SAFETY

YESCARTA^®—WELL-CHARACTERIZED SAFETY AND ESTABLISHED MANAGEMENT GUIDANCE

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.¹

The safety of YESCARTA in ≥3L relapsed/refractory (R/R) follicular lymphoma (FL) was evaluated in the ZUMA-5 pivotal trial.¹

MOST CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES IN ZUMA-5 OCCURRED EARLY, WERE GENERALLY REVERSIBLE, AND WERE MANAGED PER ESTABLISHED GUIDANCE.^1,2

CYTOKINE RELEASE SYNDROME (CRS)

CRS, including fatal or life-threatening reactions, occurred following treatment with YESCARTA.¹

GRADE ≥3 INCIDENCE

OVERALL INCIDENCE

DAYS

MEDIAN TIME TO ONSET
(range: 1 to 20 days)

DAYS

MEDIAN DURATION
(range: 1 to 27 days)

MANAGEMENT OF CRS¹

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.

CRS Grading and Management Guidance

CRS Grade^a
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.^b
Tocilizumab Administer tocilizumab^c 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 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.^b

Tocilizumab

Administer tocilizumab^c 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 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.^d

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.^d

CRS Grade^a	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.^b	Administer tocilizumab^c 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.^d

CRS Grade^a

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.^b

Administer tocilizumab^c 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.^d

a. Lee et al. 2014.

b. Refer to Neurologic Toxicity/ICANS Grading and Management Guidance table below for management of neurologic toxicity.

c. Refer to tocilizumab Prescribing Information for details.

d. Alternate therapy includes (but is not limited to): anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG and ATG.

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.¹

VIEW STUDY DESIGN

ZUMA-5 STUDY DESIGN^1,3

ZUMA-5: A phase 2, multicenter, single-arm, open-label study evaluating the efficacy and safety of YESCARTA in adults with R/R FL after ≥2 lines of therapy
146 patients received YESCARTA and were evaluated for safety
- 81 patients with FL were evaluated for efficacy
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
Primary endpoint: ORR (CR + PR)
Median age: 62 years (range: 34 to 79 years)

NEUROLOGIC TOXICITIES

Neurologic toxicities, which were fatal or life-threatening, occurred following treatment with YESCARTA.¹

GRADE ≥3 INCIDENCE

OVERALL INCIDENCE

OCCURRENCE WITHIN FIRST 7 DAYS OF INFUSION

DAYS

MEDIAN TIME TO ONSET
(range: 1 to 79 days)

DAYS

MEDIAN DURATION

MANAGEMENT OF NEUROLOGIC TOXICITIES¹

When monitoring for neurologic toxicities at the Authorized Treatment Center, rule out other causes of neurologic symptoms. Patients who experience Grade ≥2 neurologic toxicities/ICANS 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 of neurologic toxicities.

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

Neurologic Toxicity/ICANS Grading and Management Guidance

Grade 1
Concurrent CRS Administer tocilizumab per CRS Grading and Management Guidance 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 1

Concurrent CRS

Administer tocilizumab per CRS Grading and Management Guidance 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 Guidance table 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 2

Concurrent CRS

Administer tocilizumab per CRS Grading and Management Guidance table 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 Guidance table 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 3

Concurrent CRS

Administer tocilizumab per CRS Grading and Management Guidance table 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 Guidance table 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.^b 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.^b Consider levetiracetam for seizure prophylaxis.

Grade 4

Concurrent CRS

Administer tocilizumab per CRS Grading and Management Guidance table 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.^b

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.^b

Consider levetiracetam for seizure prophylaxis.

Grading Assessment^a

Concurrent CRS

No Concurrent CRS

Grade 1

Administer tocilizumab per CRS Grading and Management Guidance 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 Guidance table 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 Guidance table 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 Guidance table 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.^b

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.^b

Consider levetiracetam for seizure prophylaxis.

a. Severity based on Common Terminology Criteria for Adverse Events.

b. Alternate therapy includes (but is not limited to): anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG and ATG.

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.

DAYS

WEEKS

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.

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.

VIEW STUDY DESIGN

ZUMA-5 STUDY DESIGN^1,3

ZUMA-5: A phase 2, multicenter, single-arm, open-label study evaluating the efficacy and safety of YESCARTA in adults with R/R FL after ≥2 lines of therapy
146 patients received YESCARTA and were evaluated for safety
- 81 patients with FL were evaluated for efficacy
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
Primary endpoint: ORR (CR + PR)
Median age: 62 years (range: 34 to 79 years)

ADVERSE REACTIONS IN ZUMA-5¹

The most common non-laboratory adverse reactions (incidence ≥20%) included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with pathogen unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

Serious adverse reactions occurred in 48% of patients. Serious adverse reactions in >2% of patients included febrile neutropenia, encephalopathy, fever, CRS, infections with pathogen unspecified, pneumonia, hypoxia, and hypotension.

The most common (≥10%) Grade 3 or higher reactions included febrile neutropenia, encephalopathy, and infections with pathogen unspecified. Fatal adverse reactions occurred in 1% of patients and included CRS and fungal infection.

