BREYANZI ® ( lisocabtagene maraleucel ) suspension for intravenous infusion
Brief Summary of Prescribing Information . For complete prescribing information consult official package insert .
WARNING : CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES
• Cytokine Release Syndrome ( CRS ), including fatal or life-threatening reactions , occurred in patients receiving BREYANZI ( lisocabtagene maraleucel ). Do not administer BREYANZI to patients with active infection or inflammatory disorders . Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids [ see Dosage and Administration and Warnings and Precautions ].
• Neurologic toxicities , including fatal or life-threatening reactions , occurred in patients receiving BREYANZI , including concurrently with CRS , after CRS resolution , or in the absence of CRS . Monitor for neurologic events after treatment with BREYANZI . Provide supportive care and / or corticosteroids as needed [ see Dosage and Administration and Warnings and Precautions ].
• BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy ( REMS ) called the BREYANZI REMS [ see Warnings and Precautions ].
INDICATIONS AND USAGE
BREYANZI is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy , including diffuse large B-cell lymphoma ( DLBCL ) not otherwise specified ( including DLBCL arising from indolent lymphoma ), high-grade B-cell lymphoma , primary mediastinal large B-cell lymphoma , and follicular lymphoma grade 3B .
Limitations of Use : BREYANZI is not indicated for the treatment of patients with primary central nervous system ( CNS ) lymphoma [ see Clinical Studies ( 14 ) in full Prescribing Information ].
DOSAGE AND ADMINISTRATION Management of Severe Adverse Reactions Cytokine Release Syndrome
Identify cytokine release syndrome ( CRS ) based on clinical presentation [ see Warnings and Precautions ]. Evaluate for and treat other causes of fever , hypoxia , and hypotension . If CRS is suspected , manage according to the recommendations in Table 1 . Patients who experience Grade 2 or higher CRS ( e . g ., hypotension not responsive to fluids , or hypoxia requiring supplemental oxygenation ) should be monitored with continuous cardiac telemetry and pulse oximetry . For patients experiencing severe CRS , consider performing an echocardiogram to assess cardiac function . For severe or life-threatening CRS , consider intensive-care supportive therapy .
If concurrent neurologic toxicity is suspected during CRS , administer :
• Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades in Tables 1 and 2
• Tocilizumab according to the CRS grade in Table 1
• Antiseizure medication according to the neurologic toxicity in Table 2
Table 1 :
CRS Grading and Management Guidance CRS Grade a Tocilizumab Corticosteroids b
Grade 1 Fever
Grade 2
Symptoms require and respond to moderate intervention .
Oxygen requirement less than 40 % FiO2 , or hypotension responsive to fluids or low dose of one vasopressor , or Grade 2 organ toxicity .
Grade 3
Symptoms require and respond to aggressive intervention .
Oxygen requirement greater than or equal to 40 % FiO2 , or hypotension requiring high-dose or multiple vasopressors , or Grade 3 organ toxicity , or Grade 4 transaminitis .
Grade 4 Life-threatening symptoms
Requirements for ventilator support or continuous venovenous hemodialysis ( CVVHD ) or Grade 4 organ toxicity ( excluding transaminitis ).
If less than 72 hours after infusion , consider tocilizumab 8 mg / kg IV over 1 hour ( not to exceed 800 mg ).
If 72 hours or more after infusion , treat symptomatically .
Administer tocilizumab 8 mg / kg IV over 1 hour ( not to exceed 800 mg ).
Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids or increasing supplemental oxygen .
Limit to a maximum of 3 doses in a 24-hour period ; maximum total of 4 doses .
If less than 72 hours after infusion , consider dexamethasone 10 mg IV every 24 hours .
If 72 hours or more after infusion , treat symptomatically .
If less than 72 hours after infusion , administer dexamethasone 10 mg IV every 12-24 hours .
If 72 hours or more after infusion , consider dexamethasone 10 mg IV every 12-24 hours .
If no improvement within 24 hours or rapid progression , repeat tocilizumab and escalate dose and frequency of dexamethasone ( 10-20 mg IV every 6 to 12 hours ).
If no improvement or continued rapid progression , maximize dexamethasone , switch to high-dose methylprednisolone 2 mg / kg if needed . After 2 doses of tocilizumab , consider alternative immunosuppressants . Do not exceed 3 doses tocilizumab in 24 hours , or 4 doses in total .
Per Grade 2 .
Administer dexamethasone 10 mg IV every 12 hours .
If no improvement within 24 hours or rapid progression of CRS , repeat tocilizumab and escalate dose and frequency of dexamethasone ( 10-20 mg IV every 6 to 12 hours ).
If no improvement or continued rapid progression , maximize dexamethasone , switch to high-dose methylprednisolone 2 mg / kg if needed . After 2 doses of tocilizumab , consider alternative immunosuppressants . Do not exceed 3 doses tocilizumab in 24 hours , or 4 doses in total .
Per Grade 2 .
Administer dexamethasone 20 mg IV every 6 hours .
If no improvement within 24 hours or rapid progression of CRS , escalate tocilizumab and corticosteroid use . If no improvement or continued rapid progression , maximize dexamethasone , switch to high-dose methylprednisolone 2 mg / kg if needed . After 2 doses of tocilizumab , consider alternative immunosuppressants . Do not exceed 3 doses tocilizumab in 24 hours , or 4 doses in total .
a Lee criteria for grading CRS ( Lee et al , 2014 ). b If corticosteroids are initiated , continue corticosteroids for at least 3 doses or until complete resolution of symptoms , and consider corticosteroid taper .
