Tisagenlecleucel is a chimeric antigen receptor (CAR) T-cell therapy and the first gene therapy approved by the FDA. It is CD19-directed immunotherapy that works by using a patient's own genetically altered immune cells to kill B-cell cancer cells in the blood. Tisagenlecleucel is indicated for use in patients up to 25 years of age with relapsed or refractory B-cell precursor acute lymphoblastic leukemia and in adult patients with relapsed or refractory large B-cell lymphoma or follicular lymphoma after 2 or more lines of systemic therapy. It is not indicated for use in patients with primary central nervous system lymphoma. Cytokine release syndrome and severe neurotoxicity have been reported. Tisagenlecleucel is available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Employ universal precautions in handling leukapheresis material or tisagenlecleucel; follow local biosafety guidelines applicable for disposal of such products.
Emetic Risk
-Low
-Administer routine antiemetic prophylaxis prior to treatment.
Route-Specific Administration
Injectable Administration
Visually inspect the contents of the infusion bag(s) for any breaks or cracks and the thawed infusion bag for any visible cell clumps prior to administration. Do not infuse the contents if the bag is compromised or if clumps do not disperse after thawing and gentle mixing and call Novartis at 1-844-4KYMRIAH.
Intravenous Administration
-Tisagenlecleucel is for autologous and intravenous use.
-Each dose of tisagenlecleucel is suspended in 1 to 3 patient-specific infusion bag(s); the total infusion bag volume ranges from 10 to 50 mL.
-Each dose is patient specific; see the Certificate of Analysis for the actual number of chimeric antigen receptor (CAR)-positive T-cells in the product.
-Verify the number of bags received for the dose; see the Certificate of Conformance.
-Ensure tocilizumab and emergency equipment are available prior to the infusion and during the recovery period.
-Coordinate the timing of the tisagenlecleucel thaw and infusion; confirm the infusion time in advance, and adjust the start time for thaw so that the recipient will be ready.
-Premedicate patients with acetaminophen and a H1-antihistamine (e.g., diphenhydramine) approximately 30 to 60 minutes prior to the infusion; avoid the prophylactic use of corticosteroids.
Preparation
-Match the patient's identity with the patient identifiers on the infusion bag(s).
-Put the infusion bag inside a second, sterile bag to protect against leaks and port contamination.
-Thaw each infusion bag one at a time at 37 degrees Celsius (C) using either a water bath or dry thaw method; once there is no visible ice in the infusion bag, remove it from the thawing device immediately.
-If more than one bag is being infused for the treatment dose, wait to thaw/infuse the next bag until it is determined that the previous bag has been safely administered.
-Do not wash, spin down, and/or resuspend tisagenlecleucel in new media prior to infusion.
-If visible cell clumps remain after thawing, gently mix the contents of the bag to allow the clumps of cellular material to disperse.
-Storage of thawed infusion bag: once the product is at room temperature (20 to 25 degrees C), administer within 30 minutes.
Intravenous (IV) Infusion
-Confirm the patient's identity with the patient identifiers on the infusion bag(s).
-Prime the tubing with normal saline prior to the infusion.
-Administer as an IV infusion at a rate of 10 mL to 20 mL per minute until infusion bag is empty; adjust this rate as appropriate for smaller children and smaller volumes.
-Do not use a leukocyte-depleting filter.
-Rinse the infusion bag with 10 mL to 30 mL of normal saline; maintain a closed tubing system to assure as many cells as possible are infused into the patient.
-Cells from all of the bag(s) must be infused to complete a single dose.
Neurotoxicity was reported in 43% to 71% (grade 3 or higher, 6% to 22%) of patients who received tisagenlecleucel in clinical trials; encephalopathy lasting up to 70 days has been reported. Monitor patients for signs and symptoms of neurotoxicity 2 to 3 times during the first week at a certified healthcare facility following the infusion and continue monitoring for at least 4 weeks after the infusion. Rule out other causes of neurologic symptoms; administer supportive care and/or corticosteroids as indicated. Consider non-sedating prophylaxis (e.g., levetiracetam) in patients who have high risk of having a seizure. Neurotoxicity such as headache (21% to 35%; grade 3 or higher, 1% to 3%) including migraine, dizziness (5% to 12%; grade 3 or higher, 2% or less) including syncope, tremor (3% to 8%) including dyskinesia, speech disorder (4% or less) including dysarthria and aphasia, neuralgia (3% or less) including sciatica, ataxia (2% or less) including dysmetria, ischemic cerebral infarction/stroke (1% or less), and immune effector cell-associated neurotoxicity syndrome (ICANS: 4% or less) was reported in patients who received tisagenlecleucel in clinical studies. Additionally, motor dysfunction occurred in 1% to 9% of patients and included dyskinesia, muscle cramps/spasms, muscular weakness, musculoskeletal stiffness, myoclonus, and myopathy; encephalopathy occurred in 3% to 30% (grade 3 or higher, 11% or less) of patients and included cognitive disorder/impaired cognition, confusion, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, memory impairment, abnormal thinking, somnolence/drowsiness, and automatism; peripheral neuropathy occurred in 4% to 12% (grade 3 or higher, 3% or less) of patients and included dysesthesia, hypoesthesia, paresthesias, hypoesthesia, hyperesthesia, cranial nerve paralysis, demyelinating polyneuropathy, Horner's syndrome, polyneuropathy, and sciatica; and seizures occurred in 6% or less of patients and included generalized tonic-clonic and post-traumatic seizures and status epilepticus. The median times to first neurologic event and durations ranged from 5 to 8 days and 5 to 17 days, respectively. Of patients who experienced neurotoxicity, 84% of adverse events occurred within 8 weeks of the tisagenlecleucel infusion. Neurotoxicity may occur concurrently with cytokine release syndrome (CRS) or after CRS resolves.