SUMMARY OF ADVERSE REACTIONS OBSERVED IN AT LEAST 10% OF PATIENTS TREATED WITH YESCARTA IN ZUMA-5 (N=146)

Adverse Reaction	Any Grade (%)	Grade ≥3 (%)
Blood and Lymphatic System Disorders
Febrile neutropenia^a	41	41
Cardiac Disorders
Tachycardia^b	44	1
Arrhythmia^c	21	2
Gastrointestinal Disorders
Nausea	40	0
Diarrhea^d	29	1
Constipation	28	0
Vomiting	24	1
Abdominal pain^e	16	0
General Disorders and Administration Site Conditions
Fever	85	8
Fatigue^f	49	1
Chills	29	0
Edema^g	13	1
Immune System Disorders
Cytokine release syndrome	84	8
Immunoglobulins decreased^h	18	1
Infections and Infestations
Infections with pathogen unspecified	45	14
Pneumoniaⁱ	13	8
Fungal infections	12	2
Viral infections	13	2
Metabolism and Nutrition Disorders
Decreased appetite^j	26	1
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain^k	40	1
Motor dysfunction^l	18	2
Nervous System Disorders
Encephalopathy^m	49	16
Headache	45	1
Tremor	31	1
Dizzinessⁿ	20	0
Aphasia	14	4
Neuropathy peripheral^o	12	0
Ataxia^p	10	0
Psychiatric Disorders
Delirium^q	16	5
Insomnia	16	0
Affective disorder^r	10	1
Respiratory, Thoracic and Mediastinal Disorders
Cough^s	25	0
Hypoxia	23	8
Dyspnea^t	12	1
Nasal congestion	10	0
Skin and Subcutaneous Tissue Disorders
Rash^u	19	3
Vascular Disorders
Hypotension^v	51	4
Hypertension	13	6
Thrombosis^w	12	4

^aFebrile neutropenia includes febrile neutropenia, fever overlapping with neutropenia.

^bTachycardia includes tachycardia, sinus tachycardia.

^cArrhythmia includes atrial fibrillation, atrioventricular block first degree, bradycardia, sinus bradycardia, supraventricular tachycardia, ventricular arrhythmia, ventricular extra systoles, ventricular tachycardia, electrocardiogram QT prolonged, electrocardiogram T wave inversion.

^dDiarrhea includes diarrhea, colitis, enteritis.

^eAbdominal pain includes abdominal pain, abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, dyspepsia, epigastric discomfort.

^fFatigue includes asthenia, fatigue, decreased activity, malaise.

^gEdema includes edema, face edema, generalized edema, localized edema, edema peripheral, peripheral swelling, pulmonary edema, swelling face.

^hImmunoglobulins decreased includes hypogammaglobulinemia, blood immunoglobulin G decreased.

ⁱPneumonia includes pneumonia streptococcal, pneumonia, lung infiltration. Pneumonia is also summarized under infections with pathogen unspecified.

^jDecreased appetite includes decreased appetite, hypophagia.

^kMusculoskeletal pain includes musculoskeletal pain, arthralgia, back pain, bone pain, flank pain, groin pain, musculoskeletal chest pain, myalgia, neck pain, osteoarthritis, pain in extremity.

^lMotor dysfunction includes motor dysfunction, muscle rigidity, muscle spasms, muscle strain, muscular weakness.

^mEncephalopathy includes agraphia, amnesia, aphonia, apraxia, CAR T-cell-related encephalopathy syndrome, cognitive disorder, disturbance in attention, dysarthria, dysgraphia, dyskinesia, encephalopathy, lethargy, loss of consciousness, memory impairment, somnolence, speech disorder, confusional state, mental status changes, immune effector cell-associated neurotoxicity, neurotoxicity, toxic encephalopathy.

ⁿDizziness includes dizziness, presyncope, syncope, vertigo.

^oNeuropathy peripheral includes allodynia, cervical radiculopathy, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy.

^pAtaxia includes ataxia, balance disorder, gait disturbance, vestibular disorder.

^qDelirium includes agitation, delirium, hallucination, restlessness.

^rAffective disorder includes anxiety, depression, impulsive behavior, mania, panic attack.

^sCough includes cough, productive cough, upper-airway cough syndrome.

^tDyspnea includes dyspnea, dyspnea exertional.

^uRash includes dermatitis bullous, erythema, pruritus, rash, rash macular, rash maculo-papular, Stevens-Johnson syndrome, urticaria.

^vHypotension includes capillary leak syndrome, hypotension, hypoperfusion, orthostatic hypotension.

^wThrombosis includes deep vein thrombosis, embolism, peripheral ischemia, pulmonary embolism, thrombosis in device, vascular occlusion, jugular vein thrombosis.

