults, methylprednisolone 1,000 mg IV 1 to 2 times per day for 3 days). If no improvement, consider methylprednisolone 2 to 3 times per day or alternative therapy^b. Continue corticosteroids until improvement to grade 1 and then taper as clinically appropriate. Treat seizures, status epilepticus, and cerebral edema as per institutional guidelines.	At any grade CRS, administer tocilizumab (see dosing recommendations in previous table for management of grade 2 CRS). Administer high-dose corticosteroids as in grade 4 ICANS without concurrent CRS. Treat seizures, status epilepticus, and cerebral edema as per institutional guidelines.

Other adverse reactions:

Hemophagocytic lymphohistiocytosis/macrophage activation syndrome: Manage per institutional standards.

Hypogammaglobulinemia: Manage with IV immune globulin replacement and with infection precautions and antibiotic and/or antiviral prophylaxis as indicated.

Neutropenic fever: Evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as clinically indicated. Myeloid growth factors, particularly GM-CSF (sargramostim), are not recommended during the first 3 weeks after tisagenlecleucel infusion or until CRS has resolved.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Incidences are reported for both relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) in pediatric patients and young adults and relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in adults unless otherwise indicated.

>10%:

Cardiovascular: Edema (including facial edema, fluid retention, and peripheral edema: 23% to 27%), hypertension (ALL: 19%; DLBCL: 4%), hypotension (including orthostatic hypotension: 25% to 29%), tachycardia (13% to 24%)

Dermatologic: Skin rash (11% to 18%)

Endocrine & metabolic: Hyperglycemia (ALL: grades 3/4: 13%), hypocalcemia (ALL: 20%; DLBCL: 5%), hypokalemia (grades 3/4: 13% to 28%), hypophosphatemia (grades 3/4: 20% to 24%), weight loss (ALL: 3%; DLBCL: 12%)

Gastrointestinal: Abdominal pain (10% to 18%), constipation (17% to 18%), decreased appetite (14% to 38%), diarrhea (29% to 31%; grades ≥3: 1%), nausea (27% to 29% grades ≥3: 1% to 3%), vomiting (ALL: 32%; grades ≥3: 1%; DLBCL: 9%)

Hematologic & oncologic: Anemia (ALL: 100%; DLBCL: grades 3/4: 59%), decreased serum fibrinogen (ALL: grades 3/4: 11%), febrile neutropenia (grades ≥3: 17% to 34%), hemorrhage (including anal hemorrhage, catheter site hemorrhage, cerebral hemorrhage, conjunctival hemorrhage, disseminated intravascular coagulation, gastrointestinal hemorrhage, hemarthrosis, hematuria, hemorrhagic cystitis, retinal hemorrhage, vaginal hemorrhage: 22% to 32%; grades ≥3: 8% to 10%), hypogammaglobulinemia (ALL: 53%; grades ≥3: 13%; DLBCL: 17%; grades ≥3: 6%), leukopenia (DLBCL: grades 3/4: 78%), lymphocytopenia (DLBCL: grades 3/4: 95%), neutropenia (ALL: 100%; DLBCL: grades 3/4: 82%), thrombocytopenia (ALL: 100%; DLBCL: grades 3/4: 56%)

Hepatic: Hyperbilirubinemia (ALL: grades 3/4: 19%), increased serum alanine aminotransferase (ALL: grades 3/4: 22%), increased serum aspartate aminotransferase (ALL: grades 3/4: 29%)

Hypersensitivity: Cytokine release syndrome (74% to 77%)

Infection: Bacterial infection (17% to 29%), fungal infection (11% to 15%), infection (48% to 57%), viral infection (ALL: 37%; DLBCL: 11%)

Nervous system: Anxiety (10% to 17%), chills (9% to 12%), delirium (ALL: 19%; DLBCL: 5%), dizziness (5% to 12%), encephalopathy (16% to 30%), fatigue (23% to 27%), headache (21% to 35%), pain (14% to 25%), peripheral neuropathy (4% to 12%), sleep disorder (10% to 11%)

Neuromuscular & skeletal: Arthralgia (14%), musculoskeletal pain (13% to 32%)

Renal: Acute kidney injury (including anuria, azotemia, renal tubular necrosis, increased serum creatinine: 17% to 22%)

