HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
YESCARTA safely and effectively. See full prescribing information for
YESCARTA.
YESCARTA® (axicabtagene ciloleucel) suspension for intravenous
infusion
Initial U.S. Approval: 2017

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGICTOXICITIES and SECONDARY HEMATOLOGICALMALIGNANCIESSee full prescribing information for complete boxed warning.
• Cytokine Release Syndrome (CRS), including fatal or lifethreatening reactions, occurred in patients receiving YESCARTA.
Do not administer YESCARTA to patients with active infection or
inflammatory disorders. Treat severe or life-threatening CRS withtocilizumab or tocilizumab and corticosteroids (2.2, 2.3, 5.1).
• Neurologic toxicities, including fatal or life-threatening reactions,occurred in patients receiving YESCARTA, including
concurrently with CRS or after CRS resolution. Monitor forneurologic toxicities after treatment with YESCARTA. Provide
supportive care and/or corticosteroids, as needed (2.2, 2.3, 5.2).
• T cell malignancies have occurred following treatment ofhematologic malignancies with BCMA- and CD19-directed
genetically modified autologous T cell immunotherapies, including
YESCARTA (5.8).
• YESCARTA is available only through a restricted program undera Risk Evaluation and Mitigation Strategy (REMS) called the
YESCARTA and TECARTUS REMS (5.3).
-----------------------------RECENT MAJOR CHANGES------------------------Boxed Warning
Dosage and Administration (2.2)
Warnings and Precautions (5.3)
Warnings and Precautions, Secondary Malignancies (5.8)

04/2024
06/2024
06/2024
04/2024-----------------------------INDICATIONS AND USAGE-------------------------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. (1.1)• 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 fromfollicular lymphoma. (1.1)
Limitations of Use: YESCARTA is not indicated for the treatment of patientswith primary central nervous system lymphoma. (1.1)• 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 thisindication may be contingent upon verification and description of clinicalbenefit in confirmatory trial(s). (1.2)--------------------------DOSAGE AND ADMINISTRATION-------------------For autologous use only. For intravenous use only.
• Do NOT use a leukodepleting filter. (2.2)• Administer a lymphodepleting regimen of cyclophosphamide andfludarabine before infusion of YESCARTA. (2.2)• Verify the patient’s identity prior to infusion. (2.2)• Premedicate with acetaminophen and an H1-antihistamine. (2.2)• Confirm availability of tocilizumab prior to infusion. (2.1, 5.1)
• Dosing of YESCARTA is based on the number of chimeric antigen
receptor (CAR)-positive viable T cells. (2.1)• The target YESCARTA dose is 2 × 106 CAR-positive viable T cells per
kg body weight, with a maximum of 2 × 108 CAR-positive viable T cells.
(2.1)• Administer YESCARTA in a certified healthcare facility. (2.2, 5.1, 5.2,
5.3)-------------------DOSAGE FORMS AND STRENGTHS-----------------------• YESCARTA is available as a cell suspension for infusion. (3)• YESCARTA comprises a suspension of 2 × 106 CAR-positive viable T
cells per kg of body weight, with a maximum of 2 × 108 CAR-positive
viable T cells in approximately 68 mL. (3)----------------------------CONTRAINDICATIONS--------------------------------• None. (4)------------------------WARNINGS AND PRECAUTIONS----------------------• Hypersensitivity Reactions: Monitor for hypersensitivity reactions duringinfusion. (5.4)• Serious Infections: Monitor patients for signs and symptoms of infection;
treat appropriately. (5.5)• Prolonged Cytopenias: Patients may exhibit Grade 3 or higher cytopenias
for several weeks following YESCARTA infusion. Monitor complete
blood counts. (5.6)• Hypogammaglobulinemia: Monitor and provide replacement therapy. (5.7)• Secondary Malignancies: T cell malignancies have occurred following
treatment of hematologic malignancies with BCMA- and CD19-directed
genetically modified autologous T cell immunotherapies, including
YESCARTA (5.8). In the event that a secondary malignancy occurs after
treatment with YESCARTA, contact Kite at 1-844-454-KITE (5483). (5.8)• Effects on Ability to Drive and Use Machines: Advise patients to refrainfrom driving and engaging in hazardous occupations or activities, such as
operating heavy or potentially dangerous machinery, for at least 8 weeks
after receiving YESCARTA. (5.9)------------------------------ADVERSE REACTIONS------------------------------The most common adverse reactions (incidence ≥ 30%), excluding laboratory
abnormalities, in patients with non-Hodgkin lymphoma are CRS, fever,hypotension, encephalopathy, fatigue, tachycardia, headache, nausea, febrileneutropenia, diarrhea, musculoskeletal pain, infections with pathogen
unspecified, chills and decreased appetite. (6.1)
The most common Grade 3-4 laboratory abnormalities (≥ 30%) areleukopenia, lymphopenia, neutropenia, anemia, thrombocytopenia, andhypophosphatemia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Kite at 1-844454-KITE (5483) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.

Revised: 06/2024

FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGICTOXICITIES and SECONDARY HEMATOLOGICALMALIGNANCIES
1 INDICATIONS AND USAGE
1.1 Large B-cell Lymphoma
1.2 Follicular Lymphoma
2 DOSAGE AND ADMINISTRATION
2.1 Dose
2.2 Administration
2.3 Management of Severe Adverse Reactions
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Cytokine Release Syndrome (CRS)
5.2 Neurologic Toxicities
5.3 YESCARTA and TECARTUS REMS
5.4 Hypersensitivity Reactions
5.5 Serious Infections
5.6 Prolonged Cytopenias
5.7 Hypogammaglobulinemia
5.8 Secondary Malignancies
5.9 Effects on Ability to Drive and Use Machines
6 ADVERSE REACTIONS

6.1 Clinical Trials Experience
6.2 Immunogenicity
6.3 Postmarketing Experience
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Relapsed or Refractory Large B-Cell Lymphoma
14.2 Relapsed or Refractory Follicular Lymphoma
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION* Sections or subsections omitted from the full prescribing information are
not listed.

FULL PRESCRIBING INFORMATIONWARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES and SECONDARYHEMATOLOGICAL MALIGNANCIES• 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 [seeDosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)].
• Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving
YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities
after treatment with YESCARTA. Provide supportive care and/or corticosteroids as needed [see Dosage
and Administration (2.2, 2.3), Warnings and Precautions (5.2)].
• T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- andCD19-directed genetically modified autologous T cell immunotherapies, including YESCARTA [seeWarnings and Precautions (5.8)].
•

YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation
Strategy (REMS) called the YESCARTA and TECARTUS REMS [see Warnings and Precautions (5.3)].

1

INDICATIONS AND USAGE

1.1
Large B-cell Lymphoma
YESCARTA is 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 systemlymphoma.
1.2
Follicular Lymphoma
YESCARTA is 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 [see Clinical Studies (14.2)]. Continued
approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory
trial(s).
2

DOSAGE AND ADMINISTRATION

For autologous use only. For intravenous use only.
2.1

Dose

Each single infusion bag of YESCARTA contains a suspension of chimeric antigen receptor (CAR)-positive T cells inapproximately 68 mL. The target dose is 2 × 106 CAR-positive viable T cells per kg body weight, with a maximum of
2 × 108 CAR-positive viable T cells.

2.2

Administration

YESCARTA is for autologous use only. The patient’s identity must match the patient identifiers on the YESCARTA
cassette and infusion bag. Do not infuse YESCARTA if the information on the patient-specific label does not matchthe intended patient.
Preparing Patient for YESCARTA Infusion
Confirm availability of YESCARTA prior to starting the lymphodepleting regimen.
Pre-treatment• Administer a lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg/m2 intravenously andfludarabine 30 mg/m2 intravenously on the fifth, fourth, and third day before infusion of YESCARTA.
Premedication•

Administer acetaminophen 650 mg PO and diphenhydramine 12.5 mg intravenously or PO approximately 1hour before YESCARTA infusion.

•

Consider the use of prophylactic corticosteroid in patients after weighing the potential benefits and risks [seeWarnings and Precautions (5.1 and 5.2)].

