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Tisagenlecleucel

Pronunciation

(tis a jen lek LOO sel)

Index Terms

  • Autologous CART-19 TCR:4-1BB cells
  • CD19CAR-CD3zeta-4-1BB-Expressing Autologous T Lymphocytes
  • CTL019

Dosage Forms

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]

Brand Names: U.S.

  • 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

Pharmacology

Tisagenlecleucel is a CD19-directed genetically modified autologous T cell immunotherapy 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.

Distribution

High distribution into bone marrow.

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.

Contraindications

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

Dosing: Adult

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

Acute lymphoblastic leukemia (relapsed or 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. Actual number of CAR-positive T cells in tisagenlecleucel are provided in the certificate of analysis.

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 increasing leukemia burden following lymphodepleting chemotherapy.

Premedicate with acetaminophen and diphenhydramine (or another H1-antihistamine) ~30 to 60 minutes prior to tisagenlecleucel infusion. Do not use corticosteroids at any time (except for life-threatening situations).

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

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

Dosing: Pediatric

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

Acute lymphoblastic leukemia (relapsed or refractory): Note: A treatment course consists of chemotherapy (with fludarabine and cyclophosphamide) followed by tisagenlecleucel 2 to 14 days following completion of the fludarabine/cyclophosphamide regimen. Actual number of CAR-positive T cells in tisagenlecleucel are provided in the certificate of analysis.

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 increasing leukemia burden following lymphodepleting chemotherapy.

Premedicate with acetaminophen and diphenhydramine (or another H1-antihistamine) ~30 to 60 minutes prior to tisagenlecleucel infusion. Do not use corticosteroids at any time (except for life-threatening situations).

Children and Adolescents >50 kg: IV: 0.1 to 2.5 x 108 CAR-positive viable T cells

Children and Adolescents ≤50 kg: IV: 0.2 to 5 x 106 CAR-positive viable T cells per kg body weight

Dosing: Renal Impairment

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

Dosing: Hepatic Impairment

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

Dosing: Adjustment for Toxicity

Cytokine release syndrome (CRS):

Prodromal syndrome (low-grade fever, fatigue, anorexia): Observe in person, exclude infection, administer antibiotics (per local guidelines) if neutropenic, manage symptomatically.

Overt CRS (high fever, hypoxia, and/or mild hypotension): Administer antipyretics, oxygen, IV fluids, and/or low-dose vasopressors as needed.

Severe or life-threatening CRS (hemodynamic instability despite IV fluids and vasopressors, worsening respiratory distress [including pulmonary infiltrates, increasing oxygen requirement including high-flow oxygen and/or need for mechanical ventilation], rapid clinical deterioration): Administer high-dose or multiple vasopressors, oxygen, mechanical ventilation and/or other supportive care as needed. Administer tocilizumab (see tocilizumab monograph).

Resistant CRS (no clinical improvement in 12 to 18 hours or worsening at any time despite proper management): Administer multiple vasopressors, oxygen, mechanical ventilation and/or other supportive care as needed. Administer methylprednisolone 2 mg/kg initially, then 2 mg/kg/day until vasopressors and high-flow oxygen are no longer needed, then taper quickly. If no response to methylprednisolone within 24 hours, repeat tocilizumab dose. If no response to the second tocilizumab dose within 24 hours, consider a third tocilizumab dose or pursue alternative CRS management strategies.

Reconstitution

Inspect patient specific infusion bag for breaks or cracks prior to thawing (if bag is compromised, contact manufacturer). Place infusion bag inside a second sterile bag in case of leaks and to protect ports from contamination. Thaw at 37°C using a water bath or dry thaw method until there is no visible ice in the infusion bag, remove bag from thawing device immediately (may only be stored for up to 30 minutes at room temperature). Do not wash, spin down, and/or re-suspend tisagenlecleucel in new media prior to infusion. 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, if the infusion bag is damaged or leaking, or if it otherwise appears to be compromised (contact manufacturer).

Administration

IV: 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.

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 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.

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. Do not use corticosteroids at any time except in the case of life-threatening emergency. Confirm patient identity and match to patient identifiers on the infusion bag. 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, if the infusion bag is damaged or leaking, or if it otherwise appears to be compromised. Apply universal precautions for product handling.

Storage

Store frozen suspension in the vapor phase of liquid nitrogen (≤-120°C). After thawing, may only be stored for up to 30 minutes at room temperature of 20°C to 25°C.

