SAFETY

SAFETY AND MANAGEMENT STRATEGIES

After your patient receives their YESCARTA® infusion, monitoring will take place at the YESCARTA Authorized Treatment Center where there are approved safety protocols and physicians who are specially trained in YESCARTA administration and adverse event management. The YESCARTA Authorized Treatment Center will work with primary hematologists/oncologists to stay connected about treatment decisions, patient progress, and follow-up care. Though infusion and monitoring take place at the treatment center, long-term monitoring should continue in the community setting.

MOST CYTOKINE RELEASE SYNDROME AND NEUROLOGIC EVENTS OCCURRED EARLY, WERE GENERALLY REVERSIBLE, AND MANAGED PER ESTABLISHED GUIDANCE1,2

CYTOKINE RELEASE SYNDROME (CRS)1

CRS, including fatal or life-threatening reactions, occurred following treatment with YESCARTA.

13
%
GRADE 3 INCIDENCE
94
%
OVERALL INCIDENCE
2
DAYS
MEDIAN TIME TO ONSET
(range 1 to 12 days)
7
DAYS
MEDIAN DURATION
(range 2 to 58 days)

MANAGEMENT OF CRS

At the Authorized Treatment Center, ensure that 2 doses of tocilizumab are available prior to infusion of YESCARTA. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids will be instituted 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 Section 2.3 of the full Prescribing Information (PI).

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).

If no clinical improvement in the signs and symptoms of CRS after the first dose, repeat tocilizumab every 8 hours as needed.

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

Per Grade 2

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

Per Grade 2

Corticosteroids

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

CRS Grade Tocilizumab Corticosteroids

Grade 1

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

N/A

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.

Administer tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg).

If no clinical improvement in the signs and symptoms of CRS after the first dose, repeat tocilizumab every 8 hours as needed.

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.

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.

Per Grade 2

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).

Per Grade 2

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

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.

ZUMA-1 STUDY DESIGN

  • YESCARTA was studied in a phase 2, open-label, single-arm, multicenter trial in 101 adults with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma
  • Patients had refractory disease to the most recent therapy or relapsed within 1 year after autologous stem cell transplantation (ASCT)
  • Patients received lymphodepleting chemotherapy: 500 mg/m2 intravenous (IV) cyclophosphamide and 30 mg/m2 IV fludarabine (–5, –4, and –3 days before infusion)
  • YESCARTA was administered as a single infusion to a target dose of 2 x 106 viable CAR T cells/kg body weight (maximum of 2 x 108 viable CAR T cells)
  • Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was not permitted
    • In the commercial setting, the use of bridging therapy after leukapheresis and before lymphodepleting chemotherapy is at the discretion of the treating physician

NEUROLOGIC TOXICITIES1

Neurologic toxicities, which were fatal or life-threatening, occurred following treatment with YESCARTA.

31
%
GRADE 3 INCIDENCE
87
%
OVERALL INCIDENCE
4
DAYS
MEDIAN TIME TO ONSET
(range 1 to 43 days)
17
DAYS
MEDIAN DURATION

MANAGEMENT OF NEUROLOGIC TOXICITIES

When managing neurologic toxicities at the Authorized Treatment Center, 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.

See Section 2.3 of the full PI for additional monitoring and management guidance relating to neurologic toxicities.

Grade 2

Concurrent CRS

Administer tocilizumab per CRS Grading and Management Guidance table above 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.


Consider non-sedating, anti-seizure medicines (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 non-sedating, anti-seizure medicines (eg, levetiracetam) for seizure prophylaxis.

Grade 3

Concurrent CRS

Administer tocilizumab per CRS Grading and Management Guidance table above 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.


Consider non-sedating, anti-seizure medicines (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 non-sedating, anti-seizure medicines (eg, levetiracetam) for seizure prophylaxis.

Grade 4

Concurrent CRS

Administer tocilizumab per CRS Grading and Management Guidance table above 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 (Grade 3).