Preparation of YESCARTA for Infusion
Coordinate the timing of YESCARTA thaw and infusion. Confirm the infusion time in advance, and adjust the start
time of YESCARTA thaw such that it will be available for infusion when the patient is ready.
• Confirm patient identity: Prior to YESCARTA preparation, match the patient’s identity with the patient
identifiers on the YESCARTA cassette.
• Do not remove the YESCARTA product bag from the cassette if the information on the patient-specific label
does not match the intended patient.
• Once patient identification is confirmed, remove the YESCARTA product bag from the cassette and checkthat the patient information on the cassette label matches the bag label.
• Inspect the product bag for any breaches of container integrity such as breaks or cracks before thawing. If the
bag is compromised, follow the local guidelines (or call Kite at 1-844-454-KITE).
• Place the infusion bag inside a second sterile bag per local guidelines.
• Thaw YESCARTA at approximately 37°C using either a water bath or dry thaw method until there is novisible ice in the infusion bag. Gently mix the contents of the bag to disperse clumps of cellular material. If
visible cell clumps remain continue to gently mix the contents of the bag. Small clumps of cellular material
should disperse with gentle manual mixing. Do not wash, spin down, and/or re-suspend YESCARTA in new
medium prior to infusion.
• Once thawed, YESCARTA may be stored at room temperature (20°C to 25°C) for up to 3 hours.
Administration• For autologous use only.
• Ensure that tocilizumab and emergency equipment are available prior to infusion and during the recovery
period.
• Do NOT use a leukodepleting filter.
• Central venous access is recommended for the infusion of YESCARTA.
• Confirm the patient’s identity matches the patient identifiers on the YESCARTA product bag.
• Prime the tubing with normal saline prior to infusion.
• Infuse the entire contents of the YESCARTA bag within 30 minutes by either gravity or a peristaltic pump.
YESCARTA is stable at room temperature for up to 3 hours after thaw.
• Gently agitate the product bag during YESCARTA infusion to prevent cell clumping.
• After the entire content of the product bag is infused, rinse the tubing with normal saline at the same infusion
rate to ensure all product is delivered.

YESCARTA contains human blood cells that are genetically modified with replication incompetent retroviral vector.
Follow universal precautions and local biosafety guidelines for handling and disposal to avoid potential transmissionof infectious diseases.
Monitoring
•
•
•
2.3

Administer YESCARTA at a certified healthcare facility.
Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs andsymptoms of CRS and neurologic toxicities.
Instruct patients to remain within proximity of a certified healthcare facility for at least 4 weeks following
infusion.
Management of Severe Adverse Reactions

Cytokine Release Syndrome (CRS)
Identify CRS based on clinical presentation [see Warnings and Precautions (5.1)]. Evaluate for and treat other causesof fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in Table 1.
Patients who experience Grade 2 or higher CRS (e.g., hypotension not responsive to fluids, or hypoxia requiring
supplemental oxygenation) should be monitored with continuous cardiac telemetry and pulse oximetry. For patients
experiencing severe CRS, consider performing an echocardiogram to assess cardiac function. For severe or lifethreatening CRS, consider intensive-care supportive therapy.
Table 1.

CRS Grading and Management Guidance

CRS Grade a
Grade 1
Symptoms require symptomatic
treatment only (e.g., fever, nausea,
fatigue, headache, myalgia, malaise).
Grade 2Symptoms require and respond tomoderate intervention.
Oxygen requirement less than 40% FiO2
or hypotension responsive to fluids or
low-dose of one vasopressor orGrade 2 organ toxicity.b

Tocilizumab

Corticosteroids

If symptoms (e.g., 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.

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

Administer dexamethasone 10 mg
intravenously once daily.

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 24hour period; maximum total of 4 doses.

If improving, manage as Grade 1 above
and continue corticosteroids until theseverity is Grade 1 or less, then quickly
taper as clinically appropriate.
If not improving, manage as appropriate
grade below.

If improving, discontinue tocilizumab.
Grade 3

Per Grade 2.

Symptoms require and respond toaggressive intervention.

If improving, manage as appropriate
grade above.

Oxygen requirement greater than orequal to 40% FiO2 or hypotension
requiring high-dose or multiple
vasopressors or
Grade 3 organ toxicity or Grade 4transaminitis.

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, thenquickly taper as clinically appropriate.
If not improving, manage as Grade 4.

CRS Grade a

Tocilizumab

Corticosteroids

Grade 4

Per Grade 2.

Life-threatening symptoms.

If improving, manage as appropriate
grade above.

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

Requirements for ventilator support,
continuous veno-venous hemodialysis(CVVHD) or
Grade 4 organ toxicity (excludingtransaminitis).

If improving, manage as appropriate
grade above and continue
corticosteroids until the severity is
Grade 1 or less, then taper as clinicallyappropriate.
If not improving, consider
methylprednisolone 1000 mg 2-3 times
a day or alternate therapy.d

a.
b.
c.
d.

Lee et al. 2014.
Refer to Table 2 for management of neurologic toxicity.
Refer to tocilizumab Prescribing Information for details.
Alternate therapy includes (but is not limited to): anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG and ATG.

Neurologic Toxicity
Monitor patients for signs and symptoms of neurologic toxicity/immune effector cell-associated neurotoxicity
syndrome (ICANS) (Table 2). Rule out other causes of neurologic symptoms. Patients who experience Grade 2 orhigher 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 levetiracetam
for seizure prophylaxis for any grade of neurologic toxicities.
Table 2.
Grading
Assessmenta
Grade 1

Neurologic Toxicity/ICANS Grading and Management GuidanceConcurrent CRS

No Concurrent CRS

Administer tocilizumab per Table 1 formanagement of Grade 1 CRS.

Administer one dose of dexamethasone 10 mg
intravenously.

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

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

If not improving after 2 days, repeat
dexamethasone 10 mg intravenously.
Consider levetiracetam for seizure prophylaxis.
Grade 2Administer tocilizumab per Table 1 formanagement of Grade 2 CRS.

Administer dexamethasone 10 mg intravenously
four times a day.

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

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

If improving, continue corticosteroids until theseverity is Grade 1 or less, then quickly taper as
clinically appropriate.
If not improving, manage as appropriate grade
below.

Consider levetiracetam for seizure prophylaxis.

If not improving, manage as appropriate grade
below.

Grading
Assessmenta
Grade 3

Concurrent CRS

No Concurrent CRS

Administer tocilizumab per Table 1 formanagement of Grade 2 CRS.

Administer methylprednisolone 1000 mg
intravenously once daily.

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 clinicallyappropriate.

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

If not improving, manage as Grade 4.

If not improving, manage as Grade 4.
Consider levetiracetam for seizure prophylaxis.
Grade 4

Administer tocilizumab per Table 1 formanagement of Grade 2 CRS.

Administer methylprednisolone 1000 mg
intravenously twice per day.

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 clinicallyappropriate.

If improving, manage as appropriate grade above
and continue corticosteroids until the severity is
Grade 1 or less, then taper as clinicallyappropriate.
If not improving, consider 1000 mg of
methylprednisolone intravenously 3 times a day oralternate therapy.b

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

Consider levetiracetam for seizure prophylaxis.
a.
b.

Severity based on Common Terminology Criteria for Adverse Events.
Alternate therapy includes (but is not limited to): anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG and ATG.

3

DOSAGE FORMS AND STRENGTHSYESCARTA is available as a cell suspension for infusion.
A single dose of YESCARTA contains 2 × 106 CAR-positive viable T cells per kg of body weight (or maximum of
2 × 108 CAR-positive viable T cells for patients 100 kg and above) in approximately 68 mL suspension in an infusion
bag [see How Supplied/Storage and Handling (16)].

