Tisagenlecleucel
FDA Drug Information • Also known as: Kymriah
- Brand Names
- Kymriah
- Drug Class
- CD19-directed Chimeric Antigen Receptor [EPC], Genetically-modified Autologous T Cells [EPC]
- Route
- INTRAVENOUS
- Dosage Form
- INJECTION, SUSPENSION
- Product Type
- CELLULAR THERAPY
⚠ Boxed Warning (Black Box)
WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGICAL TOXICITIES, and SECONDARY HEMATOLOGICAL MALIGNANCIES Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH. Do not administer KYMRIAH to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)]. Neurological toxicities, including severe or life-threatening reactions, occurred following treatment with KYMRIAH, including concurrently with CRS. Monitor for neurological events after treatment with KYMRIAH. Provide supportive care and/or corticosteroids as needed [see Warnings and Precautions (5.2)]. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19- directed genetically modified autologous T cell immunotherapies, including KYMRIAH [see Warnings and Precautions (5.8)]. WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGICAL TOXICITIES, and SECONDARY HEMATOLOGICAL MALIGNANCIES See full prescribing information for complete boxed warning. Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH. Do not administer KYMRIAH to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids. ( 2.2 , 2.3 , 5.1 ) Neurological toxicities, including severe or life-threatening reactions, occurred following treatment with KYMRIAH, including concurrently with CRS. Monitor for neurological events after treatment with KYMRIAH. Provide supportive care and/or corticosteroids as needed. ( 5.2 ) T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19- directed genetically modified autologous T cell immunotherapies, including KYMRIAH. ( 5.8 )
Description
11 DESCRIPTION KYMRIAH (tisagenlecleucel) is a CD19-directed genetically modified autologous T cell immunotherapy comprised of autologous T cells that are genetically modified using a lentiviral vector to encode an anti-CD19 chimeric antigen receptor (CAR). The CAR is comprised of a murine single-chain antibody fragment (scFv) specific for CD19, followed by a CD8 hinge and transmembrane region that is fused to the intracellular signaling domains for 4-1BB (CD137) and CD3 zeta. KYMRIAH is prepared from the patient’s peripheral blood mononuclear cells, which are obtained via a standard leukapheresis procedure. The mononuclear cells are enriched for T cells, then transduced with the lentiviral vector containing the anti-CD19 CAR transgene and activated with anti-CD3/CD28 antibody coated beads. The transduced T cells are expanded in cell culture, washed, and formulated into a suspension, which then is cryopreserved. The product must pass a sterility test before release for shipping as a frozen suspension in a patient-specific infusion bag(s). The product is thawed prior to administration [see Dosage and Administration (2.2), How Supplied/Storage and Handling (16)] . The thawed product is a colorless to slightly yellow suspension of cells. In addition to T cells, other cell populations, including monocytes, NK cells, and B cells, may be present. The formulation contains 31.25% (v/v) of Plasma-Lyte A, 31.25% (v/v) of 5% Dextrose/0.45% sodium chloride, 10% Dextran 40 (LMD)/5% Dextrose, 20% (v/v) of 25% Human Serum Albumin (HSA), and 7.5% (v/v) dimethyl sulfoxide (DMSO). Pediatric and Young Adult r/r B-cell ALL: A single dose of KYMRIAH may contain up to 2.5 x 10 8 CAR-positive viable T cells provided in one to three patient-specific infusion bag(s). Based on the patient’s weight reported at the time of leukapheresis, one of two possible dose ranges will be prepared for the patient: For patients 50 kg or less: 0.2 to 5.0 x 10 6 CAR-positive viable T cells per kg body...
What Is Tisagenlecleucel Used For?
