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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 IN COHORTS 1 AND 2 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.

Incidence of CRS per safety-management strategy

Cohorts 1 and 21,3
(n=108)
Pivotal study

Grade 3 incidence

13%

Overall incidence

94%

Median time to onset

2 days
(range 1-12 days)

Median duration

7 days
(range 2-58 days)



Cohort 41,3
(n=41)
Early use
Cohort 61,3
(n=39)
Prophylactic use

Grade 3 incidence

2%

Overall incidence

93%

Median time to onset

2 days
(range 1-8 days)

Median duration

7 days
(range 2-16 days)

 

 

Grade 3 incidence

0%

Overall incidence

79%

Median time to onset

5 days
(range 1-15 days)

Median duration

4 days
(range 1-10 days)
  • 5% of patients (2/39) developed Grade 4 neurologic toxicities1

  • Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities1

There was no incidence of Grade 4 or 5 CRS with updated management strategies (Cohorts 4 and 6)1

UPDATED SAFETY-MANAGEMENT STUDY DESIGNS

  • Cohorts 1 and 2: YESCARTA was studied in a phase 2, open-label, single-arm, multicenter trial of 101 adults with relapsed/refractory (R/R) aggressive B-cell non-Hodgkin lymphoma, comprising the pivotal trial (Cohorts 1 and 2), upon which YESCARTA was FDA approved1,3-5
  • Cohort 4: The first subsequent safety-management study that evaluated the early use of corticosteroids and/or tocilizumab and prophylactic levetiracetam intervention for Grade 1 CRS or neurologic toxicity in patients treated with YESCARTA1,3
    • 46 patients with R/R DLBCL, PMBCL, TFL, or HGBCL after 2 lines of systemic therapy were enrolled, and 41 were treated with YESCARTA to assess the early use of corticosteroids and/or tocilizumab for Grade 1 CRS or neurologic toxicity on the rate and severity of CRS and neurologic toxicities1,6
    • 28 patients (68%) treated with YESCARTA received bridging therapy between leukapheresis and lymphodepleting chemotherapy1
  • Cohort 6: A second subsequent open-label, safety-management cohort of 39 patients with LBCL, investigating the effects of prophylactic corticosteroid and levetiracetam use + earlier corticosteroid and/or tocilizumab intervention on the incidence of Grade 1 CRS and neurologic toxicities in YESCARTA-treated patients with R/R LBCL1,3
    • Following leukapheresis, patients could receive optional bridging therapy per investigator discretion; 51% of patients (20/39) received bridging therapy prior to YESCARTA7,8
    • CRS and neurologic toxicity incidence and severity were assessed in Cohort 67
    • 67% of patients (n=26/39) had no CRS or neurologic toxicity events within 72 hours (days 0-3) of YESCARTA infusion9*

*These data are not included in the PI for YESCARTA.

HGBCL=high-grade B-cell lymphoma; PMBCL=primary mediastinal large B-cell lymphoma; TFL=transformed follicular lymphoma.

See Cohort 4 and Cohort 6 RESPONSE RATE AND DURATION OF RESPONSE DATA >

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, 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 Section 2.3 of the full Prescribing Information (PI).

CRS Grading and Management Guidance

Grade 1

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

Tocilizumab

If symptoms (eg, fever) not improving after 24 hours, consider managing as Grade 2.

Corticosteroids

If not improving after 3 days, administer one dose of dexamethasone 10 mg intravenously.

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.


If improving, discontinue tocilizumab.

Corticosteroids

Administer dexamethasone 10 mg intravenously once daily.

If improving, manage as Grade 1 above and continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate.

If not improving, manage as appropriate grade below.

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.

If improving, manage as appropriate grade above.

Corticosteroids

Dexamethasone 10 mg intravenously three times a day.

If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate.

If not improving, manage as Grade 4.

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.

If improving, manage as appropriate grade above.

Corticosteroids

Administer methylprednisolone 1000 mg intravenously once per day for 3 days.

If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate.

If not improving, consider methylprednisolone 1000 mg 2-3 times a day or alternate therapy.

CRS Grade Tocilizumab Corticosteroids

Grade 1

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

If symptoms (eg, fever) not improving after 24 hours, consider managing as Grade 2.

If not improving after 3 days, administer one dose of dexamethasone 10 mg intravenously.

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.

If improving, discontinue tocilizumab.

Administer dexamethasone 10 mg intravenously once daily.