4

CONTRAINDICATIONS

None.
5

WARNINGS AND PRECAUTIONS

5.1

Cytokine Release Syndrome

CRS, including fatal or life-threatening reactions, occurred following treatment with YESCARTA. CRS occurred in
90% (379/422) of patients with non-Hodgkin lymphoma (NHL) receiving YESCARTA, including ≥ Grade 3 (Leegrading system1) CRS in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL),
including ≥ Grade 3 CRS in 9% [see Adverse Reactions (6)]. Among patients with LBCL who died after receiving
YESCARTA, four 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 to 12 days) and the median duration of CRS was 7 days

(range: 2 to 58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following
infusion (range: 1 to 10 days) and the median duration was 7 days (range: 2 to 43 days).
CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including ≥Grade 3 CRS in 8% [see Adverse Reactions (6)]. Among patients with iNHL who died after receiving YESCARTA,
one patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1 to
20 days) and the median duration was 6 days (range: 1 to 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 (HLH/MAS) [see Adverse Reactions (6)].
The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in two subsequentcohorts of LBCL patients in ZUMA-1. Among patients who received tocilizumab and/or corticosteroids for ongoing
Grade 1 events (see Table 1) [see Clinical Trials Experience (6.1)], 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 to 8 days) and the median duration of CRS was 7 days (range: 2 to 16 days).
Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the dayof infusion of YESCARTA [see Clinical Trials Experience (6.1)]. Thirty-one of the 39 patients (79%) developed CRS
at which point the patients were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patientsdeveloping Grade 3 or higher CRS. The median time to onset of CRS was 5 days (range: 1 to 15 days) and the median
duration of CRS was 4 days (range: 1 to 10 days). Although there is no known mechanistic explanation, consider therisk 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 [See Neurologic Toxicities (5.2)].
Ensure that 2 doses of tocilizumab are available prior to infusion of YESCARTA. Monitor patients at least daily for 7
days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs
or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or
symptoms of CRS occur at any time [see Patient Counseling Information (17)]. At the first sign of CRS, institutetreatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated [see Dosage andAdministration (2.3)].

5.2

Neurologic Toxicities

Neurologic toxicities (including ICANS) that were fatal or life-threatening occurred following treatment with
YESCARTA. Neurologic toxicities occurred in 78% (330/422) of patients with NHL receiving YESCARTA,
including ≥ Grade 3 cases in 25%.
Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including ≥ Grade 3 cases in 31%
and in 74% (124/168) of patients in ZUMA-7 including ≥ Grade 3 cases in 25%. The median time to onset was 4 days
(range: 1 to 43 days) and the median duration was 17 days in patients with LBCL in ZUMA-1. The median time toonset for neurologic toxicity was 5 days (range:1 to 133 days) and median duration was 15 days in patients with LBCLin 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 to 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 YESCARTA
infusion in 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 with YESCARTA. Fatal and serious cases of cerebral edema and encephalopathy,
including late-onset encephalopathy, have occurred in patients treated with YESCARTA.
The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in
two subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of
Grade 1 toxicities (see Table 2), 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 to 93 days) with a median duration of 8 days (range: 1 to 144 days). Prophylactic treatment withcorticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA[see Clinical Trials Experience (6.1)]. Of these 39 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 neurological
toxicities was 6 days (range: 1 to 274 days) with a median duration of 12 days (range: 1 to 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 [See Cytokine Release
Syndrome (5.1)].
Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptomsof neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion andtreat promptly [see Dosage and Administration (2.3)].
5.3

YESCARTA and TECARTUS REMS

Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program undera Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS [see Boxed
Warning and Warnings and Precautions (5.1 and 5.2)]. The required components of the YESCARTA and
TECARTUS REMS are:•

Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS
requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensurethat a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after
YESCARTA infusion, if needed for treatment of CRS.

Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).
5.4

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of YESCARTA. Serious hypersensitivity reactions, including
anaphylaxis, may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in YESCARTA.
5.5

Serious Infections

Severe or life-threatening infections occurred in patients after YESCARTA infusion. Infections (all grades) occurred in
45% of patients with NHL. Grade 3 or higher infections occurred in 17% of patients, including Grade 3 or higher
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 YESCARTA infusion and treat
appropriately. Administer prophylactic antimicrobials according to local guidelines.
Febrile neutropenia was observed in 36% of patients with NHL after YESCARTA infusion 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) andviral 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 beconsidered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be
performed.

Hepatitis B Virus Reactivation
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.
5.6

Prolonged Cytopenias

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA
infusion. Grade 3 or higher cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 39% of all
patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts
after YESCARTA infusion.
5.7

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with YESCARTA.
Hypogammaglobulinemia was reported as an adverse reaction in 14% of all patients with NHL. Monitor
immunoglobulin levels after treatment with YESCARTA 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 with YESCARTA.
5.8

Secondary Malignancies

Patients treated with YESCARTA may develop secondary malignancies. T cell malignancies have occurred following
treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell
immunotherapies, including YESCARTA. Mature T cell malignancies, including CAR-positive tumors, may present assoon as weeks following infusion, and may include fatal outcomes [see Boxed Warning, Adverse Reactions (6.3),
Patient Counseling Information (17)].
Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844454-KITE (5483) to obtain instructions on patient samples to collect for testing.
5.9

Effects on Ability to Drive and Use Machines

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving YESCARTA
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.
6

ADVERSE REACTIONS

The following adverse reactions are described elsewhere in the labeling:
•
•
•
•
•
•
6.1

Cytokine Release Syndrome [see Warnings and Precautions (5.1, 5.3)]
Neurologic Toxicities [see Warnings and Precautions (5.2, 5.3)]
Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
Serious Infections [see Warnings and Precautions (5.5)]
Prolonged Cytopenias [see Warnings and Precautions (5.6)]
Hypogammaglobulinemia [see Warnings and Precautions (5.7)]
Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates
observed in practice.
The data described in the WARNINGS AND PRECAUTIONS reflect exposure to a single dose of YESCARTA in one
randomized, open-label study with 168 patients with relapsed or refractory LBCL (ZUMA-7) and two open-label,single-arm studies with 108 patients with relapsed or refractory LBCL (ZUMA-1 study) and 146 patients with relapsed
or refractory iNHL (including 124 with FL; ZUMA-5 study).
Relapsed or Refractory Large B-cell Lymphoma
ZUMA-7The safety of YESCARTA was evaluated in ZUMA-7, a randomized, open-label, multicenter study in which patientswith primary refractory LBCL or first relapse of LBCL received YESCARTA (N = 168) or standard therapy (N = 168)[see Clinical Studies (14)]. Patients had not yet received treatment for relapsed or refractory lymphoma and werepotential candidates for autologous HSCT. The trial excluded patients who were not deemed candidates for transplantor who had a history of central nervous system (CNS) disorders (such as seizures or cerebrovascular ischemia), serious
or uncontrolled infection, or autoimmune disease requiring systemic immunosuppression. The study required ANC ≥1000/mm3, platelet count ≥ 75,000/mm3, creatinine clearance ≥ 60 ml/min, AST/ALT ≤ 2.5 x ULN, and total bilirubin≤ 1.5 mg/dL.
The median age of the YESCARTA-treated safety population was 59 years (range: 21 to 80 years); 62% were male.
The baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 54% of patients and 1 in
46%.
The most common non-laboratory adverse reactions to YESCARTA (incidence ≥ 20%) 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. Serious adverse reactions occurred in 50% of patients. The most common
serious adverse reactions (> 5%) included CRS, fever, encephalopathy, hypotension, infection with unspecified
pathogen, and pneumonia. Fatal adverse reactions occurred in 2% of patients.
The most common (≥ 10%) Grade 3 or higher non-laboratory adverse reactions included febrile neutropenia,
encephalopathy, and hypotension.
Sixty-seven percent (112/168) of patients received tocilizumab after infusion of YESCARTA.
Table 3 summarizes selected non-laboratory adverse reactions in patients treated with YESCARTA, and Table 4summarizes selected new or worsening Grade 3 or 4 laboratory abnormalities.
Table 3.

