Important Safety Information ( cont ’ d )
Cytokine Release Syndrome ( cont ’ d ):
Sixty-one of 268 ( 23 %) patients received tocilizumab and / or a corticosteroid for CRS after infusion of BREYANZI . Twenty-seven ( 10 %) patients received tocilizumab only , 25 ( 9 %) received tocilizumab and a corticosteroid , and 9 ( 3 %) received corticosteroids only .
Neurologic Toxicities : Neurologic toxicities that were fatal or life-threatening , occurred following treatment with BREYANZI . CAR T cell-associated neurologic toxicities occurred in 35 % ( 95 / 268 ) of patients receiving BREYANZI , including ≥ Grade 3 in 12 % ( 31 / 268 ) of patients . Three patients had fatal neurologic toxicity and 7 had ongoing neurologic toxicity at time of death . The median time to onset of the first event was 8 days ( range : 1 to 46 days ). The onset of all neurologic events occurred within the first 8 weeks following BREYANZI infusion . Neurologic toxicities resolved in 81 of 95 patients ( 85 %) with a median duration of 12 days ( range : 1 to 87 days ). Three of four patients with ongoing neurologic toxicity at data cutoff had tremor and one subject had encephalopathy . Median duration of neurologic toxicity was 15 days ( range : 1 to 785 days ) in all patients , including those with ongoing neurologic events at the time of death or at data cutoff .
Seventy-eight ( 78 ) of 95 ( 82 %) patients with neurologic toxicity experienced CRS . Neurologic toxicity overlapped with CRS in 57 patients . The onset of neurologic toxicity was after onset of CRS in 30 patients , before CRS onset in 13 patients , same day as CRS onset in 7 patients , and same day as CRS resolution in 7 patients . Neurologic toxicity resolved in three patients before the onset of CRS . Eighteen patients experienced neurologic toxicity after resolution of CRS .
The most common neurologic toxicities included encephalopathy ( 24 %), tremor ( 14 %), aphasia ( 9 %), delirium ( 7 %), headache ( 7 %), dizziness ( 6 %), and ataxia ( 6 %). Serious events including cerebral edema and seizures occurred with BREYANZI . Fatal and serious cases of leukoencephalopathy , some attributable to fludarabine , have occurred in patients treated with BREYANZI .
CRS and Neurologic Toxicities Monitoring : Monitor patients daily at a certified healthcare facility during the first week following infusion , for signs and symptoms of CRS and neurologic toxicities . Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion ; evaluate and treat promptly . Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time . At the first sign of CRS , institute treatment with supportive care , tocilizumab or tocilizumab and corticosteroids as indicated .
BREYANZI REMS : Because of the risk of CRS and neurologic toxicities , BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy ( REMS ) called the BREYANZI REMS . The required components of the BREYANZI REMS are :
• Healthcare facilities that dispense and administer BREYANZI must be enrolled and comply with the REMS requirements .
• Certified healthcare facilities must have on-site , immediate access to tocilizumab .
• Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after BREYANZI infusion , if needed for treatment of CRS .
• Certified healthcare facilities must ensure that healthcare providers who prescribe , dispense , or administer BREYANZI are trained on the management of CRS and neurologic toxicities .
Further information is available at www . BreyanziREMS . com , or contact Bristol-Myers Squibb at 1-888-423-5436 .
Hypersensitivity Reactions : Allergic reactions may occur with the infusion of BREYANZI . Serious hypersensitivity reactions , including anaphylaxis , may be due to dimethyl sulfoxide ( DMSO ).
Serious Infections : Severe infections , including life-threatening or fatal infections , have occurred in patients after BREYANZI infusion . Infections ( all grades ) occurred in 45 % ( 121 / 268 ) of patients . Grade 3 or higher infections occurred in 19 % of patients . Grade 3 or higher infections with an unspecified pathogen occurred in 16 % of patients , bacterial infections occurred in 5 %, and viral and fungal infections occurred in 1.5 % and 0.4 % of patients , respectively . Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately . Administer prophylactic antimicrobials according to standard institutional guidelines .
Febrile neutropenia has been observed in 9 % ( 24 / 268 ) of patients after BREYANZI 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 .
Avoid administration of BREYANZI in patients with clinically significant active systemic infections .
Viral reactivation : 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 . Ten of the 11 patients in the TRANSCEND study with a prior history of HBV were treated with concurrent antiviral suppressive therapy to prevent HBV reactivation during and after treatment with BREYANZI . Perform screening for HBV , HCV , and HIV in accordance with clinical guidelines before collection of cells for manufacturing .
Prolonged Cytopenias : Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion . Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 31 % ( 84 / 268 ) of patients , and included thrombocytopenia ( 26 %), neutropenia ( 14 %), and anemia ( 3 %). Monitor complete blood counts prior to and after BREYANZI administration .
Hypogammaglobulinemia : B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with BREYANZI . The adverse event of hypogammaglobulinemia was reported as an adverse reaction in 14 % ( 37 / 268 ) of patients ; laboratory IgG levels fell below 500 mg / dL after infusion in 21 % ( 56 / 268 ) of patients . Hypogammaglobulinemia , either as an adverse reaction or laboratory IgG level below 500 mg / dL after infusion , was reported in 32 % ( 85 / 268 ) of patients . Monitor immunoglobulin levels after treatment with BREYANZI and manage using infection precautions , antibiotic prophylaxis , and immunoglobulin replacement as clinically indicated .
Live vaccines : The safety of immunization with live viral vaccines during or following BREYANZI 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 BREYANZI treatment , and until immune recovery following treatment with BREYANZI .
Secondary Malignancies : Patients treated with BREYANZI may develop secondary malignancies . Monitor lifelong for secondary malignancies . In the event that a secondary malignancy occurs , contact Bristol-Myers Squibb at 1-888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing .
Effects on Ability to Drive and Use Machines : Due to the potential for neurologic events , including altered mental status or seizures , patients receiving BREYANZI are at risk for altered or decreased consciousness or impaired coordination in the 8 weeks following BREYANZI administration . 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 : Serious adverse reactions occurred in 46 % of patients . The most common nonlaboratory , serious adverse reactions (> 2 %) were CRS , encephalopathy , sepsis , febrile neutropenia , aphasia , pneumonia , fever , hypotension , dizziness , and delirium . Fatal adverse reactions occurred in 4 % of patients .
The most common nonlaboratory adverse reactions of any grade ( ≥ 20 %) were fatigue , CRS , musculoskeletal pain , nausea , headache , encephalopathy , infections ( pathogen unspecified ), decreased appetite , diarrhea , hypotension , tachycardia , dizziness , cough , constipation , abdominal pain , vomiting , and edema .
Please see Brief Summary of full Prescribing Information , including Boxed WARNINGS on following pages .
References : 1 . Breyanzi [ prescribing information ]. Bothell , WA : Juno Therapeutics , Inc ., a Bristol Myers Squibb Company . 2021 . 2 . Janeway CA Jr , Travers P , Walport M , et al . lmmunobiology : The Immune System in Health and Disease . 5th edition . New York : Garland Science ; 2001 .
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