Psychiatric disorders such as delirium (1% to 19%; grade 3 or higher, 4% or less), anxiety (2% to 17%; grade 3 or higher, 3% or less), and sleep disorders (6% to 11%) including insomnia and nightmares were reported in patients who received tisagenlecleucel in clinical studies. The term delirium included agitation, hallucinations, irritability, and restlessness.
Capillary leak syndrome and multiple organ dysfunction syndrome were each reported in 3% or less of patients who received tisagenlecleucel in clinical trials.
Tumor lysis syndrome (TLS) was reported in 2% to 6% of patients who received tisagenlecleucel in clinical trials.
Infection (52% to 72%; grade 3 or higher, 21% to 48%), neutropenic fever (grade 3 or higher, 13% to 34%), and influenza-like illness (9% or less) were reported in patients who received tisagenlecleucel in clinical trials; fatal infection occurred in 4 patients. Monitor patients for signs and symptoms of infection; administer prophylactic antimicrobial therapy and other anti-infective therapy as clinically appropriate. Manage patients with febrile neutropenia with broad spectrum antibiotics, fluids, and other supportive care as indicated. Infectious events in the clinical trials included infection (pathogen unspecified) (38% to 57%; grade 3 or higher, 12% to 27%), viral infection (11% to 37%; grade 3 or higher, 2% to 22%), bacterial infection (7% to 29%; grade 3 or higher, 16% or less), and fungal infection (2% to 15%; grade 3 or higher, 9% or less).
Cardiotoxicity including tachycardia/sinus tachycardia (2% to 24%; grade 3 or higher, 4% or less), hypotension (9% to 29%; grade 3 or higher, 20% or less), hypertension (4% to 19%; grade 3 or higher, 5% or less), and heart failure (9% or less) was reported in patients who received tisagenlecleucel therapy in clinical trials. Arrhythmias occurred in 4% to 10% (grade 3 or higher, 5% or less) of patients and included atrial fibrillation, cardiac arrest, supraventricular tachycardia (SVT), first-degree AV block, QT prolongation on electrocardiogram, and ventricular extrasystoles.
Gastrointestinal (GI) toxicity including nausea (16% to 29%; grade 3 or higher, 1% to 3%), diarrhea (24% to 31%; grade 3 or higher, 1% to 2%), vomiting (9% to32%; grade 3 or higher, 1% or less), constipation (16% to 18%; grade 3 or higher, 1% or less), abdominal pain (10% to 18%; grade 3 or higher, 1% to 3%), abdominal distention (2% to 4%), decreased appetite/anorexia (8% to 38%; grade 3 or higher, 15% or less), stomatitis including oral ulceration (4% to 6%), xerostomia (1% to 5%), and abdominal compartment syndrome (1% or less) was reported in patients who received tisagenlecleucel therapy in clinical trials.
Musculoskeletal adverse events including musculoskeletal pain (13% to 32%; grade 3 or higher, 1% to 4%), arthralgia (10% to 14%; grade 3 or higher, 1% or less), pain/extremity pain (8% to 25%; grade 3 or higher, 3% or less), and myalgia (5% or less) were reported in patients who received tisagenlecleucel therapy in clinical trials. The term musculoskeletal pain included back pain, bone pain, flank pain, muscle discomfort, musculoskeletal chest pain, myalgia, neck pain, and non-cardiac chest pain.
Respiratory adverse events adverse events including hypoxia (25% or less; grade 3 or higher, 20% or less), cough/upper-airway cough syndrome (17% to 27%), dyspnea (8% to 21%; grade 3 or higher, 14% or less), pulmonary edema (15% or less; grade 3 or higher, 6% or less), tachypnea (10% or less; grade 3 or higher, 5% or less), pleural effusion (5% to 10%; grade 3 or higher, 4% or less), nasal congestion (2% to 11%), oropharyngeal pain (5% to 10%), and acute respiratory distress syndrome (ARDS) (4% or less), lung infiltration (1% or less), rhinorrhea (2% or less) were reported in patients who received tisagenlecleucel therapy in clinical trials.The term dyspnea included respiratory distress and respiratory failure.
Nephrotoxicity, specifically acute kidney injury, was reported in 4% to 22% (grade 3 or higher, 14% or less) of patients who received tisagenlecleucel therapy in clinical trials. The term acute kidney injury included anuria, azotemia, renal failure, renal tubular necrosis or dysfunction, and abnormal or increased serum creatinine level.
Graft-versus-host disease (GVHD) was reported in 3% or less of patients who received tisagenlecleucel in clinical trials.
Edema (9% to 27%; grade 3 or higher, 8% or less) and ascites (4% or less) were reported in patients who received tisagenlecleucel therapy in clinical trials. The term edema included face edema, fluid overload, fluid retention, hypervolemia, generalized and localized edema, and peripheral edema or swelling.
Fever (19% to 42%; grade 3 or higher, 1% to 13%) and chills (6% to 12%) were reported in patients who received tisagenlecleucel therapy in clinical trials.
Fatigue (23% to 27%; grade 3 or higher, 6% or less) and asthenia (7% or less) were reported in patients who received tisagenlecleucel therapy in clinical trials. The term fatigue included malaise and asthenia.
Bleeding was reported in 6% to 32% (grade 3 or higher, 10% or less) of patients who received tisagenlecleucel therapy in clinical trials; fatal intracranial bleeding was reported in 1 patient. The term bleeding included vaginal bleeding (e.g., heavy menstrual bleeding), GI bleeding (e.g., mouth or anal hemorrhage), cerebral hemorrhage/intracranial bleeding, ocular hemorrhage (e.g., conjunctival and retinal hemorrhage), catheter-site hemorrhage, post-procedural hemorrhage, contusion, hematoma, hemorrhagic cystitis, disseminated intravascular coagulation (DIC), epistaxis, hemarthrosis, hematemesis, hematuria, hemoptysis, hematochezia, melena, petechiae, pharyngeal hemorrhage, purpura, duodenal ulcer hemorrhage, pulmonary hemorrhage, and tumor hemorrhage.