If improving, manage as Grade 1 above and continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate.

If not improving, manage as appropriate grade below.

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.

If improving, manage as appropriate grade above.

Dexamethasone 10 mg intravenously three times a day.

If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate.

If not improving, manage as Grade 4.

Grade 4

Life-threatening symptoms.

Requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD) or

Grade 4 organ toxicity (excluding transaminitis).

Per Grade 2.

If improving, manage as appropriate grade above.

Administer methylprednisolone 1000 mg intravenously once per day for 3 days.

If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate.

If not improving, consider methylprednisolone 1000 mg 2-3 times a day or alternate therapy.

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.

NEUROLOGIC TOXICITIES1

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

Incidence of neurologic toxicities per safety-management strategy

Cohorts 1 and 21,3
(n=108)
Pivotal study

Grade 3 incidence

31%

Overall incidence

87%

Median time to onset

4 days
(range 1-43 days)

Median duration

17 days
 



Cohort 41,3
(n=41)
Early use
Cohort 61,3
(n=39)
Prophylactic use

Grade 3 incidence

20%

Overall incidence

78%

Median time to onset

6 days
(range 1-93 days)

Median duration

8 days
(range 1-144 days)

 

 

Grade 3 incidence

13%

Overall incidence

85%

Median time to onset

6 days
(range 1-274 days)

Median duration

12 days
 
  • 5% of patients (2/39) developed Grade 4 neurologic toxicities1

  • Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities1

UPDATED SAFETY-MANAGEMENT STUDY DESIGNS

  • Cohorts 1 and 2: YESCARTA was studied in a phase 2, open-label, single-arm, multicenter trial of 101 adults with relapsed/refractory (R/R) aggressive B-cell non-Hodgkin lymphoma, comprising the pivotal trial (Cohorts 1 and 2), upon which YESCARTA was FDA approved1,3-5
  • Cohort 4: The first subsequent safety-management study that evaluated the early use of corticosteroids and/or tocilizumab and prophylactic levetiracetam intervention for Grade 1 CRS or neurologic toxicity in patients treated with YESCARTA1,3
    • 46 patients with R/R DLBCL, PMBCL, TFL, or HGBCL after 2 lines of systemic therapy were enrolled, and 41 were treated with YESCARTA to assess the early use of corticosteroids and/or tocilizumab for Grade 1 CRS or neurologic toxicity on the rate and severity of CRS and neurologic toxicities1,6
    • 28 patients (68%) treated with YESCARTA received bridging therapy between leukapheresis and lymphodepleting chemotherapy1
  • Cohort 6: A second subsequent open-label, safety-management cohort of 39 patients with LBCL, investigating the effects of prophylactic corticosteroid and levetiracetam use + earlier corticosteroid and/or tocilizumab intervention on the incidence of Grade 1 CRS and neurologic toxicities in YESCARTA-treated patients with R/R LBCL1,3
    • Following leukapheresis, patients could receive optional bridging therapy per investigator discretion; 51% of patients (20/39) received bridging therapy prior to YESCARTA7,8
    • CRS and neurologic toxicity incidence and severity were assessed in Cohort 67
    • 67% of patients (n=26/39) had no CRS or neurologic toxicity events within 72 hours (days 0-3) of YESCARTA infusion9*

*These data are not included in the PI for YESCARTA.

HGBCL=high-grade B-cell lymphoma; PMBCL=primary mediastinal large B-cell lymphoma; TFL=transformed follicular lymphoma.

See Cohort 4 and Cohort 6 RESPONSE RATE AND DURATION OF RESPONSE DATA >

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 levetiracetam for seizure prophylaxis for any grade of neurologic toxicities.

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

Neurologic Toxicity Grading and Management Guidance

Grade 1

Concurrent CRS

Administer tocilizumab per CRS Grading and Management table above for management of Grade 1 CRS.

In addition, administer one dose of dexamethasone 10 mg intravenously.

If not improving after 2 days, repeat dexamethasone 10 mg intravenously.


Consider levetiracetam for seizure prophylaxis.

No Concurrent CRS

Administer one dose of dexamethasone 10 mg intravenously.

If not improving after 2 days, repeat dexamethasone 10 mg intravenously.


Consider levetiracetam for seizure prophylaxis.

Grade 2

Concurrent CRS

Administer tocilizumab per CRS Grading and Management table above for management of Grade 2 CRS.

In addition, administer dexamethasone 10 mg intravenously four times a day.