Adverse Reactions in ≥ 10% of Patients Treated with YESCARTA in ZUMA-7

Adverse Reaction

Febrile neutropenia
Cardiac Disorders
Tachycardia a
Arrhythmia b
Gastrointestinal Disorders
Diarrhea c
NauseaAbdominal pain dConstipation
Vomiting
Dry Mouth
General Disorders and Administration Site Conditions
Fever eFatigue f
ChillsEdema gImmune System Disorders

YESCARTA
N = 168
Any Grade (%)
31

Grade 3 or Higher (%)
31

43
14

2
3

42
40
20
20
20
10

3
2
4
0
0
0

93
52
28
23

9
7
1
1

Adverse Reaction

Cytokine release syndrome
Hypogammaglobulinemia
Infections and Infestations
Infections with pathogen unspecified
Viral infections
Bacterial infections
Fungal infections
Metabolism and Nutrition Disorders
Decreased appetite
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain hMotor dysfunction i
Nervous System Disorders
Encephalopathy j
Headache k
Tremor
Dizziness lAphasia
Neuropathy peripheral m
Psychiatric Disorders
Insomnia nDelirium o
Renal and Urinary Disorders
Renal insufficiency p
Respiratory, Thoracic and Mediastinal Disorders
Cough qHypoxia
Skin and Subcutaneous Tissue Disorders
Rash rVascular Disorders
Hypotension s

YESCARTA
N = 168
Any Grade (%)
92
11Grade 3 or Higher (%)
7
0

25
15
10
10

8
4
5
1

24

4

40
15

1
4

46
41
25
25
20
11

18
3
1
4
7
2

13
12

0
4

11

2

27
21

1
9

17

1

47

11

The following events were also counted in the incidence of CRS: coagulopathy, tachycardia, arrhythmia, cardiac failure, diarrhea, nausea,
vomiting, fever, fatigue, chills, edema, decreased appetite, musculoskeletal pain, headache, tremor, dizziness, renal insufficiency, cough,hypoxia, dyspnea, pleural effusion, respiratory failure, rash, hypotension, and hypertension.
a.
Tachycardia includes tachycardia, sinus tachycardia.
b.
Arrhythmia includes arrhythmia, atrial fibrillation, bradycardia, electrocardiogram QT prolonged, extrasystoles,
sinus bradycardia, supraventricular extrasystoles, supraventricular tachycardia, ventricular extrasystoles, ventricular tachycardia.
c.
Diarrhea includes diarrhea, colitis.
d.
Abdominal pain includes abdominal pain, abdominal discomfort, abdominal pain lower, abdominal pain upper, dyspepsia.
e.
Fever includes pyrexia.
f.
Fatigue includes fatigue, asthenia, malaise.
g.
Edema includes edema, face edema, fluid overload, generalized edema, hypervolemia, localized edema, edema genital,
edema peripheral, periorbital edema, peripheral swelling, pulmonary edema.
h.
Musculoskeletal pain includes musculoskeletal pain, arthralgia, arthritis, back pain, bone pain, flank pain, groin pain,
musculoskeletal chest pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity.
i.
Motor dysfunction includes muscle contractions involuntary, muscle spasms, muscle twitching, muscular weakness.
j.
Encephalopathy includes encephalopathy, altered state of consciousness, amnesia, apraxia, bradyphrenia, cognitive disorder,
confusional state, depressed level of consciousness, disturbance in attention, dysarthria, dysgraphia, dyspraxia, lethargy, loss of
consciousness, memory impairment, mental impairment, mental status changes, metabolic encephalopathy, slow speech, somnolence,

k.
l.
m.
n.
o.
p.
q.
r.
s.

toxic encephalopathy.
Headache includes headache and tension headache.
Dizziness includes dizziness, dizziness postural, presyncope, syncope, vertigo.
Neuropathy peripheral includes hypoesthesia, lumbar radiculopathy, neuropathy peripheral, paresthesia, peroneal nerve palsy, sciatica.
Insomnia includes insomnia and sleep deficit.
Delirium includes delirium, agitation, delusion, disorientation, hallucination, irritability, restlessness.
Renal insufficiency includes acute kidney injury, blood creatinine increased, chronic kidney disease.
Cough includes cough, productive cough, upper-airway cough syndrome.
Rash includes rash, dermatitis, dermatitis allergic, dermatitis bullous, drug eruption, erythema, pruritus,
rash macular, rash maculo-papular, rash pruritic, urticaria.
Hypotension includes hypotension, capillary leak syndrome, orthostatic hypotension.

Other clinically important adverse reactions that occurred in less than 10% of patients treated with YESCARTA
include the following:•
Blood and lymphatic system disorders: Coagulopathy (9%)•
Cardiac disorders: Cardiac failure (1%)•
Eye Disorders: Visual impairment (7%)•
Infections and infestations: Pneumonia (8%), Sepsis (4%)•
Nervous system disorders: Ataxia (6%), seizure (3%), myoclonus (2%), facial paralysis (2%), paresis(2%)•
Respiratory, thoracic and mediastinal disorders: Dyspnea (8%), pleural effusion (6%), respiratory failure(2%)•
Vascular disorders: Hypertension (9%), thrombosis (7%)
Laboratory abnormalities:
Table 4.

Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients in ZUMA-7 Following
Treatment with YESCARTA1 (N = 168)

Laboratory Abnormality

YESCARTA

Grades 3 or 4 (%)
Leukocyte decrease95
Neutrophil decrease
94
Lymphocyte decrease
94
Hemoglobin decrease40
Platelet decrease
26
Sodium decrease
12
Glucose increase
11
1
Baseline lab values were assessed prior to lymphodepleting chemotherapy.

ZUMA-1The safety of YESCARTA was evaluated in ZUMA-1, a study in which 108 patients with relapsed or refractory LBCL
received CD19-positive CAR T cells based on a recommended dose which was weight-based [see Clinical Studies(14)]. Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) or autoimmune diseaserequiring systemic immunosuppression were ineligible. The median age of the study population was 58 years (range:
23 to 76 years); 68% were male. The baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0
in 43% of patients and 1 in 57% of patients.
The most common adverse reactions (incidence ≥ 20%) 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. Serious
adverse reactions occurred in 52% of patients. The most common serious adverse reactions (> 2%) included
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 included febrile neutropenia, fever, CRS, encephalopathy,
infections with pathogen unspecified, hypotension, hypoxia, and lung infections.
Forty-five percent (49/108) of patients received tocilizumab after infusion of YESCARTA.
Table 5 summarizes non-laboratory adverse reactions that occurred in ≥ 10% of patients treated with YESCARTA, andTable 6 describes the laboratory abnormalities of Grade 3 or 4 that occurred in ≥ 10% of patients.
Table 5.

Adverse Reactions Observed in ≥ 10% of Patients Treated with YESCARTA in ZUMA-1 (N = 108)

Adverse Reaction
Blood and Lymphatic System Disorders
Febrile neutropenia
Cardiac Disorders
Tachycardia a
Arrhythmia b
Gastrointestinal Disorders
Diarrhea
NauseaVomiting
Constipation
Abdominal pain c
Dry mouth
General Disorders and Administration Site Conditions
Fever dFatigue e
ChillsEdema fImmune System Disorders
Cytokine release syndrome
Hypogammaglobulinemia g
Infections and Infestations
Infections with pathogen unspecified
Viral infections
Bacterial infections
Investigations
Decreased appetite
Weight decreased
Dehydration
Musculoskeletal and Connective Tissue Disorders
Motor dysfunction h
Pain in extremity iBack pain
Muscle pain
Arthralgia
Nervous System Disorders
Encephalopathy j
Headache k
Tremor
Dizziness lAphasia m
Psychiatric Disorders
Delirium n

Any Grade (%)

Grade 3 or Higher (%)

34

31

57
23

2
7

38
34
26
23
14
11

4
0
1
0
1
0

86
46
40
19

16
3
0
1

94
15

13
0

26
16
13

16
4
9

44
16
11

2
0
3

19
17
15
14
10

1
2
1
1
0

57
45
31
21
18

29
1
2
1
6

17

6

Adverse Reaction
Respiratory, Thoracic and Mediastinal Disorders
Hypoxia o
Cough pDyspnea q
Pleural effusion
Renal and Urinary Disorders
Renal insufficiency
Vascular Disorders
Hypotension r
Hypertension
Thrombosis s

Any Grade (%)

Grade 3 or Higher (%)