Pre-dose anti-mCAR19 antibodies were detected in 66% to 94% of patients prior to receiving tisagenlecleucel in clinical trials; treatment-induced antibody formation occurred in 33% or less of patients. However, the presence of these antibodies pre- or post-infusion did not have an impact on clinical response to tisagenlecleucel or its safety profile. T-cell immunogenicity responses were not reported in any patients.
Grade 3 or 4 elevated hepatic enzymes including increased AST (29%) and ALT (22%) levels and grade 3 or 4 hyperbilirubinemia (19%) were reported in patients with relapsed or refractory acute lymphoblastic leukemia who received tisagenlecleucel in a clinical study (n = 79).
Grade 3 or 4 hypokalemia (28% or less), hypophosphatemia (12% to 24%), hypocalcemia (20% or less; grade 3 or higher, 6% or less), and hypercalcemia (4% or less) were reported in patients who received tisagenlecleucel therapy in clinical studies.
Rash (10% to 18%; grade 3 or higher, 1% or less), pruritus (4% to 9%), erythema (2% to 6%), night sweats (1% to 5%), and hyperhidrosis (1% to 4%) were reported in patients who received tisagenlecleucel therapy in clinical studies. The term rash included maculopapular rash, contact dermatitis, acneiform rash, and pruritic rash.
Thrombosis was reported in 1% to 6% of patients who received tisagenlecleucel therapy in clinical studies. The term thrombosis included deep vein thrombosis, embolism, pulmonary embolism, vena cava thrombosis, and venous thrombosis.
Visual impairment occurred in 6% or less of patients who received tisagenlecleucel in clinical trials. The term visual impairment included blurred vision and worsened pre-existing progressive blindness.
Weight loss occurred in 12% or less (grade 3 or higher, 4% or less) of patients who received tisagenlecleucel in clinical trials.
Cytokine release syndrome (CRS) was reported in 53% to 77% (grade 3 or higher, 48% or less) of patients who received tisagenlecleucel in clinical trials; there were 5 deaths reported within 30 days of the infusion. Symptoms of CRS may include fever (85% to 93%), hypotension (40% to 69%), hypoxia (19% to 57%), and tachycardia (2% to 26%). CRS may be associated with hepatic, renal, and cardiac impairment and coagulopathy. Monitor patients for signs and symptoms of CRS 2 to 3 times during the first week following the tisagenlecleucel infusion at a certified healthcare facility, then monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment. Management of CRS may include hospitalization, supportive care (e.g., oxygen, fluids, vasopressors), medical management (e.g., tocilizumab and corticosteroids), and mechanical ventilation. Alternative CRS management strategies may be employed using institutional or academic guidelines. In clinical trials, the median times to CRS and durations ranged from 3 to 4 days and 4 to 8 days, respectively.
Hematologic toxicity such as increased serum ferritin level/hyperferritinemia (10% or less; grade 3 or higher, 4%); pancytopenia (3%); hemolysis (2% or less) including hemolytic anemia; and grade 3 or 4 lymphopenia (95% or less), neutropenia (82% or less), leukopenia (78% or less), anemia (59% or less), and thrombocytopenia (56% or less) was reported in patients who received tisagenlecleucel in clinical trials. Monitor complete blood counts regularly until hematologic recovery. The use of myeloid growth factors, especially granulocyte macrophage colony-stimulating factor, is not recommended within 3 weeks after the tisagenlecleucel infusion or until cytokine release syndrome has resolved. Prolonged cytopenias including grade 3 or 4 neutropenia (16% to 40%) and thrombocytopenia (17% to 27%) not resolved by day 28 occurred in patients who received tisagenlecleucel and achieved a response in clinical trials. Additionally, prolonged cytopenias including grade 3 or 4 neutropenia (17%) and thrombocytopenia (12%) not resolved by day 56 were reported in responding patients with acute lymphoblastic leukemia.
Coagulopathy including increased international normalized ratio (INR) level (6% or less), grade 3 or 4 decreased fibrinogen level/hypofibrinogenemia (11%), prolonged bleeding time (i.e., prolonged prothrombin time) (4% or less), and increased fibrin D dimer level (4% or less) were reported in patients who received tisagenlecleucel in clinical trials.
Hypogammaglobulineia (17% to 53%; grade 3 or higher, 1% to 13%) and B-cell aplasia (1% or less) that may lead to agammaglobulinemia due to were reported in patients who received tisagenlecleucel in clinical trials. Monitor immunoglobulin levels after tisagenlecleucel therapy; manage immunoglobulin deficiency with infection precautions, prophylactic antibiotic therapy, and immunoglobulin replacement per standard guidelines. The term hypogammaglobulinemia included decreased immunoglobulin G and M levels, decreased immunoglobulin level, and immunodeficiency.
Hypersensitivity reactions including anaphylactoid reactions were reported in were reported in postmarketing surveillance of tisagenlecleucel.
Hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) was reported in 1% to 6% of patients who received tisagenlecleucel in clinical trials. Treat patients with HLH/MAS per institutional guidelines. All HLH events occurred concurrently with cytokine release syndrome and resolved in patients with acute lymphoblastic leukemia or diffuse large B-cell lymphoma. Additionally, 1 patient with follicular lymphoma died after developing HLH more than 1 year after receiving tisagenlecleucel. This patient did not have CRS during or immediately prior to HLH.
Grade 3 or 4 hyperglycemia was reported in 13% of patients with relapsed or refractory acute lymphoblastic leukemia who received tisagenlecleucel in a clinical study (n = 79).
Infusion-related reactions were reported in 3% to 6% of patients who received tisagenlecleucel in clinical trials.
Flushing was reported in 1% or less of patients who received tisagenlecleucel in clinical trials.