If improving, continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate.

If not improving, manage as appropriate grade below.


Consider levetiracetam for seizure prophylaxis.

No Concurrent CRS

Administer dexamethasone 10 mg intravenously four times a day.

If improving, continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate.

If not improving, manage as appropriate grade below.


Consider levetiracetam for seizure prophylaxis.

Grade 3

Concurrent CRS

Administer tocilizumab per CRS Grading and Management table above for management of Grade 2 CRS.

In addition, administer methylprednisolone 1000 mg intravenously once daily.

If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate.

If not improving, manage as Grade 4.


Consider levetiracetam for seizure prophylaxis.

No Concurrent CRS

Administer methylprednisolone 1000 mg intravenously once daily.

If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate.

If not improving, manage as Grade 4.


Consider levetiracetam for seizure prophylaxis.

Grade 4

Concurrent CRS

Administer tocilizumab per CRS Grading and Management table above for management of Grade 2 CRS.

In addition, administer methylprednisolone 1000 mg intravenously twice per day.

If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate.

If not improving, consider 1000 mg of methylprednisolone intravenously 3 times a day or alternate therapy.


Consider levetiracetam for seizure prophylaxis.

No Concurrent CRS

Administer methylprednisolone 1000 mg intravenously twice per day.

If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate.

If not improving, consider 1000 mg of methylprednisolone intravenously 3 times a day or alternate therapy.


Consider levetiracetam for seizure prophylaxis.

Grading Assessment Concurrent CRS No Concurrent CRS

Grade 1

Administer tocilizumab per CRS Grading and Management table above for management of Grade 1 CRS.

In addition, administer one dose of dexamethasone 10 mg intravenously.

If not improving after 2 days, repeat dexamethasone 10 mg intravenously.

Administer one dose of dexamethasone 10 mg intravenously.

If not improving after 2 days, repeat dexamethasone 10 mg intravenously.

Consider levetiracetam for seizure prophylaxis.

Grade 2

Administer tocilizumab per CRS Grading and Management table above for management of Grade 2 CRS.

In addition, administer dexamethasone 10 mg intravenously four times a day.

If improving, continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate.

If not improving, manage as appropriate grade below.

Administer dexamethasone 10 mg intravenously four times a day.

If improving, continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate.

If not improving, manage as appropriate grade below.

Consider levetiracetam for seizure prophylaxis.

Grade 3

Administer tocilizumab per CRS Grading and Management table above for management of Grade 2 CRS.

In addition, administer methylprednisolone 1000 mg intravenously once daily.

If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate.

If not improving, manage as Grade 4.

Administer methylprednisolone 1000 mg intravenously once daily.

If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate.

If not improving, manage as Grade 4.

Consider levetiracetam for seizure prophylaxis.

Grade 4

Administer tocilizumab per CRS Grading and Management table above for management of Grade 2 CRS.

In addition, administer methylprednisolone 1000 mg intravenously twice per day.

If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate.

If not improving, consider 1000 mg of methylprednisolone intravenously 3 times a day or alternate therapy.

Administer methylprednisolone 1000 mg intravenously twice per day.

If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate.

If not improving, consider 1000 mg of methylprednisolone intravenously 3 times a day or alternate therapy.

Consider levetiracetam for seizure prophylaxis.

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.

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.

INDICATIONS

YESCARTA® is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

  • Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
  • 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)

CRS, including fatal or life-threatening reactions, occurred. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL), including  Grade 3 in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including  Grade 3 in 9%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. For patients with LBCL in ZUMA-1, the median time to onset of CRS was 2 days following infusion (range: 1-12 days) and the median duration was 7 days (range: 2-58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1-10 days) and the median duration was 7 days (range: 2-43 days). CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including Grade 3 in 8%. Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event 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 (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and fatigue (12%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events, CRS occurred in 93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients experienced a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1-8 days) and the median duration of CRS was 7 days (range: 2-16 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Thirty-one of the 39 patients (79%) developed CRS and were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing Grade 3 CRS. The median time to onset of CRS was 5 days (range: 1-15 days) and the median duration of CRS was 4 days (range: 1-10 days). Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities.