Respiratory: Cough (17% to 27%), dyspnea (19% to 21%), hypoxia (ALL: 25%; DLBCL: 8%), nasal congestion (4% to 11%), pulmonary edema (ALL: 15%; DLBCL: 3%)

Miscellaneous: Fever (35% to 42%)

1% to 10%:

Cardiovascular: Capillary leak syndrome (1% to 3%), cardiac arrhythmia (including atrial fibrillation, supraventricular tachycardia, and ventricular premature contractions: 4% to 10%), flushing (ALL: 1%), heart failure (ALL: 9%; DLBCL: 1%), thrombosis (3% to 6%)

Dermatologic: Erythema of skin (2% to 6%), hyperhidrosis (4%), night sweats (ALL: 1%; DLBCL: 5%), pruritus (4% to 9%)

Endocrine & metabolic: Hypercalcemia (4%), increased serum iron (serum ferritin increased: 4% to 10%)

Gastrointestinal: Abdominal distention (4%), acute abdominal condition (abdominal compartment syndrome; ALL: 1%), stomatitis (4% to 6%), xerostomia (ALL: 1%; DLBCL: 5%)

Hematologic & oncologic: Decreased white blood cell count (B-cell aplasia: DLBCL: 1%), disorder of hemostatic components of blood (ALL: 6%), hemophagocytic lymphohistiocytosis (2% to 6%), increased fibrin degradation products (increased fibrin D dimer: 3% to 4%), pancytopenia (3% to 4%), prolonged prothrombin time (ALL: 4%), tumor lysis syndrome (2% to 6%)

Hepatic: Ascites (3% to 4%)

Hypersensitivity: Infusion-related reaction (3% to 6%)

Immunologic: Antibody development (DLBCL: 9%), graft versus host disease (ALL: 3%)

Nervous system: Asthenia (4% to 7%), ataxia (DLBCL: 2%), cerebral infarction (DLBCL: 1%), motor dysfunction (ALL: 1%; DLBCL: 6%), neuralgia (1% to 3%), seizure (3% to 6%), speech disturbance (including aphasia: 3% to 4%), tremor (6% to 8%)

Neuromuscular & skeletal: Myalgia (5%)

Ophthalmic: Visual impairment (3% to 6%)

Respiratory: Acute respiratory distress syndrome (ALL: 4%), flu-like symptoms (3% to 9%), oropharyngeal pain (8% to 10%), pleural effusion (5% to 10%), pulmonary infiltrates (ALL: 1%), tachypnea (3% to 10%)

Miscellaneous: Multi-organ failure (3%)

Postmarketing:

Hematologic & oncologic: Hematologic malignancy (T-cell) (FDA Safety Communication 2023)

Hypersensitivity: Anaphylaxis

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to tisagenlecleucel or any component of the formulation.

Warnings/Precautions

Concerns related to adverse effects:

• Cytokine release syndrome: Cytokine release syndrome (CRS), including fatal or life-threatening reactions, has occurred with tisagenlecleucel. Grade 3 and higher CRS reactions have occurred. The median time to onset of CRS was 3 to 4 days (range: 1 to 51 days, although onset after 10 days is rare). Half of patients with acute lymphoblastic leukemia (ALL) with CRS received tocilizumab, and some patients required the addition of systemic corticosteroids. Approximately one-fifth of patients with diffuse large B-cell lymphoma (DLBCL) received tocilizumab or corticosteroids. Approximately one-fourth of the patients with follicular lymphoma (FL) received tocilizumab, with 2 patients also receiving a corticosteroid. Some patients required 2 or 3 doses of tocilizumab. One patient with DLBCL received corticosteroids without tocilizumab for CRS management; corticosteroids were used for persistent neurotoxicity following resolution of CRS (also rare). The median time to resolution of CRS was 4 to 8 days (range: 1 to 36 days). Key manifestations of CRS include fever, hypotension, hypoxia, and tachycardia, and may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy. Risk factors for severe CRS in patients with ALL are high pre-infusion tumor burden (>50% blasts in bone marrow), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy (fludarabine and cyclophosphamide), active infections, and/or inflammatory processes.

