ASH Clinical News FINAL_ACN_3.14_FULL_ISSUE_DIGITAL | Page 14

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR YESCARTA™ ( axicabtagene ciloleucel ) suspension for intravenous infusion
SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION
WARNING : CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES
• Cytokine Release Syndrome ( CRS ), including fatal or life-threatening reactions , occurred in patients receiving YESCARTA . Do not administer YESCARTA 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 )].
• Neurologic toxicities , including fatal or life-threatening reactions , occurred in patients receiving YESCARTA , including concurrently with CRS or after CRS resolution . Monitor for neurologic toxicities after treatment with YESCARTA . Provide supportive care and / or corticosteroids , as needed [ see Dosage and Administration ( 2.2 , 2.3 ), Warnings and Precautions ( 5.2 )].
• YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy ( REMS ) called the YESCARTA REMS [ see Warnings and Precautions ( 5.3 )].
1 INDICATIONS AND USAGE
YESCARTA 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 , primary mediastinal large B-cell lymphoma , high grade B-cell lymphoma , and DLBCL arising from follicular lymphoma .
Limitation of Use : YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma .
2 DOSAGE AND ADMINISTRATION
2.2 Administration : YESCARTA is for autologous use only . The patient ’ s identity must match the patient identifiers on the YESCARTA cassette and infusion bag . Do not infuse YESCARTA if the information on the patient-specific label does not match the intended patient [ see Dosage and Administration ( 2.2.3 )].
Preparing Patient for YESCARTA Infusion : Confirm availability of YESCARTA prior to starting the lymphodepleting regimen . Pre-treatment : Administer a lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg / m 2 intravenously and fludarabine 30 mg / m 2 intravenously on the fifth , fourth , and third day before infusion of YESCARTA . Premedication : Administer acetaminophen 650 mg PO and diphenhydramine 12.5 mg intravenously or PO approximately 1 hour before YESCARTA infusion . Avoid prophylactic use of systemic corticosteroids , as it may interfere with the activity of YESCARTA .
Preparation of YESCARTA for Infusion : Coordinate the timing of YESCARTA thaw and infusion . Confirm the infusion time in advance , and adjust the start time of YESCARTA thaw such that it will be available for infusion when the patient is ready . Confirm patient identity : Prior to YESCARTA preparation , match the patient ’ s identity with the patient identifiers on the YESCARTA cassette . Do not remove the YESCARTA product bag from the cassette if the information on the patient-specific label does not match the intended patient . Once patient identification is confirmed , remove the YESCARTA product bag from the cassette and check that the patient information on the cassette label matches the bag label . Inspect the product bag for any breaches of container integrity such as breaks or cracks before thawing . If the bag is compromised , follow the local guidelines ( or call Kite at 1-844-454-KITE ). Place the infusion bag inside a second sterile bag per local guidelines . Thaw YESCARTA at approximately 37 ° C using either a water bath or dry thaw method until there is no visible ice in the infusion bag . Gently mix the contents of the bag to disperse clumps of cellular material . If visible cell clumps remain continue to gently mix the contents of the bag . Small clumps of cellular material should disperse with gentle manual mixing . Do not wash , spin down , and / or re-suspend YESCARTA in new media prior to infusion . Once thawed , YESCARTA may be stored at room temperature ( 20 ° C to 25 ° C ) for up to 3 hours .
Administration : For autologous use only . Ensure that tocilizumab and emergency equipment are available prior to infusion and during the recovery period . Do NOT use a leukodepleting filter . Central venous access is recommended for the infusion of YESCARTA . Confirm the patient ’ s identity matches the patient identifiers on the YESCARTA product bag . Prime the tubing with normal saline prior to infusion . Infuse the entire contents of the YESCARTA bag within 30 minutes by either gravity or a peristaltic pump . YESCARTA is stable at room temperature for up to 3 hours after thaw . Gently agitate the product bag during YESCARTA infusion to prevent cell clumping . After the entire content of the product bag is infused , rinse the tubing with normal saline at the same infusion rate to ensure all product is delivered . YESCARTA contains human blood cells that are genetically modified with replication incompetent retroviral vector . Follow universal precautions and local biosafety guidelines for handling and disposal to avoid potential transmission of infectious diseases .
Monitoring : Administer YESCARTA at a certified healthcare facility . Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS and neurologic toxicities . Instruct patients to remain within proximity of the certified healthcare facility for at least 4 weeks following infusion .
2.3 Management of Severe Adverse Reactions
Cytokine Release Syndrome ( CRS ): Identify CRS based on clinical presentation [ see Warnings and Precautions ( 5.1 )]. 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 .
Table 1 . CRS Grading and Management Guidance CRS Grade ( a ) Tocilizumab Corticosteroids Grade 1
N / A N / A
Symptoms require symptomatic treatment only ( e . g ., fever , nausea , fatigue , headache , myalgia , malaise ).
Grade 2
Symptoms require and respond to moderate intervention .
Oxygen requirement less than 40 % FiO 2 or hypotension responsive to fluids or low-dose of one vasopressor or
Grade 2 organ toxicity ( b ).
Administer tocilizumab ( c ) 8 mg / kg intravenously 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 .
Manage per Grade 3 if no improvement within 24 hours after starting tocilizumab .
Table 1 . CRS Grading and Management Guidance ( continued )
CRS Grade ( a )
Tocilizumab
Corticosteroids
Grade 3
Per Grade 2
Symptoms require and respond to aggressive intervention .