T-cell malignancies, including chimeric antigen receptor (CAR)-positive lymphoma, have been reported in patients who received treatment with CD19-directed autologous CAR T-cell immunotherapy in clinical trials and postmarketing surveillance. If a patient develops a new primary malignancy following treatment with tisagenlecleucel, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 for instructions on how to collect patient samples for testing for the presence of the CAR transgene. Report suspected adverse events, including T-cell malignancies, to the FDA.
Cytokine release syndrome (CRS) has been reported with tisagenlecleucel; some cases were fatal or life-threatening. Do not administer tisagenlecleucel in patients with active infection or inflammatory disorders. Delay the tisagenlecleucel infusion in patients who have unresolved serious adverse reactions from preceding chemotherapy (e.g., pulmonary or cardiac reactions or hypotension), active graft-versus-host disease (GVHD), or worsening leukemia burden following lymphocyte depleting chemotherapy. Confirm that 2 doses of tocilizumab are available at the facility site prior to the tisagenlecleucel infusion. Monitor patients for signs and symptoms of CRS 2 to 3 times during the first week following the tisagenlecleucel infusion at a certified healthcare facility, then monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment. CRS may be associated with hepatic, renal, and cardiac dysfunction and coagulopathy. Management of CRS may include hospitalization, supportive care (e.g., oxygen, fluids, high-dose vasopressors), medical management (e.g., tocilizumab and corticosteroids), and mechanical ventilation. Alternative CRS management strategies may be employed using institutional or academic guidelines. Evaluate for and treat other causes of fever, hypoxia, and hypotension. Patients with B-cell acute lymphoblastic leukemia and a high tumor burden (i.e., greater than 50% blasts in the bone marrow), an active uncontrolled infection, or active GVHD may be at increased risk of developing severe CRS.
Severe and life-threatening neurotoxicity (e.g., encephalopathy, seizures) has been reported with tisagenlecleucel therapy; most cases occurred within 8 weeks of the tisagenlecleucel infusion. Consider non-sedating prophylaxis (e.g., levetiracetam) in patients who may be at high risk of having a seizure (e.g., history of seizures, central nervous system disease, abnormal EEG findings, or neoplastic brain tumor/lesions). Monitor patients for signs and symptoms of neurotoxicity 2 to 3 times during the first week at a certified healthcare facility following the infusion and continue monitoring for at least 4 weeks after the infusion. Rule out other causes of neurologic symptoms; administer supportive care and/or corticosteroids as indicated. Advise patients to avoid driving or operating machinery or performing other hazardous activities for 8 weeks after the tisagenlecleucel infusion due to the risk of neurotoxicity (e.g., altered mental status or coordination).
Because of the risk of cytokine release syndrome and neurological toxicities, use requires an experienced clinician with training on the management of these toxicities. Tisagenlecleucel administration also requires a specialized care setting that is enrolled in the KYMRIAH REMS program and can comply with all program requirements (e.g., 2 doses of tocilizumab are available for each patient within 2 hours of the tisagenlecleucel infusion).
Prolonged neutropenia and thrombocytopenia have been reported following tisagenlecleucel therapy; prolonged neutropenia may increase the risk of infection. Monitor complete blood counts regularly until hematologic recovery. The use of myeloid growth factors, especially granulocyte macrophage colony-stimulating factor, is not recommended within 3 weeks after the tisagenlecleucel infusion or until cytokine release syndrome has resolved.
Allergic reactions including infusion-related reactions have been reported with tisagenlecleucel therapy; serious hypersensitivity reactions (e.g., anaphylactoid reactions) have occurred. Premedicate patients with acetaminophen and an antihistamine prior to the tisagenlecleucel infusion. Monitor for hypersensitivity reactions during the infusion. Reactions may be due to dimethyl sulfoxide (DMSO) or dextran 40 contained in the tisagenlecleucel product.
Due to the risk of a new primary malignancy, including T-cell malignancies, life-long monitoring is recommended following tisagenlecleucel therapy.
Tumor lysis syndrome (TLS) has been reported with tisagenlecleucel therapy. Institute prophylactic measures to prevent TLS. Monitor patients for signs or symptoms of TLS and treat as clinically appropriate.
Vaccination with live viral vaccines during or following treatment with tisagenlecleucel has not been studied. It is not recommended for at least 6 weeks prior to the start of lymphocyte depleting chemotherapy, during tisagenlecleucel therapy, and until immune recovery after tisagenlecleucel therapy.
Patients who receive tisagenlecleucel should avoid cell, organ, tissue, and blood donation.
False-positive HIV test results have been reported in patients who received tisagenlecleucel therapy. The use of gammaretroviral or lentiviral vectors to reprogram T-cells as part of chimeric antigen receptor (CAR) T-cell immunotherapy has resulted in laboratory test interference with HIV-1 nucleic acid amplification testing (NAAT). False test results may occur due to vector interference with long terminal repeat (LTR) genomes in HIV NAAT. Alternative testing methods for HIV (e.g., assays that target p24 antigen and anti-HIV-1 antibodies or the integrase gene) should be performed in patients who have received CAR T-cell therapy.
Hepatitis B virus (HBV) reactivation resulting in hepatitis B exacerbation, fulminant hepatitis, hepatic failure, and death may occur with drugs directed against B cells, such as tisagenlecleucel. Screen all patients for HBV, hepatitis C virus, and HIV prior to cell collection (leukapheresis).
Serious infections including bacterial infection, fungal infection, and viral infection have been reported with tisagenlecleucel therapy; some cases were life-threatening or fatal. Monitor patients for signs and symptoms of infection; administer prophylactic antimicrobial therapy and other anti-infective therapy as clinically appropriate.
