NEUROLOGIC TOXICITIES that were fatal or life-threatening occurred. Neurologic toxicities occurred in 81% (206/254) of all patients with NHL receiving Yescarta, including Grade ?3 in 26%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL, including Grade ?3 in 31%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including Grade ?3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days for patients with iNHL. 98% of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of Yescarta infusion. Neurologic toxicities occurred within the first 7 days of infusion for 89% of affected patients with LBCL and 74% of affected patients with iNHL. The most common neurologic toxicities (?10%) in all patients combined included encephalopathy (53%), headache (45%), tremor (31%), dizziness (20%), delirium (16%), aphasia (15%), and insomnia (11%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including leukoencephalopathy and seizures, as well as fatal and serious cases of cerebral edema, have occurred. In a subsequent cohort of LBCL patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) of these patients and 20% (8/41) had Grade 3 neurologic toxicities with no patients experiencing a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). The most common neurologic toxicities were consistent with the overall LBCL population treated with Yescarta. Following Yescarta infusion, monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.
REMS: Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program called the Yescarta and Tecartus REMS Program which requires that: Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after Yescarta infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer Yescarta are trained about the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).
HYPERSENSITIVITY REACTIONS: Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of Yescarta.
SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 47% (119/254) of all patients with NHL. Grade ?3 infections occurred in 19% of patients, Grade ?3 infections with an unspecified pathogen occurred in 15%, bacterial infections in 5%, viral infections in 2%, and fungal infections in 1%. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 40% of all patients with NHL 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. In immunosuppressed patients, including those who have received Yescarta, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed. 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. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.
PROLONGED CYTOPENIAS: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion. Grade ?3 cytopenias not resolved by Day 30 following Yescarta infusion occurred in 30% of all patients with NHL and included neutropenia (22%), thrombocytopenia (13%), and anemia (5%). Monitor blood counts after infusion.
HYPOGAMMAGLOBULINEMIA and B-cell aplasia can occur. Hypogammaglobulinemia occurred in 17% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following Yescarta treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Yescarta treatment, and until immune recovery following treatment.
SECONDARY MALIGNANCIES may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Yescarta infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.
ADVERSE REACTIONS: The most common adverse reactions (incidence ?20%) in patients with LBCL included CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections with pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias. The most common non-laboratory adverse reactions (incidence ?20%) in patients with iNHL included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with pathogen unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.
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Forward-Looking Statements
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the possibility of unfavorable results from ongoing and additional clinical trials involving Yescarta. These and other risks, uncertainties and other factors are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended
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