Oxygen requirement greater than or equal to 40 % FiO 2 or hypotension requiring high-dose or multiple vasopressors or
Grade 3 organ toxicity or Grade 4 transaminitis .
Grade 4
Per Grade 2
Life-threatening symptoms .
Requirements for ventilator support , continuous veno-venous hemodialysis ( CVVHD ) or
Grade 4 organ toxicity ( excluding transaminitis ).
Administer methylprednisolone 1 mg / kg intravenously twice daily or equivalent dexamethasone ( e . g ., 10 mg intravenously every 6 hours ).
Continue corticosteroids use until the event is Grade 1 or less , then taper over 3 days .
Administer methylprednisolone 1000 mg intravenously per day for 3 days ; if improves , then manage as above .
( a ) Lee et al 2014 , ( b ) Refer to Table 2 for management of neurologic toxicity , ( c ) Refer to tocilizumab Prescribing Information for details
Neurologic Toxicity : Monitor patients for signs and symptoms of neurologic toxicities ( Table 2 ). Rule out other causes of neurologic symptoms . Patients who experience Grade 2 or higher neurologic toxicities should be monitored with continuous cardiac telemetry and pulse oximetry . Provide intensive care supportive therapy for severe or life threatening neurologic toxicities . Consider non-sedating , anti-seizure medicines ( e . g ., levetiracetam ) for seizure prophylaxis for any Grade 2 or higher neurologic toxicities .
Table 2 . Neurologic Toxicity Grading and Management Guidance Grading
Concurrent CRS
Assessment
Grade 2 Administer tocilizumab per Table 1 for management of Grade 2 CRS .
If no improvement within 24 hours after starting tocilizumab , administer dexamethasone 10 mg intravenously every 6 hours if not already taking other corticosteroids . Continue dexamethasone use until the event is Grade 1 or less , then taper over 3 days .
Grade 3
Grade 4
No Concurrent CRS
Administer dexamethasone 10 mg intravenously every 6 hours .
Continue dexamethasone use until the event is Grade 1 or less , then taper over 3 days .
Consider non-sedating , anti-seizure medicines ( e . g ., levetiracetam ) for seizure prophylaxis .
Administer tocilizumab per Table 1 for management of Grade 2 CRS .
In addition , administer dexamethasone 10 mg intravenously with the first dose of tocilizumab and repeat dose every 6 hours . Continue dexamethasone use until the event is Grade 1 or less , then taper over 3 days .
Administer dexamethasone 10 mg intravenously every 6 hours .
Continue dexamethasone use until the event is Grade 1 or less , then taper over 3 days .
Consider non-sedating , anti-seizure medicines ( e . g ., levetiracetam ) for seizure prophylaxis .
Administer tocilizumab per Table 1 for management of Grade 2 CRS .
Administer methylprednisolone 1000 mg intravenously per day with first dose of tocilizumab and continue methylprednisolone 1000 mg intravenously per day for 2 more days ; if improves , then manage as above .
Administer methylprednisolone 1000 mg intravenously per day for 3 days ; if improves , then manage as above .
Consider non-sedating , anti-seizure medicines ( e . g ., levetiracetam ) for seizure prophylaxis .
4 CONTRAINDICATIONS : None . 5 WARNINGS AND PRECAUTIONS
5.1 Cytokine Release Syndrome ( CRS ): CRS , including fatal or life-threatening reactions , occurred following treatment with YESCARTA . In Study 1 , CRS occurred in 94 % ( 101 / 108 ) of patients receiving YESCARTA , including ≥ Grade 3 ( Lee grading system ) CRS in 13 % ( 14 / 108 ) of patients . Among patients who died after receiving YESCARTA , four had ongoing CRS events at the time of death . The median time to onset was 2 days ( range : 1 to 12 days ) and the median duration of CRS was 7 days ( range : 2 to 58 days ). Key manifestations of CRS include fever ( 78 %), hypotension ( 41 %), tachycardia ( 28 %), hypoxia ( 22 %), and chills ( 20 %). Serious events that may be associated with CRS include cardiac arrhythmias ( including atrial fibrillation and ventricular tachycardia ), cardiac arrest , cardiac failure , renal insufficiency , capillary leak syndrome , hypotension , hypoxia , and hemophagocytic lymphohistiocytosis / macrophage activation syndrome ( HLH / MAS ) [ see Adverse Reactions ( 6 )]. Ensure that 2 doses of tocilizumab are available prior to infusion of YESCARTA . Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS . Monitor patients for signs or symptoms of CRS for 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 ( 17 )]. At the first sign of CRS , institute treatment with supportive care , tocilizumab or tocilizumab and corticosteroids as indicated [ See Dosage and Administration ( 2.3 )].
5.2 Neurologic Toxicities : Neurologic toxicities , that were fatal or life-threatening , occurred following treatment with YESCARTA . Neurologic toxicities occurred in 87 % of patients . Ninety-eight percent of all neurologic toxicities occurred within the first 8 weeks of YESCARTA infusion , with a median time to onset of 4 days ( range : 1 to 43 days ). The median duration of neurologic toxicities was 17 days . Grade 3 or higher neurologic toxicities occurred in 31 % of patients . The most common neurologic toxicities included encephalopathy ( 57 %), headache ( 44 %), tremor ( 31 %), dizziness ( 21 %), aphasia ( 18 %), delirium ( 17 %), insomnia ( 9 %) and anxiety ( 9 %). Prolonged encephalopathy lasting up to 173 days was noted . Serious events including leukoencephalopathy and seizures occurred with YESCARTA . Fatal and serious cases of cerebral edema have occurred in patients treated with YESCARTA . Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities . Monitor