Hypogammaglobulinemia and agammaglobulinemia (immunoglobulin deficiency) have been reported in patients who achieve a complete remission following tisagenlecleucel therapy. Monitor immunoglobulin levels after tisagenlecleucel therapy; manage immunoglobulin deficiency with infection precautions, prophylactic antibiotic therapy, and immunoglobulin replacement per standard guidelines. Assess immunoglobulin levels in neonates who are born to mothers treated with tisagenlecleucel.
Pregnancy should be avoided by females of reproductive potential during tisagenlecleucel treatment; pregnancy after tisagenlecleucel administration should be discussed with the treating physician. Report pregnancies to Novartis Pharmaceuticals Corporation at 1-888-669-6682. There are no available data with tisagenlecleucel use in pregnant women; animal reproductive and developmental toxicity studies have not been conducted. It is not known if tisagenlecleucel has the potential to be transferred to the fetus. However, based on its mechanism of action, fetal toxicity including B-cell lymphocytopenia may occur if the transduced cells cross the placenta.
Counsel patients about the reproductive risk and contraception requirements during tisagenlecleucel treatment. It is unknown whether tisagenlecleucel can cause fetal harm if taken during pregnancy, although fetal toxicity is possible based on its mechanism of action. See prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive lymphodepleting chemotherapy. There are insufficient data to recommend a duration of contraception following treatment with tisagenlecleucel. Pregnancy status of females of reproductive potential should be verified; sexually active females of reproductive potential should undergo pregnancy testing prior to initiation of tisagenlecleucel. Women who become pregnant while receiving tisagenlecleucel should be apprised of the potential hazard to the fetus. There are no data on the effect of tisagenlecleucel on fertility.
Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for tisagenlecleucel and any potential adverse effects on the breast-fed infant from tisagenlecleucel or from the underlying maternal condition. It is not known whether tisagenlecleucel is present in human milk, although many drugs are excreted in human milk.
For the treatment of acute lymphocytic leukemia (ALL):
NOTE: Tisagenlecleucel is designated as an orphan drug by the FDA for this indication.
-for the treatment of B-cell precursor ALL that is refractory or in second or later relapse:
Intravenous dosage:
Adults 25 years and younger, Adolescents, Children, Infants, and Neonates: For patients weighing greater than 50 kg, infuse a single dose of 0.1 to 2.5 X 108 CAR-positive viable T-cells (non-weight based). For patients weighing 50 kg or less, infuse a single dose of 0.2 to 5 X 106 CAR-positive viable T-cells per kg of body weight. Administer tisagenlecleucel at 2 to 14 days after the completion of lymphocyte depletion therapy. Premedicate patients with acetaminophen and a H1-antihistamine (e.g., diphenhydramine) approximately 30 to 60 minutes prior to the infusion. Ensure that tocilizumab and emergency equipment are available at the facility site prior to the infusion and during the recovery period. Additionally, confirm that tisagenlecleucel is available prior to starting the lymphocyte depletion regimen. Lymphocyte depletion therapy consists of fludarabine (30 mg/m2 IV daily for 4 days) plus cyclophosphamide (500 mg/m2 IV daily for 2 doses starting with the first fludarabine dose). The 3-month complete remission (CR) rate (CR + CR with incomplete hematologic recovery (CRi) rate) was 82% in 79 patients (median age, 12 years; range, 3 to 24 years) with relapsed or refractory B-cell ALL who received a single infusion of tisagenlecleucel in a phase 2 (ELIANA) trial. At a median follow-up time of 38.8, the median duration of response had not been reached, the median event-free survival (EFS) time was 24 months, and the median overall survival (OS) time had not been reached. At the time of analysis, the EFS and OS rates were 44% and 63%, respectively. Additionally, 22% of patients underwent a subsequent allogeneic stem-cell transplant. In this trial, leukapheresis was performed per institutional guidelines. Following leukapheresis and T-cell collection, most patients received bridging chemotherapy and all patients had lymphocyte depletion with fludarabine and cyclophosphamide. Prior to treatment with tisagenlecleucel, patients in this study had received a median of 3 (range, 1 to 8) prior therapies and 61% of patients had received a hematopoietic stem cell transplant.
For the treatment of non-Hodgkin's lymphoma (NHL):
NOTE: Tisagenlecleucel has been designated as an orphan drug by the FDA for the treatment of diffuse large B-cell lymphoma and follicular lymphoma.
-for the treatment of relapsed or refractory large B-cell lymphoma (e.g., high grade B-cell lymphoma, DLBCL not otherwise specified, and DLBCL arising from follicular lymphoma) after 2 or more lines of systemic therapy:
NOTE: Tisagenlecleucel is not indicated for use in patients with primary central nervous system lymphoma.
Intravenous dosage:
Adults: 0.6 to 6 X 108 chimeric antigen receptor (CAR)-positive viable T-cells infused as a single-dose which may be suspended in 1 or more patient-specific infusion bag(s). Administer tisagenlecleucel at 2 to 11 days after the completion of lymphocyte depletion therapy. Premedicate patients with acetaminophen and a H1-antihistamine (e.g., diphenhydramine) approximately 30 to 60 minutes prior to the infusion. Ensure that tocilizumab and emergency equipment are available at the facility site prior to the infusion and during the recovery period. Additionally, confirm that tisagenlecleucel is available prior to starting the lymphocyte depletion regimen. Lymphocyte depletion therapy consists of fludarabine (25 mg/m2 IV daily for 3 days) plus cyclophosphamide (250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine); alternative therapy consists of bendamustine (90 mg/m2 IV daily for 2 days) for patients who experienced grade 4 hemorrhagic cystitis with prior cyclophosphamide administration or had resistance to a previous cyclophosphamide-containing regimen. Lymphocyte depletion therapy may be omitted in patients who have a white blood cell count of 1 X 109 cells/L or less within 1 week prior to the tisagenlecleucel infusion. The independent review committee-assessed overall response rate was 53% following a single infusion of tisagenlecleucel in 115 adult patients with relapsed or refractory DLBCL included in the efficacy analysis who received 2 or more lines of prior chemotherapy (including rituximab and an anthracycline) and had a relapse following autologous hematopoietic stem-cell transplantation (HSCT) or were ineligible for a HSCT in a nonrandomized, phase 2a trial (the JULIET trial). In these patients, the complete response rate was 39% and the partial response rate was 14%. At a median follow-up time of 40.3 months, the median progression-free survival time was 2.9 months and the median overall survival time was 11.1 months. Most patients (90%) received bridging therapy prior to the tisagenlecleucel infusion; additionally, 93% of patients received lymphocyte depletion therapy.