Consider non-sedating, anti-seizure medicines (eg, levetiracetam) for seizure prophylaxis.

No Concurrent CRS

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


Consider non-sedating, anti-seizure medicines (eg, levetiracetam) for seizure prophylaxis.

Grading Assessment Concurrent CRS No Concurrent CRS

Grade 2

Administer tocilizumab per CRS Grading and Management Guidance table above 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.

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 (eg, levetiracetam) for seizure prophylaxis.

Grade 3

Administer tocilizumab per CRS Grading and Management Guidance table above 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 (eg, levetiracetam) for seizure prophylaxis.

Grade 4

Administer tocilizumab per CRS Grading and Management Guidance table above 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 (eg, levetiracetam) for seizure prophylaxis.

ZUMA-1 STUDY DESIGN

  • YESCARTA was studied in a phase 2, open-label, single-arm, multicenter trial in 101 adults with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma
  • Patients had refractory disease to the most recent therapy or relapsed within 1 year after autologous stem cell transplantation (ASCT)
  • Patients received lymphodepleting chemotherapy: 500 mg/m2 intravenous (IV) cyclophosphamide and 30 mg/m2 IV fludarabine (–5, –4, and –3 days before infusion)
  • YESCARTA was administered as a single infusion to a target dose of 2 x 106 viable CAR T cells/kg body weight (maximum of 2 x 108 viable CAR T cells)
  • Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was not permitted
    • In the commercial setting, the use of bridging therapy after leukapheresis and before lymphodepleting chemotherapy is at the discretion of the treating physician

PATIENT MONITORING AT AUTHORIZED TREATMENT CENTERS1

Monitoring takes place at the YESCARTA Authorized Treatment Centers where there are approved safety protocols and physicians who are specially trained in YESCARTA administration and adverse event management. Long-term monitoring should continue in the community setting.

7
DAYS
4
WEEKS
7
DAYS

Patients will be monitored at least daily for 7 days at the Authorized Treatment Center following infusion for signs and symptoms of CRS and neurologic toxicities.

4
WEEKS

Patients will be instructed to remain within proximity of the Authorized Treatment Center for at least 4 weeks following infusion. Monitor patients for signs or symptoms of CRS or neurologic toxicities for 4 weeks after infusion. Patients will be counseled to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicities occur at any time.

ZUMA-1 STUDY DESIGN

  • YESCARTA was studied in a phase 2, open-label, single-arm, multicenter trial in 101 adults with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma
  • Patients had refractory disease to the most recent therapy or relapsed within 1 year after autologous stem cell transplantation (ASCT)
  • Patients received lymphodepleting chemotherapy: 500 mg/m2 intravenous (IV) cyclophosphamide and 30 mg/m2 IV fludarabine (–5, –4, and –3 days before infusion)
  • YESCARTA was administered as a single infusion to a target dose of 2 x 106 viable CAR T cells/kg body weight (maximum of 2 x 108 viable CAR T cells)
  • Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was not permitted
    • In the commercial setting, the use of bridging therapy after leukapheresis and before lymphodepleting chemotherapy is at the discretion of the treating physician

ADVERSE REACTIONS1

The most common adverse reactions (incidence 20%) include 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.

Serious adverse reactions occurred in 52% of patients. The most common serious adverse reactions (>2%) include encephalopathy, fever, lung infection, febrile neutropenia, cardiac arrhythmia, cardiac failure, urinary tract infection, renal insufficiency, aphasia, cardiac arrest, Clostridium difficile infection, delirium, hypotension, and hypoxia.

The most common (10%) Grade 3 or higher reactions include febrile neutropenia, fever, CRS, encephalopathy, infections with pathogen unspecified, hypotension, hypoxia, and lung infections.

This is not a complete list of adverse events associated with YESCARTA. For additional information, please see Important Safety Information.

