WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGICAL TOXICITIES
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.
Important Safety Information for KYMRIAH™ (tisagenlecleucel)
Warnings and Precautions
Cytokine Release Syndrome: CRS, including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. In Study 1, CRS occurred in 79% (54/68) of patients receiving KYMRIAH, including grade 3 or 4 (Penn grading system) CRS in 49% (33/68) of patients. The median time to onset of CRS was 3 days (range: 1-22 days). Of the 54 patients with CRS, 27 (50%) received tocilizumab; 7 (13%) patients received 2 doses of tocilizumab, 3 (6%) patients received 3 doses of tocilizumab and 14 (26%) patients received addition of corticosteroids (e.g. methylprednisolone). The median time to resolution of CRS was 8 days (range: 1-36 days).
Key manifestations of CRS may 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, uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes. Delay KYMRIAH infusion after lymphodepleting chemotherapy if patient has unresolved serious adverse reactions from preceding chemotherapies, active uncontrolled infection, active graft vs host disease, or worsening of leukemia burden.
Ensure tocilizumab is available on-site prior to KYMRIAH infusion. Monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur. At the first sign of CRS, immediately evaluate the patient for hospitalization and institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated.
Neurological Toxicities: Neurological toxicities, which may be severe or life-threatening, can occur following treatment with KYMRIAH. The majority of neurological toxicities occurred within 8 weeks following KYMRIAH infusion. In Study 1, neurological toxicities within 8 weeks after KYMRIAH infusion occurred in 65% of patients, including grade 3 or 4 neurological toxicities in 18% of patients, and 75% of events resolved within 12 days. The most common neurological toxicities were headache (37%), encephalopathy (34%), delirium (21%), anxiety (13%), and tremor (9%). Other manifestations of neurological toxicities included disturbances in consciousness, disorientation, confusion, agitation, seizures, mutism and aphasia. Monitor patients for neurological events and exclude other causes for symptoms. Provide supportive care as needed for KYMRIAH-associated neurological events.
KYMRIAH REMS to Mitigate CRS and Neurological Toxicities: Because of the risk of CRS and neurological toxicities, KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS. Further information is available at www.kymriah-rems.com or 1-844-4KYMRIAH (1-844-459-6742).
Hypersensitivity Reactions: Allergic reactions may occur with KYMRIAH. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide or dextran 40 in KYMRIAH.
Serious Infections: Serious infections, including life-threatening or fatal infections, occurred in patients after KYMRIAH infusion. In Study 1, infections (all grades) after KYMRIAH infusion occurred in 40 patients (59%), including 24 patients (35%) with grade 3 and 4 infections and 2 patients (3%) with fatal infections. Infections with an unknown pathogen occurred in 41% of patients, viral infections in 26%, bacterial infections in 19%, and fungal infections in 13%. Prior to KYMRIAH infusion, infection prophylaxis should follow local guidelines. Monitor patients for signs and symptoms of infection after treatment with KYMRIAH and treat appropriately. Febrile neutropenia (grade 3 or 4) was also observed in 37% of patients after KYMRIAH infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells. 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. Perform screening for HBV, HCV and HIV in accordance with clinical guidelines before cell collection for manufacturing.
Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and KYMRIAH infusion. Grades 3 and 4 cytopenias not resolved by Day 28 following KYMRIAH treatment included neutropenia (40%) and thrombocytopenia (27%) among 52 responding patients. At 56 days following KYMRIAH, 17% and 12% of responding patients had grades 3 and 4 neutropenia or thrombocytopenia respectively. Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly GM-CSF, are not recommended during the first 3 weeks after KYMRIAH infusion or until CRS has resolved.
Hypogammaglobulinemia: Hypogammaglobulinemia and agammaglobulinemia (IgG) can occur in patients with a complete remission after KYMRIAH infusion. In Study 1, 43% of patients had hypogammaglobulinemia. B-cell aplasia is an on-target effect of KYMRIAH and therefore a patient may experience hypogammaglobulinemia for as long as KYMRIAH persists. Monitor immunoglobulin levels after treatment with KYMRIAH and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement standard guidelines.
The safety of immunization with live viral vaccines during or following KYMRIAH treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of lymphodepleting chemotherapy, during KYMRIAH treatment, and until immune recovery following treatment with KYMRIAH.
Pregnant women who have received KYMRIAH may have hypogammaglobulinemia. Assess immunoglobulin levels in newborns of mothers treated with KYMRIAH.
Secondary Malignancies: Patients treated with KYMRIAH may develop secondary malignancies or recurrence of their leukemia. Monitor life-long for secondary malignancies. If a second malignancy occurs, call 1-844-4KYMRIAH (1-844-459-6742) to obtain instructions on patient samples to collect for testing.
Effects on Ability to Drive and Use Machines: Due to the potential for neurological events, patients receiving KYMRIAH are at risk for altered or decreased consciousness or coordination in the 8 weeks following infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities during this initial period.
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.
Pregnancy, Lactation, Females and Males of Reproductive Potential
There are no available data of KYMRIAH use in pregnant or lactating women. Therefore, KYMRIAH is not recommended for women who are pregnant or breastfeeding. Pregnancy after KYMRIAH administration should be discussed with the treating physician. Pregnancy status of females of reproductive potential should be verified with a pregnancy test prior to starting treatment with KYMRIAH. Report pregnancies to Novartis Pharmaceuticals Corporation at 1-888-669-6682.
The most common adverse reactions (incidence greater than 20%) are cytokine release syndrome, hypogammaglobulinemia, infections-pathogen unspecified, pyrexia, decreased appetite, headache, encephalopathy, bleeding, hypotension, tachycardia, nausea, diarrhea, vomiting, viral infection disorders, hypoxia, fatigue, acute kidney injury, and delirium.
Please see full Prescribing Information for KYMRIAH, including Boxed WARNING, and Medication Guide.