Ensure that 2 doses of tocilizumab are available prior to YESCARTA 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

Neurologic toxicities (including immune effector cell-associated neurotoxicity syndrome) that were fatal or life-threatening occurred. Neurologic toxicities occurred in 78% (330/422) of patients with NHL receiving YESCARTA, including Grade 3 in 25%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including Grade 3 in 31% and in 74% (124/168) of patients in ZUMA-7 including Grade 3 in 25%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL in ZUMA-1. The median time to onset for neurologic toxicity was 5 days (range: 1-133 days) and median duration was 15 days in patients with LBCL in ZUMA-7. 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. Ninety-eight percent 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 87% of affected patients with LBCL and 74% of affected patients with iNHL.

The most common neurologic toxicities ( 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred. Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Of those patients, 85% (33/39) developed neurologic toxicities; 8% (3/39) developed Grade 3, and 5% (2/39) developed Grade 4 neurologic toxicities. The median time to onset of neurologic toxicities was 6 days (range: 1-274 days) with a median duration of 12 days (range: 1-107 days). Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset and decrease the duration of CRS.

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 45% of patients with NHL. Grade 3 infections occurred in 17% of patients, including Grade 3 infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, 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 antimicrobials according to local guidelines.

Febrile neutropenia was observed in 36% of 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, has occurred in patients treated with drugs directed against B cells, including YESCARTA. Perform screening for HBV, HCV, and HIV and management 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 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA

B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia was reported as an adverse reaction in 14% 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

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 non-laboratory adverse reactions (incidence 20%) in patients with LBCL in ZUMA-7 included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, musculoskeletal pain, nausea, febrile neutropenia, chills, cough, infection with unspecified pathogen, dizziness, tremor, decreased appetite, edema, hypoxia, abdominal pain, aphasia, constipation, and vomiting.

The most common adverse reactions (incidence 20%) in patients with LBCL in ZUMA-1 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 accompanying full Prescribing Information, including BOXED WARNING and Medication Guide.

INDICATIONS

YESCARTA® is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

  • Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
  • 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)

CRS, including fatal or life-threatening reactions, occurred. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL), including  Grade 3 in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including  Grade 3 in 9%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. For patients with LBCL in ZUMA-1, the median time to onset of CRS was 2 days following infusion (range: 1-12 days) and the median duration was 7 days (range: 2-58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1-10 days) and the median duration was 7 days (range: 2-43 days). CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including Grade 3 in 8%. Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event 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 (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and fatigue (12%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events, CRS occurred in 93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients experienced a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1-8 days) and the median duration of CRS was 7 days (range: 2-16 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Thirty-one of the 39 patients (79%) developed CRS and were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing Grade 3 CRS. The median time to onset of CRS was 5 days (range: 1-15 days) and the median duration of CRS was 4 days (range: 1-10 days). Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities.

Ensure that 2 doses of tocilizumab are available prior to YESCARTA 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

Neurologic toxicities (including immune effector cell-associated neurotoxicity syndrome) that were fatal or life-threatening occurred. Neurologic toxicities occurred in 78% (330/422) of patients with NHL receiving YESCARTA, including Grade 3 in 25%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including Grade 3 in 31% and in 74% (124/168) of patients in ZUMA-7 including Grade 3 in 25%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL in ZUMA-1. The median time to onset for neurologic toxicity was 5 days (range: 1-133 days) and median duration was 15 days in patients with LBCL in ZUMA-7. 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. Ninety-eight percent 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 87% of affected patients with LBCL and 74% of affected patients with iNHL.

The most common neurologic toxicities ( 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred. Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Of those patients, 85% (33/39) developed neurologic toxicities; 8% (3/39) developed Grade 3, and 5% (2/39) developed Grade 4 neurologic toxicities. The median time to onset of neurologic toxicities was 6 days (range: 1-274 days) with a median duration of 12 days (range: 1-107 days). Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset and decrease the duration of CRS.

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 45% of patients with NHL. Grade 3 infections occurred in 17% of patients, including Grade 3 infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, 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 antimicrobials according to local guidelines.

Febrile neutropenia was observed in 36% of 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, has occurred in patients treated with drugs directed against B cells, including YESCARTA. Perform screening for HBV, HCV, and HIV and management 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 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA

B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia was reported as an adverse reaction in 14% 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

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 non-laboratory adverse reactions (incidence 20%) in patients with LBCL in ZUMA-7 included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, musculoskeletal pain, nausea, febrile neutropenia, chills, cough, infection with unspecified pathogen, dizziness, tremor, decreased appetite, edema, hypoxia, abdominal pain, aphasia, constipation, and vomiting.