Drug Interactions

Corticosteroids (Systemic): May diminish the therapeutic effect of Tisagenlecleucel. Management: Avoid use of corticosteroids as premedication or at any time during treatment with tisagenlecleucel, except in the case of life-threatening emergency (such as resistant cytokine release syndrome). Consider therapy modification

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

Sargramostim: May enhance the adverse/toxic effect of Tisagenlecleucel. Avoid combination

Vaccines (Live): Tisagenlecleucel may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of infection may be increased. Tisagenlecleucel may diminish the therapeutic effect of Vaccines (Live). Management: Avoid live virus vaccines for two weeks prior to initiation of lymphodepleting therapy, during tisagenlecleucel infusion, and after treatment until full immune recovery is achieved. Consider therapy modification

Test Interactions

May result in false positive results with some commercial HIV nucleic acid tests.

Adverse Reactions

>10%:

Cardiovascular: Hypotension (31%), tachycardia (26%), hypertension (19%)

Central nervous system: Headache (37%), brain disease (34%), fatigue (22%), delirium (21%), anxiety (13%)

Endocrine & metabolic: Hypokalemia (grades 3/4: 27%), hypophosphatemia (grades 3/4: 19%)

Gastrointestinal: Decreased appetite (37%), diarrhea (26%), nausea (26%), vomiting (26%), constipation (18%), abdominal pain (16%)

Hematologic & oncologic: Anemia (100%), neutropenia (100%; grades 3/4: 40%, within 14 days after day 28; grades 3/4: 17%; within 14 days after day 56), thrombocytopenia (100%; grades 3/4: 27%; within 14 days after day 28; grades 3/4: 12% within 14 days after day 56), hypogammaglobulinemia (43%; grades ≥3: 7%), febrile neutropenia (grades 3/4: 37%), hypofibrinogenemia (grades 3/4: 16%; with cytokine release syndrome), increased INR (13%)

Hepatic: Increased serum AST (grades 3/4: 28%), increased serum ALT (grades 3/4: 21%), increased serum bilirubin (grades 3/4: 21%)

Hypersensitivity: Cytokine release syndrome (79%)

Infection: Infection (41%; unknown pathogen), viral infection (26%), bacterial infection (19%), fungal infection (13%)

Neuromuscular & skeletal: Limb pain (16%), myalgia (15%), arthralgia (12%)

Renal: Acute renal failure (22%)

Respiratory: Hypoxia (24%), cough (19%), pulmonary edema (16%), tachypnea (12%)

Miscellaneous: Fever (40%)

1% to 10%:

Cardiovascular: Facial edema (10%), peripheral edema (10%), cardiac failure (7%), capillary leak syndrome (3%)

Central nervous system: Chills (10%), seizure (3%), intracranial hemorrhage (1%)

Endocrine & metabolic: Fluid retention (10%)

Gastrointestinal: Abdominal distress (1%)

Hematologic & oncologic: Disseminated intravascular coagulation (9%), hemophagocytic syndrome (7%), blood coagulation disorder (6%), prolonged partial thromboplastin time (6%), tumor lysis syndrome (6%)

Immunologic: Graft versus host disease (1%)

Neuromuscular & skeletal: Back pain (10%), tremor (9%)

Renal: Increased serum creatinine (7%)

Respiratory: Nasal congestion (10%), pleural effusion (10%), respiratory distress (6%), respiratory failure (6%), respiratory distress syndrome (4%)

Miscellaneous: Multi-organ failure (3%)

Frequency not defined:

Central nervous system: Agitation, aphasia, confusion, disorientation, impaired consciousness, mutism

ALERT: U.S. 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.

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.

Warnings/Precautions

Concerns related to adverse effects:

• Cytokine release syndrome: [US Boxed Warning]: 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. Grade 3 or 4 CRS reactions have occurred. The median time to onset of CRS was 3 days (range: 1 to 22 days). Half of patients with CRS received tocilizumab; some patients required 2 or 3 doses of tocilizumab, and some patients required addition of corticosteroids (methylprednisolone). The median time to resolution of CRS was 8 days (range: 1 to 36 days). Key manifestations of CRS include high fever, lower than normal blood pressure, difficulty breathing, and may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy. Risk factors for severe CRS 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. Delay tisagenlecleucel infusion after lymphodepleting chemotherapy for unresolved serious adverse reactions from preceding chemotherapies (including pulmonary toxicity, cardiac toxicity, or hypotension), active uncontrolled infection, active graft versus host disease (GVHD), or worsening leukemia burden. Ensure that tocilizumab is available (a minimum of 2 doses) on site prior to tisagenlecleucel infusion. Monitor for signs or symptoms of CRS for at least 4 weeks after treatment. Patients should seek immediate medical attention if signs or symptoms of CRS occur at any time. Evaluate patients immediately at the first sign of CRS; hospitalize and begin supportive care, tocilizumab and/or corticosteroids as indicated.

• Cytopenias: Prolonged cytopenias may occur several weeks after lymphodepleting chemotherapy and tisagenlecleucel infusion. Unresolved (by day 28 following tisagenlecleucel treatment) grade 3 and 4 cytopenias included neutropenia and thrombocytopenia; some patients still experienced grade 3 and 4 neutropenia or thrombocytopenia at 56 days post infusion. Prolonged neutropenia is associated with an increased risk of infection. Myeloid growth factors, particularly GM-CSF, are not recommended during the first 3 weeks after tisagenlecleucel infusion or until CRS has resolved.