• Cytopenias: Prolonged cytopenias may occur several weeks after lymphodepleting chemotherapy and tisagenlecleucel infusion. Unresolved (by day 28 following tisagenlecleucel treatment) grade 3 or higher cytopenias included neutropenia and thrombocytopenia; some patients still experienced grade 3 or higher neutropenia or thrombocytopenia at 56 days post infusion. Prolonged neutropenia is associated with an increased risk of infection.

• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome: Hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS), which can be life-threatening or fatal, has occurred with tisagenlecleucel. HLH cases generally occurred during ongoing cytokine release syndrome.

• Hepatitis B virus reactivation: Hepatitis B virus (HBV) reactivation (sometimes resulting in fulminant hepatitis, hepatic failure and death) can occur in patients treated with medications directed against B cells.

• Hypersensitivity: Allergic reactions may occur with tisagenlecleucel infusion. Serious hypersensitivity reactions, including anaphylaxis, may occur due to the dimethyl sulfoxide (DMSO) or dextran 40 components in tisagenlecleucel.

• Hypogammaglobulinemia: Hypogammaglobulinemia and IgG agammaglobulinemia related to B-cell aplasia may occur in patients with a complete remission after tisagenlecleucel infusion.

• Infection: Infections (including life-threatening or fatal infections) occurred in patients after tisagenlecleucel infusion, including grades 3 and higher infections. Neutropenic fever (grade 3 or higher) has been observed after tisagenlecleucel infusion and may occur concurrently with CRS. There is no experience manufacturing tisagenlecleucel for patients with a positive HIV test or with active HBV or hepatitis C virus.

• Neurological toxicities: Neurological toxicities, which may be severe or life-threatening, can occur following treatment with tisagenlecleucel and may occur concurrently with CRS. Most neurological toxicities occurred within 8 weeks following tisagenlecleucel infusion. The median time to the first event was 5 to 8 days (range: 1 to 368 days) from infusion and the median duration was 7 days (ALL), 5 days (FL), and 17 days (DLBCL). Neurotoxicity generally resolved within 3 weeks of onset, although encephalopathy lasting up to 70 days was reported. Grade 3 and higher neurologic toxicities have been observed. The most common neurological toxicities were headache, encephalopathy, delirium, anxiety, sleep disorders, dizziness, tremor, and peripheral neuropathy; other manifestations included seizures and aphasia. The onset of neurologic toxicity may be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Due to the potential for neurologic events, including altered mental status or seizures, patients receiving tisagenlecleucel are at risk for altered or decreased consciousness or coordination in the 8 weeks following administration; during this initial period, advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery for at least 8 weeks following tisagenlecleucel infusion.

• Secondary malignancy: Patients treated with tisagenlecleucel may develop secondary malignancies or cancer recurrence. If a secondary malignancy occurs, contact the manufacturer (1-844-4KYMRIAH) to obtain patient sampling instructions for testing.

Concurrent drug therapy issues:

• Immunizations: Vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel treatment, and until immune recovery following treatment. The safety of immunization with live vaccines during or following tisagenlecleucel treatment has not been studied.

Other warnings/precautions:

• Appropriate use: For autologous use only. Confirm availability of tisagenlecleucel prior to starting lymphodepleting regimen. Confirm patient identity and match to patient identifiers on the infusion bag(s) prior to infusion. The manufacturer recommends administering at a Risk Evaluation and Mitigation Strategy (REMS)–certified facility and with appropriate monitoring capabilities. Patients should remain within proximity of the certified facility for at least 4 weeks following infusion.

• REMS program: Tisagenlecleucel is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS. Information is available at http://www.kymriah-rems.com or 1-844-4KYMRIAH.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Intravenous:

Kymriah: (1 ea) [contains albumin human, dextran 40, dimethyl sulfoxide]

Generic Equivalent Available: US

Pricing: US

Suspension (Kymriah Intravenous)

250000000CELLS (per each): $0.00

600000000CELLS (per each): $0.00

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Intravenous:

Kymriah: 600000000 CELLS (1 ea) [contains albumin human, dextran 40, dimethyl sulfoxide]

Administration: Adult

IV: For IV use only. Coordinate the timing of administration with thawing (once thawed and at room temperature, infuse within 30 minutes); infusion start time may need to be adjusted based on thawing.