32
30
19
13

11
0
3
2

12

5

57
15
10

15
6
1

The following events were also counted in the incidence of CRS: tachycardia, arrhythmia, fever, chills, hypoxia, renal insufficiency, andhypotension.
a. Tachycardia includes tachycardia, sinus tachycardia.
b. Arrhythmia 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,
ventricular tachycardia.
c. Abdominal pain includes abdominal pain, abdominal pain lower, abdominal pain upper.
d. Fever includes fever, febrile neutropenia.
e. Fatigue includes fatigue, malaise.
f. Edema includes face edema, generalized edema, local swelling, localized edema, edema, edema genital, edema peripheral, periorbital
edema, peripheral swelling, scrotal edema.
g. Hypogammaglobulinemia includes hypogammaglobulinemia, blood immunoglobulin D decreased, blood immunoglobulin G decreased.
h. Motor dysfunction includes muscle spasms, muscular weakness.
i. Pain in extremity includes pain not otherwise specified, pain in extremity.
j. Encephalopathy includes cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention,
encephalopathy, hypersomnia, leukoencephalopathy, memory impairment, mental status changes, paranoia, somnolence, stupor.
k. Headache includes headache, head discomfort, sinus headache, procedural headache.
l. Dizziness includes dizziness, presyncope, syncope.
m. Aphasia includes aphasia, dysphasia.
n. Delirium includes agitation, delirium, delusion, disorientation, hallucination, hyperactivity, irritability, restlessness.
o. Hypoxia includes hypoxia, oxygen saturation decreased.
p. Cough includes cough, productive cough, upper-airway cough syndrome.
q. Dyspnea includes acute respiratory failure, dyspnea, orthopnea, respiratory distress.
r. Hypotension includes diastolic hypotension, hypotension, orthostatic hypotension.
s. Thrombosis includes deep vein thrombosis, embolism, embolism venous, pulmonary embolism, splenic infarction, splenic veinthrombosis, subclavian vein thrombosis, thrombosis, thrombosis in device.

Other clinically important adverse reactions that occurred in less than 10% of patients treated with YESCARTA
include the following:•
Blood and lymphatic system disorders: Coagulopathy (2%)•
Cardiac disorders: Cardiac failure (6%), cardiac arrest (4%)•
Immune system disorders: Hemophagocytic lymphohistiocytosis/macrophage activation syndrome(HLH/MAS) (1%), hypersensitivity (1%)•
Infections and infestations disorders: Fungal infections (5%)•
Nervous system disorders: Ataxia (6%), seizure (4%), dyscalculia (2%), myoclonus (2%)•
Respiratory, thoracic and mediastinal disorders: Pulmonary edema (9%)•
Skin and subcutaneous tissue disorders: Rash (9%)•
Vascular disorders: Capillary leak syndrome (3%)

Laboratory abnormalities:
Table 6.

Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients in ZUMA-1 Following
Treatment with YESCARTA1 (N = 108)

Laboratory Abnormality
Lymphocyte decrease
Leukocyte decrease
Neutrophil decrease
Hemoglobin decrease
Platelet decrease
Phosphate decrease
Sodium decrease
Albumin decrease
Direct bilirubin increased
Uric acid increased
Potassium decrease

Grades 3 or 4 (%)
96
96
92
60
56
52
19
19
14
13
11

1

Baseline lab values were assessed prior to lymphodepleting chemotherapy.

The safety and efficacy of YESCARTA was evaluated in two subsequent cohorts of LBCL patients. The first
subsequent, open label, safety management cohort in ZUMA-1 evaluated the safety and efficacy of YESCARTA withthe use of tocilizumab and/or corticosteroid and prophylactic levetiracetam (750 mg PO or IV twice daily) for Grade 1
CRS or neurologic events (see Tables 1 and 2). A total of 46 patients with relapsed or refractory LBCL were enrolled
and 41 patients were treated with YESCARTA. Of the remaining 5 patients who were not treated, 2 patients died prior
to receiving YESCARTA and 3 patients were ineligible due to disease progression. Twenty-eight patients (68%)
treated with YESCARTA received bridging therapy between leukapheresis and lymphodepleting chemotherapy.
Thirty-two patients (78%) treated with YESCARTA received tocilizumab and/or corticosteroid for CRS and/or
neurologic events. Fifteen of 36 with Grade 1 CRS and 21 of 24 patients with Grade 2 CRS received tocilizumab
and/or corticosteroids. Among patients who received treatment for Grade 1 or Grade 2 CRS, most patients (13 of 15
and 19 of 21 patients, respectively) received both tocilizumab and corticosteroids. Most patients received 1 or 2 dosesof each drug. Ten of 27 patients with Grade 1 and 7 of 15 patients with Grade 2 neurologic events received
corticosteroids alone or in combination with tocilizumab.
The second subsequent, open label, safety management cohort in ZUMA-1 evaluated the safety and efficacy of
YESCARTA with the use of prophylactic corticosteroids (oral dexamethasone 10 mg once daily for 3 days, starting
prior to YESCARTA infusion on Day 0) and prophylactic levetiracetam (750 mg PO or IV) [see Warnings andPrecautions (5.1 and 5.2)].
Relapsed or Refractory Follicular Lymphoma
The safety of YESCARTA was evaluated in ZUMA-5, a study that included 146 patients with relapsed or refractoryiNHL (124 patients with FL and 22 with marginal zone lymphoma) who received CD19-positive CAR T cells [seeClinical Studies (14)]. Patients with a history of CNS disorders or autoimmune disease requiring systemic
immunosuppression were ineligible. The median age was 61 years (range: 34 to 79 years), 43% were female, 93%
were white, 3% were black, and 1% were Asian.
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.
Fifty-one percent (75/146) of patients received tocilizumab after infusion of YESCARTA.
Table 7 summarizes the adverse reactions, excluding laboratory terms, that occurred in at least 10% of patients treatedwith YESCARTA and Table 8 describes Grade 3 or 4 laboratory abnormalities that developed or worsened in at least
10% of patients.
Table 7.

Adverse Reactions in ≥ 10% of Patients Treated with YESCARTA in ZUMA-5 (N = 146)

Adverse Reaction
Blood and lymphatic system disorders
Febrile neutropenia a
Cardiac Disorders
Tachycardia b
Arrhythmia c
Gastrointestinal Disorders
NauseaDiarrhea dConstipation
Vomiting
Abdominal pain e
General Disorders and Administration Site Conditions
Fever
Fatigue f
ChillsEdema gImmune System Disorders
Cytokine release syndrome
Immunoglobulins decreased h
Infections and Infestations
Infections with pathogen unspecified
Pneumonia i
Fungal infections
Viral Infections
Metabolism and Nutrition Disorders
Decreased appetite j
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain kMotor dysfunction l
Nervous System Disorders
Encephalopathy mHeadache
Tremor
Dizziness n
Aphasia
Neuropathy peripheral oAtaxia p
Psychiatric Disorders
Delirium q
Insomnia
Affective disorder r

Any Grade (%)

Grade 3 or Higher (%)

41

41

44
21

1
2

40
29
28
24
16

0
1
0
1
0

85
49
29
13

8
1
0
1

84
18

8
1

45
13
12
13

14
8
2
2

26

1

40
18

1
2

49
45
31
20
14
12
10

16
1
1
0
4
0
0

16
16
10

5
0
1

Adverse Reaction
Respiratory, Thoracic and Mediastinal Disorders
Cough sHypoxia
Dyspnea t
Nasal congestion
Skin and Subcutaneous Tissue Disorders
Rash uVascular Disorders
Hypotension v
Hypertension
Thrombosis w

Any Grade (%)

Grade 3 or Higher (%)

25
23
12
10

0
8
1
0

19

3

51
13
12

4
6
4

a.
b.
c.

Febrile neutropenia includes febrile neutropenia, fever overlapping with neutropenia.
Tachycardia includes tachycardia, sinus tachycardia.
Arrhythmia 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.
d. Diarrhea includes diarrhea, colitis, enteritis.
e. Abdominal pain includes abdominal pain, abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness,
dyspepsia, epigastric discomfort.
f. Fatigue includes asthenia, fatigue, decreased activity, malaise.
g. Edema includes edema, face edema, generalized edema, localized edema, edema peripheral, peripheral swelling, pulmonary edema,swelling face.
h. Immunoglobulins decreased includes hypogammaglobulinemia, blood immunoglobulin G decreased.
i. Pneumonia includes pneumonia streptococcal, pneumonia, lung infiltration. Pneumonia is also summarized under infections withpathogen unspecified.
j. Decreased appetite includes decreased appetite, hypophagia.
k. Musculoskeletal pain includes musculoskeletal pain, arthralgia, back pain, bone pain, flank pain, groin pain, musculoskeletal chest
pain, myalgia, neck pain, osteoarthritis, pain in extremity.
l. Motor dysfunction includes motor dysfunction, muscle rigidity, muscle spasms, muscle strain, muscular weakness.
m. Encephalopathy 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.
n. Dizziness includes dizziness, presyncope, syncope, vertigo.
o. Neuropathy peripheral includes allodynia, cervical radiculopathy, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral,paresthesia, peripheral sensory neuropathy.
p. Ataxia includes ataxia, balance disorder, gait disturbance, vestibular disorder.
q. Delirium includes agitation, delirium, hallucination, restlessness.
r. Affective disorder includes anxiety, depression, impulsive behavior, mania, panic attack.
s. Cough includes cough, productive cough, upper-airway cough syndrome.
t. Dyspnea includes dyspnea, dyspnea exertional.
u. Rash includes dermatitis bullous, erythema, pruritus, rash, rash macular, rash maculo-papular, Stevens-Johnson syndrome, urticaria.
v. Hypotension includes capillary leak syndrome, hypotension, hypoperfusion, orthostatic hypotension.
w. Thrombosis includes deep vein thrombosis, embolism, peripheral ischemia, pulmonary embolism, thrombosis in device, vascularocclusion, jugular vein thrombosis.