Adverse Reaction Any Grade (%) Grade 3 (%)
Blood and Lymphatic System Disorders
Febrile neutropenia 34 31
Cardiac Disorders
Tachycardiaa 57 2
Arrhythmiab 23 7
Gastrointestinal Disorders
Diarrhea 38 4
Nausea 34 0
Vomiting 26 1
Constipation 23 0
Abdominal painc 14 1
Dry mouth 11 0
General Disorders and Administration Site Conditions
Feverd 86 16
Fatiguee 46 3
Chills 40 0
Edemaf 19 1
Immune System Disorders
Cytokine release syndrome 94 13
Hypogammaglobulinemiag 15 0
Infections and Infestations
Infections with 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 dysfunctionh 19 1
Pain in extremityi 17 2
Back pain 15 1
Muscle pain 14 1
Arthralgia 10 0
Nervous System Disorders
Encephalopathyj 57 29
Headachek 45 1
Tremor 31 2
Dizzinessl 21 1
Aphasiam 18 6
Psychiatric Disorders
Deliriumn 17 6
Respiratory, Thoracic and Mediastinal Disorders
Hypoxiao 32 11
Coughp 30 0
Dyspneaq 19 3
Pleural effusion 13 2
Renal and Urinary Disorders
Renal insufficiency 12 5
Vascular Disorders
Hypotensionr 57 15
Hypertension 15 6
Thrombosiss 10 1

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

aTachycardia includes tachycardia and sinus tachycardia.

bArrhythmia includes arrhythmia, atrial fibrillation, atrial flutter, atrioventricular block, bundle branch block right, electrocardiogram QT prolonged, extra-systoles, heart rate irregular, supraventricular extra systoles, supraventricular tachycardia, ventricular arrhythmia, and ventricular tachycardia.

cAbdominal pain includes abdominal pain, abdominal pain lower, and abdominal pain upper.

dFever incudes fever and febrile neutropenia.

eFatigue includes fatigue and malaise.

fEdema includes face edema, generalized edema, local swelling, localized edema, edema, edema genital, edema peripheral, periorbital edema, peripheral swelling, and scrotal edema.

gHypogammaglobulinemia includes hypogammaglobulinemia, blood immunoglobulin D decreased, and blood immunoglobulin G decreased.

hMotor dysfunction includes muscle spasms, and muscular weakness.

iPain in extremity includes pain not otherwise specified, and pain in extremity.

jEncephalopathy includes cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, encephalopathy, hypersomnia, leukoencephalopathy, memory impairment, mental status changes, paranoia, somnolence, and stupor.

kHeadache includes headache, head discomfort, sinus headache, and procedural headache.

lDizziness includes dizziness, presyncope, and syncope.

mAphasia includes aphasia, and dysphasia.

nDelirium includes agitation, delirium, delusion, disorientation, hallucination, hyperactivity, irritability, and restlessness.

oHypoxia includes hypoxia and oxygen saturation decreased.

pCough includes cough, productive cough, and upper-airway cough syndrome.

qDyspnea includes acute respiratory failure, dyspnea, orthopnea, and respiratory distress.

rHypotension includes diastolic hypotension, hypotension, and orthostatic hypotension.

sThrombosis includes deep vein thrombosis, embolism, embolism venous, pulmonary embolism, splenic infarction, splenic vein thrombosis, subclavian vein thrombosis, thrombosis, and thrombosis in device.

ZUMA-1 STUDY DESIGN

  • YESCARTA was studied in a phase 2, open-label, single-arm, multicenter trial in 101 adults with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma
  • Patients had refractory disease to the most recent therapy or relapsed within 1 year after autologous stem cell transplantation (ASCT)
  • Patients received lymphodepleting chemotherapy: 500 mg/m2 intravenous (IV) cyclophosphamide and 30 mg/m2 IV fludarabine (–5, –4, and –3 days before infusion)
  • YESCARTA was administered as a single infusion to a target dose of 2 x 106 viable CAR T cells/kg body weight (maximum of 2 x 108 viable CAR T cells)
  • Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was not permitted
    • In the commercial setting, the use of bridging therapy after leukapheresis and before lymphodepleting chemotherapy is at the discretion of the treating physician

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.

Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.

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 and TECARTUS REMS Program.

CYTOKINE RELEASE SYNDROME (CRS), including fatal or life-threatening reactions, occurred. CRS occurred in 88% (224/254) of all patients with non-Hodgkin lymphoma (NHL), including Grade 3 in 10%. CRS occurred in 94% (101/108) of patients with large B-cell lymphoma (LBCL), including Grade 3 in 13%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. The median time to onset of CRS was 2 days (range: 1-12 days) and the median duration was 7 days (range: 2-58 days) for patients with LBCL. CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL), including Grade 3 in 8% (11/146). Among patients with iNHL who died after receiving YESCARTA, 1 patient had ongoing CRS events at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and median duration was 6 days (range: 1-27 days) for patients with iNHL. Key manifestations of CRS (10%) in all patients combined included fever (80%), hypotension (38%), tachycardia (29%), hypoxia (21%), chills (21%), and headache (13%). 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, multi-organ failure and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Ensure that 2 doses of tocilizumab are available prior to YESCARTA infusion. Following infusion, monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. 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 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. 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.

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.

Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.

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 and TECARTUS REMS Program.

CYTOKINE RELEASE SYNDROME (CRS), including fatal or life-threatening reactions, occurred. CRS occurred in 88% (224/254) of all patients with non-Hodgkin lymphoma (NHL), including Grade 3 in 10%. CRS occurred in 94% (101/108) of patients with large B-cell lymphoma (LBCL), including Grade 3 in 13%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. The median time to onset of CRS was 2 days (range: 1-12 days) and the median duration was 7 days (range: 2-58 days) for patients with LBCL. CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL), including Grade 3 in 8% (11/146). Among patients with iNHL who died after receiving YESCARTA, 1 patient had ongoing CRS events at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and median duration was 6 days (range: 1-27 days) for patients with iNHL. Key manifestations of CRS (10%) in all patients combined included fever (80%), hypotension (38%), tachycardia (29%), hypoxia (21%), chills (21%), and headache (13%). 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, multi-organ failure and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Ensure that 2 doses of tocilizumab are available prior to YESCARTA infusion. Following infusion, monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. 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 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. 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.

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.

Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.

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 and TECARTUS REMS Program.

CYTOKINE RELEASE SYNDROME (CRS), including fatal or life-threatening reactions, occurred. CRS occurred in 88% (224/254) of all patients with non-Hodgkin lymphoma (NHL), including Grade 3 in 10%. CRS occurred in 94% (101/108) of patients with large B-cell lymphoma (LBCL), including Grade 3 in 13%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. The median time to onset of CRS was 2 days (range: 1-12 days) and the median duration was 7 days (range: 2-58 days) for patients with LBCL. CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL), including Grade 3 in 8% (11/146). Among patients with iNHL who died after receiving YESCARTA, 1 patient had ongoing CRS events at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and median duration was 6 days (range: 1-27 days) for patients with iNHL. Key manifestations of CRS (10%) in all patients combined included fever (80%), hypotension (38%), tachycardia (29%), hypoxia (21%), chills (21%), and headache (13%). 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, multi-organ failure and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Ensure that 2 doses of tocilizumab are available prior to YESCARTA infusion. Following infusion, monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. 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 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. 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.

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

Authorized Treatment Centers are independently owned and operated. Kite does not endorse any Authorized Treatment Center.

References: 1. YESCARTA® (axicabtagene ciloleucel). Prescribing information. Kite Pharma, Inc; 2021. 2. Data on file. Kite Pharma, Inc; 2018.