Prime the tubing with NS prior to infusion. Infuse at a rate of 10 to 20 mL/minute, adjusting as appropriate for smaller volumes. Infuse entire contents of bag (infusion bag volume ranges from 10 to 50 mL), then (while maintaining a closed tubing system) rinse infusion bag with 10 to 30 mL NS to assure as many cells as possible are infused. Do not use a lymphocyte depleting filter. If more than 1 bag is being administered, thaw 1 bag at a time, wait to thaw/infuse the next bag until it is determined that the previous bag is safely administered. Cells from all bags must be infused to complete a single dose.

Prior to administration: Ensure tocilizumab and emergency equipment are available prior to infusion and during recovery period. Premedicate with acetaminophen and diphenhydramine (or other histamine-1 antihistamine) ~30 to 60 minutes prior to tisagenlecleucel infusion. Avoid prophylactic use of corticosteroids (may interfere with tisagenlecleucel activity). Confirm patient identity and match to patient identifiers (preceded by the letters "DIN" or "Aph ID") on the infusion bag. Inspect the contents of the thawed infusion bag(s) for visible cell clumps; if visible cell clumps remain, gently mix the contents of the bag (small clumps of cellular material should disperse with gentle manual mixing). Do not infuse if clumps are not dispersed, if the infusion bag is damaged or leaking, or if it otherwise appears to be compromised. Apply universal precautions for product handling.

Administration: Pediatric

For autologous use only; confirm patient identity prior to infusion.

For IV use only. Coordinate the timing of administration with thawing (may only be stored for up to 30 minutes at room temperature); infusion start time may need to be adjusted based on thawing.

Prior to administration: Confirm patient identity and match to patient identifiers on the infusion bag (preceded by the letters "DIN" or "Aph ID"; see manufacturer's labeling). Ensure tocilizumab (at least 2 doses) and emergency equipment are available prior to infusion and during recovery period. Premedicate with acetaminophen and diphenhydramine (or other H₁-antihistamine) ~30 to 60 minutes prior to tisagenlecleucel infusion. Do not use corticosteroids at any time (may interfere with tisagenlecleucel activity) except in the case of life-threatening emergency.

Inspect the contents of the thawed infusion bag for visible cell clumps; if visible cell clumps remain, gently mix the contents of the bag (small clumps of cellular material should disperse with gentle manual mixing). Do not infuse if clumps are not dispersed, the infusion bag is damaged or leaking, or it otherwise appears to be compromised. Apply universal precautions for product handling.

Administration: Prime the tubing with NS prior to infusion. Infuse at a rate of 10 to 20 mL/minute, adjusting as appropriate for smaller children and smaller infusion volumes. Infuse entire contents of bag (infusion bag volume ranges from 10 to 50 mL), then (while maintaining a closed tubing system) rinse infusion bag with 10 to 30 mL NS to assure as many cells as possible are infused. Do not use a lymphocyte depleting filter.

Use: Labeled Indications

Acute lymphoblastic leukemia, relapsed or refractory: Treatment of B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse in patients up to 25 years of age.

Diffuse large B-cell lymphoma, relapsed or refractory: Treatment of relapsed or refractory large B-cell lymphoma in adults (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.

Limitation of use: Not indicated for treatment of primary CNS lymphoma.

Follicular lymphoma, relapsed or refractory: Treatment of relapsed or refractory (r/r) follicular lymphoma in adults (after 2 or more lines of systemic therapy).

Medication Safety Issues

Sound-alike/look-alike issues:

Kymriah may be confused with Kynamro.

Tisagenlecleucel may be confused with axicabtagene ciloleucel, betibeglogene autotemcel, brexucabtagene autoleucel, ciltacabtagene autoleucel, elivaldogene autotemcel, idecabtagene vicleucel, lisocabtagene maraleucel, sipuleucel-T.