-for the treatment of relapsed or refractory follicular lymphoma after 2 or more lines of systemic therapy:
Intravenous dosage:
Adults: 0.6 to 6 X 108 chimeric antigen receptor (CAR)-positive viable T-cells infused as a single-dose which may be suspended in 1 or more patient-specific infusion bag(s). Administer tisagenlecleucel at 2 to 6 days after the completion of lymphocyte depletion therapy. Premedicate patients with acetaminophen and a H1-antihistamine (e.g., diphenhydramine) approximately 30 to 60 minutes prior to the infusion. Ensure that tocilizumab and emergency equipment are available at the facility site prior to the infusion and during the recovery period. Additionally, confirm that tisagenlecleucel is available prior to starting the lymphocyte depletion regimen. Lymphocyte depletion therapy consists of fludarabine (25 mg/m2 IV daily for 3 days) plus cyclophosphamide (250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine); alternative therapy consists of bendamustine (90 mg/m2 IV daily for 2 days) for patients who experienced grade 4 hemorrhagic cystitis with prior cyclophosphamide administration or had resistance to a previous cyclophosphamide-containing regimen. Lymphocyte depletion therapy may be omitted in patients who have a white blood cell count of 1 X 109 cells/L or less within 1 week prior to the tisagenlecleucel infusion. The independent review committee-assessed complete response (CR) rate (primary endpoint) was 69.1% following a single dose of tisagenlecleucel in 94 adult patients with relapsed or refractory grade 1, 2, or 3A follicular lymphoma included in the efficacy analysis who received 2 or more lines of prior chemotherapy in a multinational, phase 2 (ELARA) trial. In these patients, the overall response rate was 86.2%. At a median follow-up time of 28.9 months, the median progression-free survival (PFS) and overall survival (OS) times were not reached. The estimated 24-month PFS rate was 57.4% and the estimated 24-month OS rate for patients who achieved CR was 87.7%. Patients in this study had received a median of 4 (range, 2 to 13) prior therapies; all patients had received an anti-CD20 monoclonal antibody plus an alkylating agent and 36.1% of patients had received an autologous hematopoietic stem-cell transplantation. Bridging therapy prior to the tisagenlecleucel infusion was administered in 45% of patients.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
NOTE: When indicated, administer tocilizumab 8 mg/kg IV over 1 hour (maximum dose, 800 mg) in patients weighing 30 kg or more OR tocilizumab 12 mg/kg in patients weighing less than 30 kg; repeat tocilizumab every 8 hours in patients show no clinical improvement in CRS signs and symptoms. Do not exceed 3 tocilizumab doses in a 24-hour period or a maximum of 4 doses total.
Cytokine Release Syndrome (CRS)
Grade 1 toxicity (only requiring symptomatic treatment symptoms including low-grade fever, fatigue, and anorexia): Start symptomatic treatment (e.g., antipyretics, antiemetics, analgesics); consider adding tocilizumab according to grade 2 toxicity for persistent (lasting more than 3 days) or refractory fever despite symptomatic treatment.
Grade 2 toxicity (symptoms require and respond to moderate intervention, oxygen requirement less than 40%, hypotension responsive to fluids or a low-dose of 1 vasopressor agent, or grade 2 organ toxicity): Start symptomatic treatment (e.g., antipyretics, oxygen, IV fluids, low-dose vasopressor). Administer tocilizumab; if no improvement within 24 hours, add methylprednisolone 2 mg/kg IV (or equivalent) once daily until oxygen and vasopressor is no longer required. Taper steroids as clinically indicated. If the toxicity is not improving, manage corticosteroids according to grade 3 or 4 CRS toxicity.
Grade 3 toxicity (symptoms require and respond to aggressive intervention, oxygen requirement of 40% or greater, hypotension requiring high-dose or multiple vasopressor agents, grade 3 organ toxicity, or grade 4 transaminitis): Start symptomatic treatment (e.g., high-flow oxygen, IV fluids, high-dose or multiple vasopressors; use local guidelines for organ toxicity). Administer tocilizumab; if no improvement within 24 hours, add methylprednisolone 2 mg/kg IV (or equivalent) once daily until oxygen and vasopressor is no longer required. Taper steroids as clinically indicated. If the toxicity is not improving, consider alternate anti-cytokine/T-cell therapy (e.g., anakinra, siltuximab, ruxolitinib, cyclophosphamide, immunoglobulin (IVIG), and antithymocyte globulin (ATG) therapy) and manage corticosteroids according to grade 4 CRS toxicity.
Grade 4 toxicity (life-threatening symptoms, requirements for ventilator support, or grade 4 organ toxicity (excluding transaminitis)): Start symptomatic treatment (e.g., mechanical ventilation, IV fluids, high-dose or multiple vasopressors; use local guidelines for organ toxicity). Administer tocilizumab and methylprednisolone 1,000 mg IV once or twice daily for 3 days; continue corticosteroids until toxicity improves to grade 1 or less and then taper as clinically appropriate. If no improvement with tocilizumab, consider alternate anti-cytokine/T-cell therapy. If no improvement with corticosteroids, consider increasing methylprednisolone dosage to 1,000 mg IV twice or three times daily or switching to alternative anti-cytokine/T-cell therapy.