VIEW STUDY DESIGN

ZUMA-5 STUDY DESIGN^1,3

ZUMA-5: A phase 2, multicenter, single-arm, open-label study evaluating the efficacy and safety of YESCARTA in adults with R/R FL after ≥2 lines of therapy
146 patients received YESCARTA and were evaluated for safety
- 81 patients with FL were evaluated for efficacy
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
Primary endpoint: ORR (CR + PR)
Median age: 62 years (range: 34 to 79 years)

INDICATION

YESCARTA^® is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.

This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

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 iNHL in ZUMA-5 included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with pathogen unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

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

INDICATION

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)

NEUROLOGIC TOXICITIES

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

HYPERSENSITIVITY REACTIONS

Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.

SERIOUS INFECTIONS

PROLONGED CYTOPENIAS

HYPOGAMMAGLOBULINEMIA

SECONDARY MALIGNANCIES

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

ADVERSE REACTIONS

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

INDICATION

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)

NEUROLOGIC TOXICITIES

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

HYPERSENSITIVITY REACTIONS

Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.

SERIOUS INFECTIONS

PROLONGED CYTOPENIAS

HYPOGAMMAGLOBULINEMIA

SECONDARY MALIGNANCIES

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

ADVERSE REACTIONS

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

Authorized Treatment Centers are independent facilities certified to dispense Kite 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.

3L=third line; CAR=chimeric antigen receptor; CR=complete remission; ICANS=immune effector cell-associated neurotoxicity syndrome; ORR=objective response rate; PR=partial remission.

References: 1. YESCARTA^® (axicabtagene ciloleucel). Prescribing information. Kite Pharma, Inc; 2022. 2. Data on file. Kite Pharma, Inc; 2020. 3. A phase 2 multicenter study of axicabtagene ciloleucel in subjects with relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5). Clinicaltrials.gov. Published April 7, 2017. Updated June 3, 2021. Accessed February 24, 2022. https://clinicaltrials.gov/ct2/show/NCT03105336

YESCARTA^®—WELL-CHARACTERIZED SAFETY AND ESTABLISHED MANAGEMENT GUIDANCE

MOST CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES IN ZUMA-5 OCCURRED EARLY, WERE GENERALLY REVERSIBLE, AND WERE MANAGED PER ESTABLISHED GUIDANCE.^1,2

CYTOKINE RELEASE SYNDROME (CRS)

MANAGEMENT OF CRS¹

ZUMA-5 STUDY DESIGN^1,3

NEUROLOGIC TOXICITIES

MANAGEMENT OF NEUROLOGIC TOXICITIES¹

PATIENT MONITORING AT AUTHORIZED TREATMENT CENTERS¹

ZUMA-5 STUDY DESIGN^1,3

ADVERSE REACTIONS IN ZUMA-5¹

ZUMA-5 STUDY DESIGN^1,3

WHAT ARE THE EFFICACY DATA FROM ZUMA-5?

WHO IS RIGHT FOR YESCARTA?

HOW DO I GET MY
PATIENT STARTED?

INDICATION

IMPORTANT SAFETY INFORMATION

INDICATION

IMPORTANT SAFETY INFORMATION

INDICATION

IMPORTANT SAFETY INFORMATION

YESCARTA®—WELL-CHARACTERIZED SAFETY AND ESTABLISHED MANAGEMENT GUIDANCE

MOST CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES IN ZUMA-5 OCCURRED EARLY, WERE GENERALLY REVERSIBLE, AND WERE MANAGED PER ESTABLISHED GUIDANCE.1,2

CYTOKINE RELEASE SYNDROME (CRS)

MANAGEMENT OF CRS1

ZUMA-5 STUDY DESIGN1,3

NEUROLOGIC TOXICITIES

MANAGEMENT OF NEUROLOGIC TOXICITIES1

PATIENT MONITORING AT AUTHORIZED TREATMENT CENTERS1

ZUMA-5 STUDY DESIGN1,3

ADVERSE REACTIONS IN ZUMA-51

ZUMA-5 STUDY DESIGN1,3

WHAT ARE THE EFFICACY DATA FROM ZUMA-5?

WHO IS RIGHT FOR YESCARTA?

HOW DO I GET MY PATIENT STARTED?

INDICATION

IMPORTANT SAFETY INFORMATION

INDICATION

IMPORTANT SAFETY INFORMATION

INDICATION

IMPORTANT SAFETY INFORMATION

YESCARTA^®—WELL-CHARACTERIZED SAFETY AND ESTABLISHED MANAGEMENT GUIDANCE

MOST CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES IN ZUMA-5 OCCURRED EARLY, WERE GENERALLY REVERSIBLE, AND WERE MANAGED PER ESTABLISHED GUIDANCE.^1,2

MANAGEMENT OF CRS¹

ZUMA-5 STUDY DESIGN^1,3

MANAGEMENT OF NEUROLOGIC TOXICITIES¹

PATIENT MONITORING AT AUTHORIZED TREATMENT CENTERS¹

ZUMA-5 STUDY DESIGN^1,3

ADVERSE REACTIONS IN ZUMA-5¹

ZUMA-5 STUDY DESIGN^1,3

HOW DO I GET MY
PATIENT STARTED?