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

Blood and lymphatic system disorders: Coagulopathy (6%)
Cardiac disorders: Cardiac failure (2%)
Eye disorders: Visual impairment (5%), blindness (1%)
Gastrointestinal disorders: Dysphagia (6%)
General disorders and administration site conditions: Multiple organ dysfunction syndrome (1%)
Infections and infestations: Bacterial infections (8%), sepsis (2%), herpesvirus infection (4%)

•
•
•
•
•

Musculoskeletal and connective tissue disorders: Muscle injury (1%)
Nervous system disorders: Seizure (2%), hemiparesis (2%), ischemic stroke (1%)
Renal and urinary disorders: Renal insufficiency (8%)
Respiratory, thoracic and mediastinal disorders: Respiratory failure (1%)
Vascular disorders: Hemorrhage (8%)

Laboratory abnormalities:
Table 8. Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients in ZUMA-5 Following
Treatment with YESCARTA1 (N = 146)
Laboratory Abnormality
Lymphocyte decrease
Leukocyte decrease
Neutrophil decrease
Platelet decrease
Hemoglobin decrease
Phosphate decrease
Sodium decrease
Glucose increase
Calcium decrease

Grades 3 or 4 (%)
96
94
92
35
32
25
10
10
10

1

Baseline lab values were assessed prior to lymphodepleting chemotherapy.

6.2

Immunogenicity

YESCARTA has the potential to induce anti-product antibodies. The immunogenicity of YESCARTA has been
evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection of binding antibodies against
FMC63, the originating antibody of the anti-CD19 CAR. Eleven patients (4%) tested positive for pre-dose anti-FMC63
antibodies at baseline in ZUMA-7 and ZUMA-1, and one patient (1%) who had a negative test result at baseline had apositive test result post administration of YESCARTA in the screening ELISA in ZUMA-7. In ZUMA-5, 19 patients(13%) were antibody-positive at baseline, and 3 patients (2%) who had negative test results at baseline had positive
test results post administration of YESCARTA in the screening ELISA. Results of a confirmatory cell-based assay,
leveraging a properly folded and expressed extracellular portion of the CAR (ScFv, hinge and linker) demonstrated
that all patients treated with YESCARTA that had a positive result in the screening ELISA were antibody negative at
all time points tested. There is no evidence that the kinetics of initial expansion and persistence of YESCARTA, or thesafety or effectiveness of YESCARTA, was altered in these patients.
6.3

Postmarketing Experience

Because adverse events to marketed products are reported voluntarily from a population of uncertain size, it is notalways possible to reliably estimate their frequency or establish a causal relationship to product exposure.
The following adverse event has been identified during postmarketing use of YESCARTA.
Nervous System Disorders
Spinal cord edema, myelitis, quadriplegia, dysphagia, and status epilepticus.
Immune System Disorders
Infusion related reactions
Neoplasms
T cell malignancies

8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Risk Summary
There are no available data with YESCARTA use in pregnant women. No animal reproductive and developmental
toxicity studies have been conducted with YESCARTA to assess whether it can cause fetal harm when administered toa pregnant woman. It is not known if YESCARTA has the potential to be transferred to the fetus. Based on themechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell
lymphocytopenia. Therefore, YESCARTA is not recommended for women who are pregnant, and pregnancy after
YESCARTA infusion should be discussed with the treating physician.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinicallyrecognized pregnancies is 2% - 4% and 15% - 20%, respectively.
8.2

Lactation

Risk Summary
There is no information regarding the presence of YESCARTA in human milk, the effect on the breastfed infant, andthe effects on milk production. The developmental and health benefits of breastfeeding should be considered alongwith the mother’s clinical need for YESCARTA and any potential adverse effects on the breastfed infant fromYESCARTA or from the underlying maternal condition.
8.3

Females and Males of Reproductive Potential

Pregnancy Testing
Pregnancy status of females with reproductive potential should be verified. Sexually active females of reproductive
potential should have a pregnancy test prior to starting treatment with YESCARTA.
Contraception
See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective
contraception in patients who receive the lymphodepleting chemotherapy.
There are insufficient exposure data to provide a recommendation concerning duration of contraception following
treatment with YESCARTA.
Infertility
There are no data on the effect of YESCARTA on fertility.
8.4

Pediatric Use

The safety and efficacy of YESCARTA have not been established in pediatric patients.
8.5

Geriatric Use

Of the 422 patients with NHL who received YESCARTA in clinical trials, 127 patients (30%) were 65 years of age
and older. No clinically important differences in safety or effectiveness were observed between patients aged 65 years
and older and younger patients.
11

DESCRIPTIONYESCARTA (axicabtagene ciloleucel) is a CD19-directed genetically modified autologous T cell immunotherapy. To
prepare YESCARTA, a patient’s own T cells are harvested and genetically modified ex vivo by retroviral transduction
to express a chimeric antigen receptor (CAR) comprising a murine anti-CD19 single chain variable fragment (scFv)

linked to CD28 and CD3-zeta co-stimulatory domains. The anti-CD19 CAR T cells are expanded and infused backinto the patient, where they can recognize and eliminate CD19-expressing target cells.
YESCARTA is prepared from the patient’s peripheral blood mononuclear cells, which are obtained via a standard
leukapheresis procedure. The mononuclear cells are enriched for T cells and activated with anti-CD3 antibody in thepresence of IL-2, then transduced with the replication incompetent retroviral vector containing the anti-CD19 CAR
transgene. The transduced T cells are expanded in cell culture, washed, formulated into a suspension, andcryopreserved. The product must pass a sterility test before release for shipping as a frozen suspension in a patientspecific infusion bag. The product is thawed prior to infusion [see Dosage and Administration (2.2), How
Supplied/Storage and Handling (16)].
In addition to T cells, YESCARTA may contain NK and NK-T cells. The formulation contains 5% dimethyl sulfoxide(DMSO) and 2.5% albumin (human).

12

CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

YESCARTA, a CD19-directed genetically modified autologous T cell immunotherapy, binds to CD19-expressing
cancer cells and normal B cells. Studies demonstrated that following anti-CD19 CAR T cell engagement with
CD19-expressing target cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signaling cascadesthat lead to T cell activation, proliferation, acquisition of effector functions and secretion of inflammatory cytokinesand chemokines. This sequence of events leads to killing of CD19-expressing cells.
12.2

Pharmacodynamics

After YESCARTA infusion, pharmacodynamic responses were evaluated over a 4-week interval by measuringtransient elevation of cytokines, chemokines and other molecules in blood. Levels of cytokines and chemokines suchas IL-6, IL-8, IL-10, IL-15, TNF-α, IFN-γ, and sIL2Rα were analyzed. Peak elevation was observed within the first 14
days after infusion, and levels generally returned to baseline within 28 days.
Due to the on-target effect of YESCARTA, a period of B-cell aplasia is expected.
Large B-cell lymphoma
Among patients with LBCL with an ongoing response at 24 months in the ZUMA-7 study, 21 of 61 evaluable patients(34%) had no detectable B cells at baseline, and the majority of patients at Month 3 (43 of 69 evaluable patients[62%]) and Month 6 (8 of 13 evaluable patients [62%]) had no detectable B cells. At Month 24, 20 of 24 evaluable
patients (83%) had detectable B cells.
Among patients with LBCL with an ongoing response at 24 months in the ZUMA-1 study, 13 of 29 evaluable patients(45%) had no detectable B cells at baseline, and the majority of patients at Month 3 (28 of 35 evaluable patients[80%]) and Month 6 (25 of 32 evaluable patients [78%]) had no detectable B cells. At Month 24, 24 of 32 evaluable
patients (75%) had detectable B cells.
12.3

