Safety

YES
Safety is a Priority

//Adverse Reactions1

In the ZUMA-1 (study design) pivotal trial, adverse reactions (ARs) were observed with YESCARTA (axicabtagene ciloleucel), including serious, fatal, or life-threatening ARs such as cytokine release syndrome (CRS) and neurologic toxicities. The median follow-up was 8.7 months.

//ZUMA-1 Adverse Reactions*1

SUMMARY OF ARs IN ≥10% OF PATIENTS

Preferred Terms ANY GRADE (%) GRADE ≥3 (%)
Cardiac Disorders
Tachycardia 57 2
Arrhythmia 23 7
Gastrointestinal disorders
Diarrhea 38 4
Nausea 34 0
Vomiting 26 1
Constipation 23 0
Abdominal pain 14 1
Dry mouth 11 0
General disorders and administration site conditions
Fever 86 16
Fatigue 46 3
Chills 40 0
Edema 19 1
Immune system disorders
Cytokine release syndrome 94 13
Hypogammaglobulinemia 15 0
Infections and infestations
Infections-pathogen unspecified 26 16
Viral infections 16 4
Bacterial infections 13 9
Investigations
Decreased appetite 44 2
Weight decreased 16 0
Dehydration 11 3
Musculoskeletal and connective tissue disorders
Motor dysfunction 19 1
Pain in extremity 17 2
Back pain 15 1
Muscle pain 14 1
Arthralgia 10 0
Nervous system disorders
Encephalopathy 57 29
Headache 45 1
Tremor 31 2
Dizziness 21 1
Aphasia 18 6
Psychiatric disorders
Delirium 17 6
renal and urinary disorders
Renal insufficiency 12 5
Respiratory, thoracic and mediastinal disorders
Hypoxia 32 11
Cough 30 0
Dyspnea 19 3
Pleural effusion 13 2
Vascular disorders
Hypotension 57 15
Hypertension 15 6
Thrombosis 10 1

The following events were also counted in the incidence of CRS: tachycardia, arrhythmia, fever, chills, hypoxia, renal insufficiency, and hypotension.

Other clinically important adverse reactions that occurred in less than 10% of patients treated with YESCARTA include the following:

  • Blood and lymphatic system disorders: coagulopathy (2%)
  • Cardiac disorders: cardiac failure (6%) and cardiac arrest (4%)
  • Immune system disorders: hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) (1%), hypersensitivity (1%)
  • Infections and infestations disorders: fungal infections (5%)
  • Nervous system disorders: ataxia (6%), seizure (4%), dyscalculia (2%), and myoclonus (2%)
  • Respiratory, thoracic and mediastinal disorders: pulmonary edema (9%)
  • Skin and subcutaneous tissue disorders: rash (9%)
  • Vascular disorders: capillary leak syndrome (3%)

* Data reflect results from the ZUMA-1 (study design) pivotal trial.

//Zuma-I Laboratory Abnormalities*1

GRADE 3/4 LABORATORY ABNORMALITIES IN ≥10% OF PATIENTS

GRADE 3/4 (%)
Lymphopenia 100
Leukopenia 96
Neutropenia 93
Anemia 66
Thrombocytopenia 58
Hypophosphatemia 50
Hyponatremia 19
Uric acid increased 13
Direct bilirubin increased 13
Hypokalemia 10
Alanine aminotransferase increased 10

* Data reflect results from the ZUMA-1 (study design) pivotal trial.

//Cytokine Release Syndrome (CRS)*1

13%
GRADE 3

94%
Overall

Overall Incidence

CRS of any grade occurred in 94% of patients, including Grade ≥3 in 13% of patients. The median time to onset was 2 days (range: 1-12 days) and the median duration of CRS was 7 days (range: 2-58 days).


Signs And Symptoms

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). Key manifestations of CRS include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%).


Patient Monitoring

Ensure that 2 doses of tocilizumab are available prior to infusion of YESCARTA. Monitor patients at least daily for 7 days at the authorized treatment center 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. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in the table below. Patients who experience Grade ≥2 CRS (eg, 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.

CRS Grading and Management Guidance

Grade 1

Symptoms require symptomatic treatment only (eg, fever, nausea, fatigue, headache, myalgia, malaise)

Tocilizumab

N/A

Corticosteroids

N/A

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.

Tocilizumab

Administer tocilizumab 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.

Corticosteroids

Manage per Grade 3 if no improvement within 24 hours after starting tocilizumab.

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.

Tocilizumab

Administer tocilizumab 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.