1 INDICATIONS AND USAGE KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of: Patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. ( 1.1 ) Adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Limitations of Use : KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma. ( 1.2 ) Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). ( 1.3 ) 1.1 Pediatric and Young Adult Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia KYMRIAH is indicated for treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. 1.2 Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma KYMRIAH is indicated for treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Limitation of Use: KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma. 1.3 Adult Relapsed or Refractory Follicular Lymphoma KYMRIAH is indicated for treatment of adult patients with relapsed or refractory (r/r) follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response [see Clinical Studies (14.3)] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
Dosage and Administration
2 DOSAGE AND ADMINISTRATION For autologous use only. For intravenous use only. Administer a lymphodepleting regimen if needed before infusion of KYMRIAH. ( 2.2) Do NOT use a leukodepleting filter. ( 2.2 ) Verify the patient’s identity prior to infusion. ( 2.2 ) Premedicate with acetaminophen and an H1-antihistamine. ( 2.2 ) Confirm availability of tocilizumab prior to infusion. ( 2.2 , 5.1 ) Dosing of KYMRIAH is based on the number of chimeric antigen receptor (CAR)-positive viable T cells. Pediatric and Young Adult B-cell ALL (up to 25 years of age)
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS Pediatric and Young Adult B-cell ALL (up to 25 years of age): The most common adverse reactions (incidence greater than 20%) are CRS, infections-pathogen unspecified, hypogammaglobulinemia, fever, decreased appetite, viral infectious disorders, headache, febrile neutropenia, hemorrhage, musculoskeletal pain, vomiting, encephalopathy, diarrhea, hypotension, cough, nausea, bacterial infectious disorders, pain, hypoxia, tachycardia, edema, fatigue, and acute kidney injury. ( 6.1 ) Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma: The most common adverse reactions (incidence greater than 20%) are CRS, infections-pathogen unspecified, fever, diarrhea, nausea, fatigue, hypotension, edema, hemorrhage, dyspnea, and headache. ( 6.1 ) Adult Relapsed or Refractory Follicular Lymphoma: The most common adverse reactions (incidence greater than 20%) are CRS, infections-pathogens unspecified, fatigue, musculoskeletal pain, headache, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described in the WARNINGS AND PRECAUTIONS and in this section reflect exposure to KYMRIAH in three non-randomized, single-arm studies in which 79 pediatric and young adult patients with relapsed/refractory (r/r) B-cell ALL (Study 1: CCTL019B2202), 115 adults with r/r diffuse large B-cell lymphoma (Study 2: CCTL019C2201), and 97 adults with r/r follicular lymphoma (Study 3: CCTL019E2202) received a single dose of CAR-positive viable T cells. Pediatric and Young Adult r/r B-cell Acute Lymphoblastic Leukemia (ALL) (up to 25 years of age) Based on a recommended dose which was weight-based, all 79 patients in the Study 1 received a single intravenous dose of KYMRIAH [see Clinical Studies (14.1)] . The most common adverse reactions (> 20%) were CRS (77%), infections-pathogen unspecified (57%), hypogammaglobulinemia (53%), fever (42%), decreased appetite (38%), viral infectious disorders (38%), headache (35%), febrile neutropenia (34%), hemorrhage (32%), musculoskeletal pain (32%), vomiting (32%), encephalopathy (30%), bacterial infectious disorders (29%), diarrhea (29%), hypotension (29%), cough (27%), nausea (27%), pain (25%), hypoxia (25%), tachycardia (24%), edema (23%), fatigue (23%), and acute kidney injury (22%). The adverse reactions with greater than or equal to 10% incidence for any Grade are summarized in Table 3. Table 3. Adverse Reactions in ≥ 10% of Pediatric and Young Adults Patients with r/r B-cell ALL in Study 1 (N = 79) a Includes multiple related composite terms. b Encephalopathy includes encephalopathy, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, somnolence, memory impairment, and automatism. Encephalopathy is a dominant feature of immune effector cell-associated neurotoxicity syndrome (ICANS), along with other symptoms. c Dyspnea includes acute respiratory failure, dyspnea, respiratory distress, and respiratory failure. Adverse reaction All Grades (%) Grades 3 or higher (%) Blood and lymphatic system disorders Febrile neutropenia 34 34 Cardiac disorders Tachycardia a 24 4 Gastrointestinal disorders Vomiting 32 1 Diarrhea 29 1 Nausea 27 3 Abdominal pain a 18 3 Constipation 18 0 General disorders and administration site conditions Fever 42 13 Pain a 25 3 Fatigue a 23 0 Edema a 23 8 Immune system disorders Cytokine release syndrome 77 48 Hypogammaglobulinemia a 53 13 Infections and infestations Infections-pathogen unspecified 57 27 Viral infectious disorders 37 22 Bacterial infectious disorders 29 16 Fungal...
Drug Interactions
7 DRUG INTERACTIONS HIV and the lentivirus used to make KYMRIAH have limited, short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests (NATs) may yield false-positive results in patients who have received KYMRIAH.
Contraindications
4 CONTRAINDICATIONS None. None. ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary There are no available data with KYMRIAH use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with KYMRIAH to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known if KYMRIAH has the potential to be transferred to the fetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia. Therefore, KYMRIAH is not recommended for women who are pregnant, and pregnancy after KYMRIAH administration should be discussed with the treating physician. Report pregnancies to Novartis Pharmaceuticals Corporation at 1-888-669-6682. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING KYMRIAH is supplied as a frozen suspension of genetically modified autologous T cells in an infusion bag(s) labeled for the specific recipient. KYMRIAH is shipped directly to the cell lab associated with the infusion center in a liquid nitrogen Dewar. Product and patient-specific labels are located inside the Dewar. Ped ALL: NDC 0078-0846-19 DLBCL and FL: NDC 0078-0958-19 Confirm patient identity upon receipt. Store infusion bag(s) in a temperature-monitored system less than or equal to minus 120°C, e.g., in the vapor phase of liquid nitrogen. Use closed, break-proof, leak-proof containers when transporting infusion bags within the facility. Thaw KYMRIAH prior to infusion [see Dosage and Administration (2)] .
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.