Pharmacokinetics

Following infusion of YESCARTA, anti-CD19 CAR T cells exhibited an initial rapid expansion followed by a decline
to near baseline levels by 3 months. Peak levels of anti-CD19 CAR T cells occurred within the first 7 - 14 days after
YESCARTA infusion.
Age (range: 21 to 80 years) and gender had no significant impact on AUC Day 0 - 28 and Cmax of YESCARTA.
Large B-cell Lymphoma
Among patients with LBCL in the ZUMA-1 study (n=96 evaluable), the number of anti-CD19 CAR T cells in blood
was positively associated with objective response (CR or PR). The median anti-CD19 CAR T cell Cmax levels in
responders (n=73) were 205% higher compared to the corresponding level in nonresponders (n=23) (43.6 cells/μL vs21.2 cells/μL). Median AUC Day 0 - 28 in responding patients (n=73) was 251% of the corresponding level innonresponders (n=23) (557.1 days × cells/μL vs. 222.0 days × cells/μL).
Among patients with LBCL in the ZUMA-7 study (n=162 evaluable), the number of anti-CD19 CAR T cells in blood
was positively associated with objective response [complete remission (CR) or partial remission (PR)]. The mediananti-CD19 CAR T cell Cmax levels in responders (n=142) were 275% higher compared to the corresponding level innonresponders (n=20) (28.9 cells/μL vs 10.5 cells/μL). Median AUC Day 0 - 28 in responding patients (n=142) was
418% of the corresponding level in nonresponders (n=20) (292.9 days × cells/μL vs. 70.1 days × cells/μL). No
association between peak anti-CD19 CAR T-cell levels and OS was observed among 163 subjects with an evaluable
pharmacokinetic sample when anti-CD19 CAR T-cell peaks were categorized as > median relative to ≤ median.
Follicular Lymphoma
Among patients with FL in the ZUMA-5 study (n=81 evaluable), the median anti-CD19 CAR T cell Cmax levels in
responders (n=74) were 40.1 cells/μL and 46.0 cells/μL in nonresponders (n=7). The median AUC Day 0 - 28 in
responding FL patients (n=74) were 465.8 days × cells/μL and 404.5 days × cells/μL in nonresponders (n=7).
Some patients required tocilizumab and corticosteroids for management of CRS and neurologic toxicities. Patientstreated with tocilizumab (n=44) had 262% and 232% higher anti-CD19 CAR T cells as measured by AUC Day 0 - 28
and Cmax respectively, as compared to patients who did not receive tocilizumab (n=57). Similarly, patients thatreceived corticosteroids (n=26) had 217% and 155% higher AUC Day 0 - 28 and Cmax compared to patients who did
not receive corticosteroids (n=75).
Hepatic and renal impairment studies of YESCARTA were not conducted.
13

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or genotoxicity studies have been conducted with YESCARTA. No studies have been conducted toevaluate the effects of YESCARTA on fertility.
14

CLINICAL STUDIES

14.1

Relapsed or Refractory Large B-Cell Lymphoma

ZUMA-7A randomized, open-label, multicenter trial evaluated the efficacy of YESCARTA in adult patients with relapsed or
refractory LBCL after first-line chemoimmunotherapy that included rituximab and anthracycline (ZUMA-7;
NCT03391466). Patients had not yet received treatment for relapsed or refractory lymphoma and were potential
candidates for autologous HSCT. Patients were required to have primary refractory disease or relapse within 12
months following completion of first-line therapy. The study excluded patients with primary mediastinal B-cell
lymphoma, any history of central nervous system lymphoma, need for urgent therapy due to tumor mass effect, active
or serious infections, and ECOG performance status of 2 or greater.
In total, 359 patients were randomized in a 1:1 ratio to receive a single infusion of YESCARTA or to receive secondline standard therapy, consisting of 2 or 3 cycles of chemoimmunotherapy followed by high-dose therapy andautologous HSCT in patients who attained CR or PR. Randomization was stratified by response to first-line therapy
and second-line age-adjusted International Prognostic Index.
Following lymphodepleting chemotherapy, YESCARTA was administered as a single intravenous infusion at a target
dose of 2 × 106 CAR-positive viable T cells/kg (maximum permitted dose: 2 × 108 cells). The lymphodepleting
regimen consisted of cyclophosphamide 500 mg/m2 intravenously and fludarabine 30 mg/m2 intravenously, both givenon the fifth, fourth, and third day before YESCARTA. All patients who received YESCARTA were monitored at ahealthcare facility for a minimum of 7 days. Bridging therapy, administered between leukapheresis andlymphodepleting chemotherapy, was limited to corticosteroids and was permitted for patients with high disease
burden.
In the overall study population, the median age was 59 years (range: 21 to 81 years), 66% were male, 83% were white,
6% were Asian, and 5% were Black. The diagnoses included de novo DLBCL NOS (63%), HGBL with or without
MYC and BCL-2 and/or BCL-6 rearrangements (19%), and large cell transformation of follicular lymphoma (13%). Intotal, 74% of patients had primary refractory LBCL, and 26% had relapsed disease within 12 months of first-line
therapy.
Of the 180 patients randomized to receive YESCARTA, 178 underwent leukapheresis and 170 were treated with
YESCARTA, of whom 60 (33%) received bridging corticosteroid therapy. Eight patients (4%) were not treatedfollowing leukapheresis, primarily due to progressive disease, serious adverse events, or death. The median time fromleukapheresis to product delivery was 18 days (range: 13 to 49 days), and from leukapheresis to YESCARTA infusion
was 26 days (range: 16 to 52 days). The median dose was 2.0 × 106 CAR-positive viable T cells/kg (range: 1.0 to 2.1 ×
106 cells/kg).
Of the 179 patients randomized to receive standard therapy, 168 patients received any study treatment, and 62 (35%)
received high-dose therapy and on-protocol HSCT. The most common reason for not receiving HSCT was lack of
response to salvage chemotherapy.
The primary efficacy measure was event-free survival (EFS) as determined by an independent review committee.
Efficacy is summarized in Table 9 and Figure 1. With an estimated median follow-up of 22.1 months overall, theestimated EFS rate at 18 months was 41.5% [95% CI: 34.2, 48.6] in the YESCARTA arm and 17.0% [95% CI: 11.8,
23.0] in the standard therapy arm.
In the YESCARTA arm, the estimated median DOR was 28.4 months (95% CI: 26.9, NE) in patients who achieved
CR and 1.6 months (95% CI: 1.4, 1.9) in patients who achieved a best response of PR.
At the time of the primary EFS analysis, the interim analysis of overall survival (OS) did not meet criteria forstatistical significance.
With an estimated median follow-up of 46.7 months overall, the primary analysis of OS showed a statisticallysignificant improvement in the YESCARTA arm compared to the standard therapy arm. Fifty-seven percent of patients
received cellular immunotherapy after no response to or relapse after randomization to standard therapy arm.
The efficacy results are summarized in Table 9 and Figure 1 and Figure 2.
Table 9.