Corticosteroids

Administer methylprednisolone 1 mg/kg intravenously twice daily or equivalent dexamethasone (eg, 10 mg intravenously every 6 hours).

Continue corticosteroids use until the event is Grade 1 or less, then taper over 3 days.

Grade 4

Life-threatening symptoms.
Requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD) or
Grade 4 organ toxicity (excluding transaminitis).

Tocilizumab

Administer tocilizumab 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.

Corticosteroids

Administer methylprednisolone 1000 mg intravenously per day for 3 days; if improves, then manage as above.


* Data reflect results from the ZUMA-1 (study design) pivotal trial.

Grade ≥3 CRS was defined as severe, life-threatening, or fatal events.

//Neurologic Toxicities*1

31%
Grade 3

87%
Overall

Overall Incidence

Neurologic toxicities of any grade occurred in 87% of patients, including Grade ≥3 in 31% of patients. 98% of all neurologic toxicities occurred within the first 8 weeks of YESCARTA infusion, with a median time to onset of 4 days (range: 1-43 days). The median duration of neurologic toxicities was 17 days.


Signs and Symptoms

The most common neurologic toxicities included encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%), and anxiety (9%). Serious events including leukoencephalopathy and seizures occurred with YESCARTA. Fatal and serious cases of cerebral edema have occurred in patients treated with YESCARTA.


Patient Monitoring

Monitor patients at least daily for 7 days at the authorized treatment center following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly.

Monitor patients for signs and symptoms of neurologic toxicities (see table below). Rule out other causes of neurologic symptoms. Patients who experience Grade ≥2 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 nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis for any Grade ≥2 neurologic toxicities.

NEUROLOGIC TOXICITY GRADING AND MANAGEMENT GUIDANCE

Grade 2

Concurrent CRS

Administer tocilizumab per Grade 2 in the CRS Management table above.

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.

Consider nonsedating, antiseizure medications
(eg, levetiracetam) for seizure prophylaxis.

 

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 nonsedating, antiseizure medications
(eg, levetiracetam) for seizure prophylaxis.

Grade 3

Concurrent CRS

Administer tocilizumab per Grade 2 in the CRS Management table above.

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.

Consider nonsedating, antiseizure medications
(eg, levetiracetam) for seizure prophylaxis.

 

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 nonsedating, antiseizure medications
(eg, levetiracetam) for seizure prophylaxis

Grade 4

Concurrent CRS

Administer tocilizumab per Grade 2 in the CRS Management table above.

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.

Consider nonsedating, antiseizure medications
(eg, levetiracetam) for seizure prophylaxis.

 

No Concurrent CRS

Administer methylprednisolone 1000 mg intravenously per day for 3 days; if improves, then manage as above.

Consider nonsedating, antiseizure medications
(eg, levetiracetam) for seizure prophylaxis.


* Data reflect results from the ZUMA-1 (study design) pivotal trial.

Grade ≥3 neurologic toxicities were defined as severe, life-threatening, or fatal events.

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Available at
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//IMPORTANT SAFETY INFORMATION

BOXED 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.
  • 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.
  • YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA REMS.

Cytokine Release Syndrome (CRS): CRS occurred in 94% of patients, including 13% with ≥ Grade 3. Among patients who died after receiving YESCARTA, 4 had ongoing CRS at death. The median time to onset was 2 days (range: 1-12 days) and median duration was 7 days (range: 2-58 days). Key manifestations 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. 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. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.

Neurologic Toxicities: Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all neurologic toxicities occurred within the first 8 weeks, with a median time to onset of 4 days (range: 1-43 days) and a median duration of 17 days. Grade 3 or higher 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 patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly.

YESCARTA REMS: Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA REMS. The required components of the YESCARTA REMS are: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available 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.YESCARTAREMS.com or 1-844-454-KITE (5483).

Hypersensitivity Reactions: Allergic reactions may occur. Serious hypersensitivity reactions including anaphylaxis may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in YESCARTA.

Serious Infections: Severe or life-threatening infections occurred. Infections (all grades) occurred in 38% of patients, and in 23% with ≥ Grade 3. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after YESCARTA infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 36% of patients 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. 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 or higher cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 28% of patients and included thrombocytopenia (18%), neutropenia (15%), and anemia (3%). Monitor blood counts after YESCARTA infusion.

Hypogammaglobulinemia: B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia occurred in 15% of patients. 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: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy 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%) include CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

INDICATION

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.

Reference: 1. YESCARTA [package insert]. Santa Monica, CA: Kite Pharma; 2017.