Neurologic Toxicity
Monitor patients for signs and symptoms of neurologic toxicities ( Table 2 ). Rule out other causes of neurologic symptoms . Provide intensive care supportive therapy for severe or life-threatening neurologic toxicities . If neurologic toxicity is suspected , manage according to the recommendations in Table 2 .
If concurrent CRS is suspected during neurologic toxicity , administer :
• Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades in Tables 1 and 2
• Tocilizumab according to the CRS grade in Table 1
• Antiseizure medication according to the neurologic toxicity in Table 2
Table 2 : NT Grade a
Neurologic Toxicity ( NT ) Grading and Management Guidance Corticosteroids and Antiseizure Medication
Grade 1 Start non-sedating , antiseizure medicines ( e . g ., levetiracetam ) for seizure prophylaxis . If 72 hours or more after infusion , observe .
If less than 72 hours after infusion , consider dexamethasone 10 mg IV every 12 to 24 hours for 2 to 3 days .
Grade 2 Start non-sedating , antiseizure medicines ( e . g ., levetiracetam ) for seizure prophylaxis .
Dexamethasone 10 mg IV every 12 hours for 2-3 days , or longer for persistent symptoms . Consider taper for a total steroid exposure of greater than 3 days .
If no improvement after 24 hours or worsening of neurologic toxicity , increase the dose and / or frequency of dexamethasone up to a maximum of 20 mg IV every 6 hours .
If no improvement after another 24 hours , rapidly progressing symptoms , or life-threatening complications arise , give methylprednisolone ( 2 mg / kg loading dose , followed by 2 mg / kg divided 4 times a day ; taper within 7 days ).
Grade 3 Start non-sedating , antiseizure medicines ( e . g ., levetiracetam ) for seizure prophylaxis .
Dexamethasone 10 to 20 mg IV every 8 to 12 hours . Steroids are not recommended for isolated Grade 3 headaches .
If no improvement after 24 hours or worsening of neurologic toxicity , escalate to methylprednisolone ( dose and frequency as per Grade 2 ).
If cerebral edema is suspected , consider hyperventilation and hyperosmolar therapy . Give high-dose methylprednisolone ( 1-2 g , repeat every 24 hours if needed ; taper as clinically indicated ) and cyclophosphamide 1.5 g / m 2 .
Grade 4 Start non-sedating , antiseizure medicines ( e . g ., levetiracetam ) for seizure prophylaxis . Dexamethasone 20 mg IV every 6 hours .
If no improvement after 24 hours or worsening of neurologic toxicity , escalate to methylprednisolone ( dose and frequency as per Grade 2 ).
If cerebral edema is suspected , consider hyperventilation and hyperosmolar therapy . Give high-dose methylprednisolone ( 1-2 g , repeat every 24 hours if needed ; taper as clinically indicated ), and cyclophosphamide 1.5 g / m 2 .
a NCI CTCAE criteria for grading neurologic toxicities version . 4.03 .
CONTRAINDICATIONS None .
WARNINGS AND PRECAUTIONS
Cytokine Release Syndrome
Cytokine Release Syndrome ( CRS ), including fatal or life-threatening reactions , occurred following treatment with BREYANZI ( lisocabtagene maraleucel ). CRS occurred in 46 % ( 122 / 268 ) of patients receiving BREYANZI , including ≥ Grade 3 ( Lee grading system 1 ) CRS in 4 % ( 11 / 268 ) of patients . One patient had fatal CRS and 2 had ongoing CRS at time of death . The median time to onset was 5 days ( range : 1 to 15 days ). CRS resolved in 119 of 122 patients ( 98 %) with a median duration of 5 days ( range : 1 to 17 days ). Median duration of CRS was 5 days ( range 1 to 30 days ) in all patients , including those who died or had CRS ongoing at time of death .
Among patients with CRS , the most common manifestations of CRS include fever ( 93 %), hypotension ( 49 %), tachycardia ( 39 %), chills ( 28 %), and hypoxia ( 21 %) [ see Adverse Reactions ]. Serious events that may be associated with CRS include cardiac arrhythmias ( including atrial fibrillation and ventricular tachycardia ), cardiac arrest , cardiac failure , diffuse alveolar damage , renal insufficiency , capillary leak syndrome , hypotension , hypoxia , and hemophagocytic lymphohistiocytosis / macrophage activation syndrome ( HLH / MAS ) [ see Adverse Reactions ].
Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI .
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 .
Monitor patients daily at a certified healthcare facility during the first week following infusion for signs and symptoms of CRS . Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion . Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [ see Patient Counseling Information ]. At the first sign of CRS , institute treatment with supportive care , tocilizumab or tocilizumab and corticosteroids as indicated [ see Dosage and Administration ].
Neurologic Toxicities
Neurologic toxicities that were fatal or life-threatening , occurred following treatment with BREYANZI . CAR T cellassociated 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 %), ataxia ( 6 %), and dizziness ( 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 .
Monitor patients daily at a certified healthcare facility during the first week following infusion for signs and symptoms of neurologic toxicities . Monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after