• 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. Hepatitis has been reported in patients who are hepatitis B surface antigen (HBsAg) positive, and in patients who are HBsAg-negative but are hepatitis B core antibody (anti-HBc) positive. HBV reactivation has occurred in patients who appear to have resolved hepatitis B infection (HBsAg-negative, anti-HBc-positive and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg-negative and anti-HBc-positive. Reactivation of HBV replication is often followed by hepatitis (increased transaminase levels). Increased bilirubin levels, liver failure, and death can occur in severe cases. Screen for HBV, HCV, and HIV in accordance with clinical guidelines prior to collection of cells for manufacturing.

• 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 may occur in patients with a complete remission (CR) after tisagenlecleucel infusion. Because B-cell aplasia is an on-target effect of tisagenlecleucel, hypogammaglobulinemia may persist as long as tisagenlecleucel persists. Monitor immunoglobulin levels after tisagenlecleucel treatment. Manage hypogammaglobulinemia with infection precautions, antibiotic prophylaxis and immunoglobulin treatment (per standard replacement guidelines). Pregnant women who have received tisagenlecleucel may have hypogammaglobulinemia; assess immunoglobulin levels in newborns of mothers treated with tisagenlecleucel.

• Infection: Serious infections (including life-threatening or fatal infections) occurred in patients after tisagenlecleucel infusion, including grades 3 and 4 infections. Viral, bacterial, and fungal infections were reported as well as infections due to unknown pathogens. Begin prophylaxis according to local guidelines prior to tisagenlecleucel infusion. Monitor for signs and symptoms of infection following treatment and manage appropriately. Neutropenic fever (grade 3 or 4) has been observed after tisagenlecleucel infusion and may occur concurrently with CRS. If neutropenic fever occurs, evaluate for infection and manage with broad spectrum antibiotics, fluids and other supportive care as clinically indicated.

• Neurological toxicities: [US Boxed Warning]: Neurological toxicities, which may be severe or life-threatening, can occur following treatment with tisagenlecleucel, and may occur concurrently with CRS. Monitor for neurological events and provide supportive care as needed. Most neurological toxicities occurred within 8 weeks following tisagenlecleucel infusion and generally resolved within 12 days of onset. Grade 3 and 4 neurologic toxicities have been observed. The most common neurological toxicities were headache, encephalopathy, delirium, anxiety, and tremor; other manifestations included disturbances in consciousness, disorientation, confusion, agitation, seizures, mutism and aphasia. The onset of neurologic toxicity may be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Exclude other causes for neurological symptoms and manage supportively as needed. 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.

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

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Immunizations: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel treatment, and until immune recovery following treatment. The safety of immunization with live viral vaccines during or following tisagenlecleucel treatment has not been studied.

Other warnings/precautions:

• Appropriate use: For autologous use only. Confirm patient identity and match to patient identifiers on the infusion bag prior to infusion.

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

Monitoring Parameters

Screen for HBV, HCV, and HIV (prior to collection of cells for manufacturing). Monitor immunoglobulin levels (after treatment).

Monitor for signs/symptoms of CRS for at least 4 weeks after treatment (evaluate immediately at the first sign of CRS), monitor for hypersensitivity reactions, neurologic toxicity, signs/symptoms of infection. Monitor (life-long) for secondary malignancies.

Pregnancy Considerations

Animal reproduction studies have not been conducted. If placental transfer were to occur, fetal toxicity, including B-cell lymphocytopenia may occur.

Pregnancy testing is recommended prior to therapy in sexually active women of reproductive potential. Refer to the cyclophosphamide and fludarabine monographs for information related to use of effective contraception in patients using these medications for lymphodepleting chemotherapy. The duration of contraception needed following tisagenlecleucel administration is not known. Pregnant women who have received tisagenlecleucel may have hypogammaglobulinemia; assess immunoglobulin levels in newborns of mothers treated with tisagenlecleucel.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite, nausea, vomiting, diarrhea, constipation, abdominal pain, painful extremities, muscle pan, joint pain, back pain, or rhinitis. Have patient report immediately to prescriber signs of cytokine release syndrome (chills, dizziness, loss of strength and energy, fever, headache, passing out, rash, angioedema, difficulty breathing, nausea, vomiting, or wheezing), signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), anxiety, confusion, nervousness, agitation, restlessness, vision changes, dizziness, passing out, hallucinations, headache, seizures, tremors, difficulty speaking, behavioral changes, mood changes, shortness of breath, excessive weight gain, swelling of arms or legs, fast breathing, severe loss of strength and energy, or tachycardia (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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