The most common adverse reactions (incidence 20%) in patients with LBCL in ZUMA-1 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 accompanying full Prescribing Information, including BOXED WARNING and Medication Guide.

INDICATIONS

YESCARTA® is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

  • Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
  • 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)

CRS, including fatal or life-threatening reactions, occurred. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL), including  Grade 3 in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including  Grade 3 in 9%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. For patients with LBCL in ZUMA-1, the median time to onset of CRS was 2 days following infusion (range: 1-12 days) and the median duration was 7 days (range: 2-58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1-10 days) and the median duration was 7 days (range: 2-43 days). CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including Grade 3 in 8%. Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event 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 (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and fatigue (12%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events, CRS occurred in 93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients experienced a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1-8 days) and the median duration of CRS was 7 days (range: 2-16 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Thirty-one of the 39 patients (79%) developed CRS and were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing Grade 3 CRS. The median time to onset of CRS was 5 days (range: 1-15 days) and the median duration of CRS was 4 days (range: 1-10 days). Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities.

Ensure that 2 doses of tocilizumab are available prior to YESCARTA 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

Neurologic toxicities (including immune effector cell-associated neurotoxicity syndrome) that were fatal or life-threatening occurred. Neurologic toxicities occurred in 78% (330/422) of patients with NHL receiving YESCARTA, including Grade 3 in 25%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including Grade 3 in 31% and in 74% (124/168) of patients in ZUMA-7 including Grade 3 in 25%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL in ZUMA-1. The median time to onset for neurologic toxicity was 5 days (range: 1-133 days) and median duration was 15 days in patients with LBCL in ZUMA-7. 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. Ninety-eight percent 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 87% of affected patients with LBCL and 74% of affected patients with iNHL.

The most common neurologic toxicities ( 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred. Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Of those patients, 85% (33/39) developed neurologic toxicities; 8% (3/39) developed Grade 3, and 5% (2/39) developed Grade 4 neurologic toxicities. The median time to onset of neurologic toxicities was 6 days (range: 1-274 days) with a median duration of 12 days (range: 1-107 days). Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset and decrease the duration of CRS.

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 45% of patients with NHL. Grade 3 infections occurred in 17% of patients, including Grade 3 infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, 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 antimicrobials according to local guidelines.

Febrile neutropenia was observed in 36% of 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, has occurred in patients treated with drugs directed against B cells, including YESCARTA. Perform screening for HBV, HCV, and HIV and management 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 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA

B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia was reported as an adverse reaction in 14% 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

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 non-laboratory adverse reactions (incidence 20%) in patients with LBCL in ZUMA-7 included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, musculoskeletal pain, nausea, febrile neutropenia, chills, cough, infection with unspecified pathogen, dizziness, tremor, decreased appetite, edema, hypoxia, abdominal pain, aphasia, constipation, and vomiting.

The most common adverse reactions (incidence 20%) in patients with LBCL in ZUMA-1 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 accompanying full Prescribing Information, including BOXED WARNING and Medication Guide.

Authorized Treatment Centers are independent facilities certified to dispense Kite CAR T therapies. Choice of an Authorized Treatment Center is within the sole discretion of the physician and patient. Kite does not endorse any individual treatment sites.

References: 1. YESCARTA® (axicabtagene ciloleucel). Prescribing information. Kite Pharma, Inc; 2022. 2. Data on file. Kite Pharma, Inc; 2018. 3. Oluwole OO, Forcade E, Munoz J, et al. Prophylactic corticosteroid use with axicabtagene ciloleucel in patients with relapsed/refractory large B-cell lymphoma: one-year follow-up of ZUMA-1 Cohort 6. Presented at: 63rd ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 2832. 4. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 2019;20(1):31-42. 5. Locke FL, Ghobadi A, Jacobson CA, et al. Durability of response in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (axi-cel) in patients (pts) with refractory large B-cell lymphoma. Presented at: 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract 3003. 6. Topp MS, van Meerten T, Houot R, et al. Earlier steroid use with axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B cell lymphoma. Presented at: 61st ASH Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Abstract 243. 7. Oluwole OO, Bouabdallah K, Muñoz J, et al. Prophylactic corticosteroid use in patients receiving axicabtagene ciloleucel for large B-cell lymphoma. Br J Haematol. 2021;194(4):690-700. 8. Data on file [1]. Kite Pharma, Inc; 2022. 9. Data on file [2]. Kite Pharma, Inc; 2022.