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination

Antithymocyte Globulin (Equine): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of immunosuppressive therapy is reduced. Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy

Baricitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination

BCG Products: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination

Brincidofovir: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy

Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination

Chikungunya Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy

Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination

Cladribine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing these oncologic agents several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification

Corticosteroids (Systemic): May enhance the adverse/toxic effect of CAR-T Cell Immunotherapy. Specifically, the severity and duration of neurologic toxicities may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of CAR-T Cell Immunotherapy. Management: Avoid use of corticosteroids as premedication before treatment with CAR-T cell immunotherapy agents. Corticosteroids are indicated and may be required for treatment of toxicities such as cytokine release syndrome or neurologic toxicity. Risk D: Consider therapy modification

COVID-19 Vaccine (Adenovirus Vector): CAR-T Cell Immunotherapy may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: The CDC recommends that CAR-T-cell recipients who received COVID-19 vaccine prior to or during treatment with CAR-T-cell therapy should be revaccinated with a primary mRNA vaccine series at least 3 months (12 weeks) after CAR-T-cell therapy. Risk D: Consider therapy modification

COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy

COVID-19 Vaccine (mRNA): CAR-T Cell Immunotherapy may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: The CDC recommends that CAR-T-cell recipients who received COVID-19 vaccine prior to or during treatment with CAR-T-cell therapy should be revaccinated with a primary vaccine series at least 3 months (12 weeks) after CAR-T-cell therapy. Risk D: Consider therapy modification

COVID-19 Vaccine (Subunit): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy

COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification

Dengue Tetravalent Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination

Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification

Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination

Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination

Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination

Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination

Granulocyte Colony-Stimulating Factors: May enhance the adverse/toxic effect of Tisagenlecleucel. Risk X: Avoid combination

Inebilizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy

Influenza Virus Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification

Leflunomide: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification

Mumps- Rubella- or Varicella-Containing Live Vaccines: May enhance the adverse/toxic effect of Immunosuppressants (Miscellaneous Oncologic Agents). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination

Nadofaragene Firadenovec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination

Natalizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination

Ocrelizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy

Ofatumumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy

Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy

Pidotimod: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy

Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination

Pneumococcal Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy

Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination

Polymethylmethacrylate: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Rabies Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification

Ritlecitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination

Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification

Ruxolitinib (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination

Sipuleucel-T: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification

Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor therapy

Tacrolimus (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination

Talimogene Laherparepvec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination

Tertomotide: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination

Tofacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination

Typhoid Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination

Ublituximab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy

Upadacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination

Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 3 after therapy is complete. Risk D: Consider therapy modification

Vaccines (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination

Yellow Fever Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination

Reproductive Considerations

Evaluate pregnancy status prior to use in patients who could become pregnant. The duration of contraception needed following tisagenlecleucel administration is not known.

Pregnancy Considerations

Based on the mechanism of action, if placental transfer were to occur, fetal toxicity, including B-cell lymphocytopenia, may occur. Pregnant patients who have received tisagenlecleucel may have hypogammaglobulinemia; assess immunoglobulin levels in newborns of mothers treated with tisagenlecleucel.

Data collection to monitor pregnancy and infant outcomes following exposure to tisagenlecleucel is ongoing. Pregnancies that may occur during treatment should be reported to Novartis Pharmaceuticals Corporation (888-669-6682).

Breastfeeding Considerations

It is not known if tisagenlecleucel is present in breast milk. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Monitoring Parameters

Screen for HBV, HCV, and HIV (prior to collection of cells for manufacturing). Monitor immunoglobulin levels (after treatment). Evaluate pregnancy status (prior to therapy in sexually active patients who could become pregnant).

Monitor for signs/symptoms of cytokine release syndrome (CRS) and neurotoxicity 2 to 3 times during the first week following infusion; monitor for signs/symptoms of CRS for at least 4 weeks after treatment (evaluate immediately at the first sign of CRS or neurotoxicity). Evaluate for evidence of hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) in patients with progressive CRS symptoms or refractory CRS despite treatment. Monitor for hypersensitivity reactions during infusion; monitor for signs/symptoms of infection. Monitor (life-long) for secondary malignancies.

The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]). Obtain baseline ECG, natriuretic peptides, and troponins; a baseline echocardiography is recommended in patients with preexisting cardiovascular disease; consider baseline echocardiography in all patients; for patients who develop ≥ grade 2 cytokine release syndrome, assess natriuretic peptides and troponins, and obtain echocardiography (ESC [Lyon 2022]). Refer to a cardiologist when clinically indicated.