Neurologic Toxicity/Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
NOTE: Consider non-sedating prophylaxis (e.g., levetiracetam) in patients who have high risk of seizure.
ICANS Grade:
Grade 1 toxicity: immune effector cell encephalopathy (ICE) score, 7 to 9 with no depressed level of consciousness.
Grade 2 toxicity: ICE score of 3 to 6 and/or mild somnolence awaking to voice.
Grade 3 toxicity: ICE score of 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 OR ICE score of 0 if awake with global aphasia.
Grade 4 toxicity: ICE score of 0 and unarousable; stupor or coma; life-threatening prolonged seizure (over 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.
Without Concurrent CRS
Grade 1 toxicity: Administer supportive care with IV hydration and aspiration precautions.
Grade 2 toxicity: Administer 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; continue corticosteroids until the toxicity resolves to grade 1 or less. Taper steroids as clinically indicated.
Grade 3 toxicity: Administer dexamethasone 10 mg IV every 6 to 12 hours OR methylprednisolone 1 mg/kg IV every 12 hours.
Grade 4 toxicity: Consider mechanical ventilation for airway protection and treat seizures, status epilepticus, and cerebral edema using institutional guidelines. Administer methylprednisolone 1,000 mg IV once or twice daily for 3 days; continue corticosteroids until the toxicity resolves to grade 1 or less. Taper steroids as clinically indicated. If no improvement, consider increasing methylprednisolone dosage to 1,000 mg IV twice or three times daily or switching to alternative therapy (e.g., anakinra, siltuximab, ruxolitinib, cyclophosphamide, ATG therapy, or intrathecal hydrocortisone 50 mg plus methotrexate 12 mg).
With Concurrent CRS
Grade 1 toxicity: Administer tocilizumab according to CRS grade; use caution with repeated doses. Consider adding corticosteroids past the first tocilizumab dose.
Grade 2 toxicity: Administer tocilizumab according to CRS grade. If no improvement after the first tocilizumab dose, add dexamethasone 10 mg IV every 6 to 12 hours OR methylprednisolone 1 mg/kg IV every 12 hours; continue corticosteroids until the toxicity resolves to grade 1 or less. Taper steroids as clinically indicated.
Grade 3 toxicity: Administer tocilizumab according to CRS grade. Start corticosteroid therapy with dexamethasone 10 mg IV every 6 to 12 hours OR methylprednisolone 1 mg/kg IV every 12 hours; continue corticosteroids until the toxicity resolves to grade 1 or less. Taper steroids as clinically indicated. If the toxicity does not improve, treat according to grade 4 toxicity.
Grade 4 toxicity: Treat seizures, status epilepticus, and cerebral edema using institutional guidelines.
Administer tocilizumab according to CRS grade. Start methylprednisolone 1,000 mg IV once or twice daily for 3 days; continue corticosteroids until the toxicity resolves to grade 1 or less. Taper steroids as clinically indicated. If no improvement, consider increasing methylprednisolone dosage to 1,000 mg IV twice or three times daily or switching to alternative therapy (e.g., anakinra, siltuximab, ruxolitinib, cyclophosphamide, ATG therapy, or intrathecal hydrocortisone 50 mg plus methotrexate 12 mg).
Maximum Dosage Limits:
-Adults
Diffuse Large B-cell Lymphoma or Follicular Lymphoma
Adults 18 years and older: 6 X 108 CAR-positive viable T-cells.
Acute Lymphocytic Leukemia
Older than 25 years: Safety and Efficacy not established.
25 years or younger:
Greater than 50 kg: 2.5 X 108 CAR-positive viable T-cells.
50 kg or less: 5 X 106 CAR-positive viable T-cells per kg.
-Geriatric
6 X 108 CAR-positive viable T-cells.
-Adolescents
Greater than 50 kg: 2.5 X 108 CAR-positive viable T-cells.
50 kg or less: 5 X 106 CAR-positive viable T-cells per kg.
-Children
Greater than 50 kg: 2.5 X 108 CAR-positive viable T-cells.
50 kg or less: 5 X 106 CAR-positive viable T-cells per kg.
-Infants
5 X 106 CAR-positive viable T-cells per kg.
-Neonates
5 X 106 CAR-positive viable T-cells per kg.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel therapy, and prior to immune recovery following treatment with tisagenlecleucel. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period of altered immunocompetence.
Chikungunya Vaccine, Live: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel therapy, and prior to immune recovery following treatment with tisagenlecleucel. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period of altered immunocompetence.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Intranasal Influenza Vaccine: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel therapy, and prior to immune recovery following treatment with tisagenlecleucel. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period of altered immunocompetence.
Live Vaccines: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel therapy, and prior to immune recovery following treatment with tisagenlecleucel. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period of altered immunocompetence.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel therapy, and prior to immune recovery following treatment with tisagenlecleucel. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period of altered immunocompetence.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel therapy, and prior to immune recovery following treatment with tisagenlecleucel. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period of altered immunocompetence.
Rotavirus Vaccine: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel therapy, and prior to immune recovery following treatment with tisagenlecleucel. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period of altered immunocompetence.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel therapy, and prior to immune recovery following treatment with tisagenlecleucel. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period of altered immunocompetence.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel therapy, and prior to immune recovery following treatment with tisagenlecleucel. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period of altered immunocompetence.
Typhoid Vaccine: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel therapy, and prior to immune recovery following treatment with tisagenlecleucel. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period of altered immunocompetence.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel therapy, and prior to immune recovery following treatment with tisagenlecleucel. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period of altered immunocompetence.
Yellow Fever Vaccine, Live: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel therapy, and prior to immune recovery following treatment with tisagenlecleucel. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period of altered immunocompetence.