Mechanism of Action

Tisagenlecleucel is a CD19-directed genetically modified autologous T cell immunotherapy (containing human cells modified with a lentivirus) in which a patient's T cells are reprogrammed with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. The CAR is comprised of a murine single-chain antibody fragment which recognizes CD19 and is fused to intracellular signaling domains from 4-1BB (CD137) and CD3 zeta. CD3 zeta is a critical component for initiating T-cell activation and antitumor activity, while 4-1BB enhances expansion and persistence of tisagenlecleucel. After 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. Tisagenlecleucel is prepared from the patient's peripheral blood cells obtained via leukapheresis.

Pharmacokinetics (Adult Data Unless Noted)

Distribution: High distribution into bone marrow.

Duration: B-cell aplasia: Due to the mechanism of action, a period of B-cell aplasia is expected. In patients with B-cell acute lymphoblastic leukemia, 33% had no detectable B cells at baseline (prior to infusion); at month 24, 88% had no detectable B cells. Most patients with diffuse large B-cell lymphoma and follicular lymphoma had B-cell depletion at baseline (prior to infusion); at month 24, no patients (who had an ongoing response) had detectable B cells.

Half-life, elimination: Acute lymphoblastic leukemia (ALL): ~17 days (in responding patients); Diffuse large B-cell lymphoma (DLBCL): ~45 days (in responding patients); Follicular lymphoma: 44 days (in responding patients).

Time to peak: ~10 days (in responding patients)

Note: Tisagenlecleucel exhibits an initial rapid expansion followed by a bi-exponential decline; tisagenlecleucel is present in blood and bone marrow and is measurable beyond 2 years in patients with ALL, up to 18 months (in peripheral blood) and up to 9 months (in marrow) in patients with DLBCL, and up to 18 months (in peripheral blood) and up to 3 months (in marrow) in patients with follicular lymphoma. In patients who received tocilizumab to manage cytokine release syndrome (CRS), the tisagenlecleucel AUC and C_max are 238% and 311% higher, respectively, in patients with DLBCL, 298% and 183% higher, respectively in patients with ALL, and 245% and 312% higher, respectively in patients with follicular lymphoma, compared with patients who did not receive tocilizumab. In patients who received corticosteroids for CRS management, the tisagenlecleucel AUC and C_max are 104% and 179% higher, respectively, in patients with DLBCL and in patients with ALL, the AUC was 280% higher, compared with patients who did not receive corticosteroids.

Brand Names: International

International Brand Names by Country

For country code abbreviations (show table)

(AU) Australia: Kymriah;
(BE) Belgium: Kymriah;
(CZ) Czech Republic: Kymriah;
(DE) Germany: Kymriah;
(ES) Spain: Kymriah;
(FI) Finland: Kymriah;
(FR) France: Kymriah;
(GB) United Kingdom: Kymriah;
(GR) Greece: Kymriah;
(HK) Hong Kong: Kymriah;
(IE) Ireland: Kymriah;
(IT) Italy: Kymriah;
(JP) Japan: Kymriah;
(NL) Netherlands: Kymriah;
(NO) Norway: Kymriah;
(PL) Poland: Kymriah;
(PR) Puerto Rico: Kymriah;
(PT) Portugal: Kymriah;
(SE) Sweden: Kymriah;
(SI) Slovenia: Kymriah;
(TW) Taiwan: Kymriah

Armenian SH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2017;35(8):893-911. doi:10.1200/JCO.2016.70.5400 [PubMed 27918725]
Fitzgerald JC, Weiss SL, Maude SL, et al. Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Crit Care Med. 2017;45(2):e124-e131. [PubMed 27632680]
Hayden PJ, Roddie C, Bader P, et al. Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA). Ann Oncol. 2022;33(3):259-275. doi:10.1016/j.annonc.2021.12.003 [PubMed 34923107]
Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B virus screening and management for patients with cancer prior to therapy: ASCO provisional clinical opinion update. J Clin Oncol. 2020;38(31):3698-3715. doi:10.1200/JCO.20.01757 [PubMed 32716741]
Kymriah (tisagenlecleucel) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; May 2022.
Kymriah (tisagenlecleucel) [product labeling]. Dorval, Quebec, Canada: Novartis Pharmaceuticals Canada Inc; received December 2022.
Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-195. doi:10.1182/blood-2014-05-552729 [PubMed 24876563]
Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385(9967):517-528. [PubMed 25319501]
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Topic 114674 Version 115.0

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Tisagenlecleucel: Drug information