Tisagenlecleucel is a chimeric antigen receptor (CAR) T-cell therapy that works by redirecting T-cells to target the CD19 antigen on B-cells in patients with hematologic malignancies. The extracellular domain of tisagenlecleucel is a murine monoclonal antibody that targets human CD19. The intracellular domain, CD3-zeta, initiates T-cell activation and mediates antitumor activity; the 4-1BB (CD137) costimulatory domain promotes antitumor activity and enhances proliferation of CAR T-cells. The binding of CAR to CD19 activates tisagenlecleucel and promotes cell expansion and differentiation and triggers the lysis of CD19-positive cells.
This immunotherapy involves removing, genetically modifying, and then re-infusing a patient's own T-cells. During the manufacturing process, a lentiviral vector encodes the CAR molecule via transduction; the vector enters the cell and becomes integrated into the chromosomes of T cells and directs transcription of the tisagenlecleucel CAR.
To produce CAR T-cell therapy, T-cells are collected from the blood by leukapheresis; enriched by counterflow centrifugal elutriation; activated by using antibody-coated beads; incubated with a viral vector encoding the CD19 CAR; expanded to large numbers in a bioreactor culture system; and then washed, concentrated, and cryopreserved.
Tisagenlecleucel is administered intravenously. In patients with acute lymphoblastic leukemia (ALL), tisagenlecleucel distribution in bone marrow was 44% of that present in blood at day 28; at months 3 and 6, tisagenlecleucel distribution in the bone marrow was 67% and 69%, respectively. In ALL patients, the geometric mean half-life was 16.8 days (coefficient of variance, (CV), 155.9%) in responding patients (n = 54) and 2.52 days (CV, 171.9%) in nonresponding patients (n = 3). In diffuse large B-cell lymphoma (DLBCL) patients, the geometric mean half-life was 45.3 days (CV, 157.7%) in responding patients (n = 21) and 13.6 days (CV, 167%) in nonresponding patients (n = 22). In follicular lymphoma patients, the geometric mean half-life was 44 days (CV, 296%) in responding patients (n = 42) and 24.4 days (CV, 180%) in nonresponding patients (n = 6).
-Route-Specific Pharmacokinetics
Intravenous Route
After IV administration, tisagenlecleucel exhibits an initial rapid expansion followed by a bi-exponential decline. The Cmax and AUC(0 to 28 days) values were similar in responding acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL) patients compared with nonresponding ALL and DLBCL patients. In patients with follicular lymphoma, the geometric mean Cmax and AUC(0 to 28 days) values were 108% and 183% higher, respectively, in responders compared with nonresponders. In patients with ALL, the geometric mean Cmax in responding patients (n = 61) was 34,700 copies/microgram (mcg) (CV, 155.4%), reached at a median Tmax of 9.91 days; the geometric mean AUC(0 to 28 days) in responding patients was 318,000 copies/mcg X day (CV, 177.8%). Concentrations were lower in ALL patients who did not respond, with a geometric mean Cmax (n = 7) of 20,000 copies/mcg (CV, 71.6%), median Tmax of 20 days, and geometric mean AUC (n = 6) of 156,000 copies/mcg X day (CV, 99.4%). In patients with DLBCL, the geometric mean Cmax in responding patients (n = 33) was 5,210 copies/mcg (CV, 256.5%), reached at a median Tmax of 9.83 days; the geometric mean AUC(0 to 28 days) in responding patients was 582,000 copies/mcg X day (CV, 165.1%). Concentrations were higher in DLBCL patients who did not respond, with a geometric mean Cmax (n = 32) of 6,450 copies/mcg (CV, 408.2%), median Tmax of 8.39 days, and geometric mean AUC(0 to 28 days) (n = 25) of 75,800 copies/mcg X day (CV, 292.3%). The median Tmax for the expansion of transgene levels in peripheral blood occurred at 9 to 10 days in both responding and non-responding patients. In patients with follicular lymphoma, the geometric mean Cmax in responding patients (n = 64) was 6,250 copies/mcg (CV, 344%), reached at a median Tmax of 9.94 days; the geometric mean AUC(0 to 28 days) in responding patients was 56,900 copies/mcg X day (CV, 270%). Concentrations were lower in follicular lymphoma patients who did not respond, with a geometric mean Cmax (n = 8) of 3,000 copies/mcg (CV, 1,190%), median Tmax of 13 days, and geometric mean AUC(0 to 28 days) of 20,100 copies/mcg X day (CV, 18,100%).
-Special Populations
Hepatic Impairment
Hepatic impairment studies of tisagenlecleucel were not conducted.
Renal Impairment
Renal impairment studies of tisagenlecleucel were not conducted.
Pediatrics
Children younger than 10 years and between 10 to 18 years old had similar to 1.7-fold higher Cmax and AUC(0 to 28 days) values than adults. Due to small sample size and high variability, the impact of age on the pharmacokinetics of tisagenlecleucel is difficult to assess.
Other
Immunosuppressive therapy
Patients with acute lymphoblastic leukemia (ALL) who received tocilizumab due to CRS (n = 28) had 183% and 298% higher tisagenlecleucel Cmax and AUC(0 to 28 days) values, respectively, compared to patients who did not receive tocilizumab (n = 46). Similarly, patients with ALL who received corticosteroids (n = 17) had 280% higher AUC value compared with patients who did not receive corticosteroids. Patients with diffuse large B-cell lymphoma (DLBCL) who received tocilizumab due to CRS (n = 18) had 311% and 238% higher tisagenlecleucel Cmax and AUC(0 to 28 days) values, respectively, compared to patients who did not receive tocilizumab (n = 97). DLBCL patients who received corticosteroids (n = 12) had 179% and 104% higher Cmax and AUC values, respectively, compared with patients who did not receive corticosteroids (n = 79). Patients with follicular lymphoma who received tocilizumab due to CRS (n = 14) had 312% and 245% higher tisagenlecleucel Cmax and AUC(0 to 28 days) values, respectively, compared to patients who did not receive tocilizumab (n = 76). A comparison for exposure differences was not performed for corticosteroid use in these patients.