Efficacy Results for ZUMA-7

Outcomea
Event-Free Survivalb
Number of events, n (%)
Median, months [95% CI]c
Stratified hazard ratio [95% CI]
Stratified log-rank p-value
Overall Survivald
Number of events, n (%)
Median OS, months [95% CI]c
Stratified hazard ratio [95% CI]
Stratified log-rank p-valuee
Best Objective Response Rate, % [95% CI]
Difference in ORR, % [95% CI]
Stratified p-valuef
Complete remission rate, % [95% CI]
Partial remission rate, % [95% CI]
Progression-Free Survival
Number of events, n (%)
Median, months [95% CI]c
Stratified hazard ratio [95% CI]

YESCARTA(N = 180)g

Standard Therapy(N = 179)

108 (60)
8.3 [4.5, 15.8]

144 (80)
2.0 [1.6, 2.8]
0.40 [0.31, 0.51]<0.000182 (46)
NE (28.6, NE)

95 (53)31.1 (17.1, NE)
0.73 (0.54, 0.98)
0.016883 [77, 88]

50 [43, 58]
33 [23, 42]<0.000165 [58, 72]
18 [13, 25]

32 [26, 40]
18 [13, 24]

93 (52)14.9 [7.2, NE]

81 (45)5.0 [3.4, 8.5]
0.56 [0.41, 0.76]

CI, confidence interval; NE, not estimable.
a. Per the International Working Group Lugano Classification (Cheson 2014), as assessed by the independent review committee.
b. EFS is defined as time from randomization to the earliest date of disease progression or relapse, best response of stable disease up to andincluding the Day 150 assessment, commencement of new lymphoma therapy, or death from any cause.

c.
d.
e.
f.

g.

Kaplan-Meier estimate.
Overall survival was conducted at the time of the primary OS analysis
p-value is compared with 0.0249, the one-sided efficacy boundary (significance level) for the primary OS analysis.
Per Cochran-Mantel-Haenszel method. For all stratified analyses, stratification was based on response to first-line therapy (primaryrefractory, vs relapse within 6 months of first-line therapy vs relapse within > 6 but ≤ 12 months) and second-line age-adjusted
International Prognostic Index.
Two recipients of non-conformal product are included in the efficacy analysis.

Figure 1. Kaplan-Meier Curve of Event-Free Survival in ZUMA-7 (Primary EFS Analysis)

Figure 2. Kaplan-Meier Curve of Overall Survival in ZUMA-7 (Primary OS Analysis)

ZUMA-1
A single-arm, open-label, multicenter trial evaluated the efficacy of a single infusion of YESCARTA in adult patientswith relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (ZUMA-1; NCT02348216). Eligible patients
had refractory disease to the most recent therapy or relapse within 1 year after autologous hematopoietic stem celltransplantation (HSCT). The study excluded patients with prior allogeneic HSCT, any history of central nervous
system lymphoma, ECOG performance status of 2 or greater, absolute lymphocyte count less than 100/µL, creatinine
clearance less than 60 mL/min, hepatic transaminases more than 2.5 times the upper limit of normal, cardiac ejection
fraction less than 50%, or active serious infection.
Following lymphodepleting chemotherapy, YESCARTA was administered as a single intravenous infusion at a target
dose of 2 × 106 CAR-positive viable T cells/kg (maximum permitted dose: 2 × 108 cells). The lymphodepleting
regimen consisted of cyclophosphamide 500 mg/m2 intravenously and fludarabine 30 mg/m2 intravenously, both givenon the fifth, fourth, and third day before YESCARTA. Bridging chemotherapy between leukapheresis andlymphodepleting chemotherapy was not permitted. All patients were hospitalized for YESCARTA infusion and for aminimum of 7 days afterward.
Of 111 patients who underwent leukapheresis, 101 received YESCARTA. Of the patients treated, the median age was
58 years (range: 23 to 76 years), 67% were male, and 89% were white. Most (76%) had DLBCL, 16% had transformed
follicular lymphoma, and 8% had primary mediastinal large B-cell lymphoma. The median number of prior therapies
was 3 (range: 1 to 10), 77% of the patients had refractory disease to a second or greater line of therapy, and 21% had
relapsed within 1 year of autologous HSCT.
One out of 111 patients did not receive the product due to manufacturing failure. Nine other patients were not treated,primarily due to progressive disease or serious adverse reactions following leukapheresis. The median time fromleukapheresis to product delivery was 17 days (range: 14 to 51 days), and the median time from leukapheresis toinfusion was 24 days (range: 16 to 73 days). The median dose was 2.0 × 106 CAR-positive viable T cells/kg (range: 1.1
to 2.2 × 106 cells/kg).
Efficacy was established on the basis of complete remission (CR) rate and duration of response (DOR), as determinedby an independent review committee (Table 10 and Table 11). The median time to response was 0.9 months (range:
0.8 to 6.2 months). Response durations were longer in patients who achieved CR, as compared to patients with a best
response of partial remission (PR) (Table 11). Of the 52 patients who achieved CR, 14 initially had stable disease (7patients) or PR (7 patients), with a median time to improvement of 2.1 months (range: 1.6 to 5.3 months).

Table 10.

Response Rate in Patients with Relapsed or Refractory LBCL in ZUMA-1

Objective Response Ratea(95% CI)
Complete Remission Rate
(95% CI)
Partial Remission Rate
(95% CI)

Recipients of YESCARTA(N = 101)
73 (72%)(62, 81)52 (51%)(41, 62)
21 (21%)(13, 30)

CI, confidence interval.
a. Per 2007 revised International Working Group criteria, as assessed by the independent review committee.

Table 11.

Duration of Response in Patients with Relapsed or Refractory LBCL in ZUMA-1

Number of Responders
DOR (Months)aMedianb(95% CI)
RangecDOR if Best Response is CR (Months)
Medianb(95% CI)
RangecDOR if Best Response is PR (Months)
Medianb(95% CI)
RangecMedian Follow-up for DOR (Months)a, b

From N of 101
73
9.2(5.4, NE)
0.03+, 14.4+
NE(8.1, NE)
0.4, 14.4+
2.1(1.3, 5.3)
0.03+, 8.4+
7.9

CR, complete remission; DOR, duration of response; NE, not estimable; PR, partial remission.
a. Among all responders. DOR is measured from the date of first objective response to the date of progression or death from relapse or
toxicity.
b. Kaplan-Meier estimate.
c. A “+” sign indicates a censored value.

14.2

Relapsed or Refractory Follicular Lymphoma

Efficacy in FL is based on a single-arm, open-label, multicenter trial (ZUMA-5; NCT03105336) that evaluated a single
infusion of YESCARTA in adult patients with relapsed or refractory FL after two or more lines of systemic therapy,
including the combination of an anti-CD20 monoclonal antibody and an alkylating agent. The study excluded patientswith active or serious infections, transformed lymphoma or other aggressive lymphomas, prior allogeneic HSCT, or
any history of CNS lymphoma or CNS disorders. Following lymphodepleting chemotherapy, YESCARTA wasadministered as a single intravenous infusion with a target dose of 2 × 106 anti-CD19 CAR T cells/kg (maximum
permitted dose: 2 x 108 cells). The lymphodepleting regimen consisted of cyclophosphamide 500 mg/m2 intravenously
and fludarabine 30 mg/m2 intravenously, both given on the fifth, fourth, and third day before YESCARTA.
Of 123 patients with FL who underwent leukapheresis, 120 received YESCARTA. Of the remaining three patients(2%) who were not treated, one was ineligible due to thrombocytopenia, one went into remission prior to initiating
lymphodepletion, and one died of cardiac arrest. There were no manufacturing failures. Of the 120 patients with FL
infused with YESCARTA, the 81 consecutive patients included in the primary efficacy analysis had at least 9 monthsof potential follow-up from date of first response.
Among the 81 patients with FL included in the primary efficacy analysis, the median age was 62 years (range: 34 to 79
years), 46% were female, 93% were white, 4% were black, and 3% were Asian. The median number of prior systemic
therapies was 3 (range: 2 to 9), with 32% having 2 prior lines, 22% having 3 prior lines, and 46% having ≥ 4 priorlines. Thirty-one percent had received a PI3K inhibitor, 72% had progression within 6 months of the most recent
regimen, and 56% had progression within 24 months of initiating their first anti-CD20 combination therapy. Between
leukapheresis and administration of YESCARTA, one patient (1%) in the primary efficacy analysis received bridging
therapy.
Among the 81 patients included in the primary efficacy analysis, the median time from leukapheresis to productdelivery was 17 days (range: 13 to 33 days) and leukapheresis to product infusion was 27 days (range: 19 to 250 days).
The median dose of YESCARTA was 2.0 × 106 CAR T cells/kg (range 1.3 to 2.1 × 106 CAR T cells/kg). All treatedpatients received YESCARTA infusion on day 0 and were hospitalized until at least day 7.
Efficacy was established on the basis of objective response rate and DOR as determined by an independent review
committee (Table 12 and Table 13). The median time to response in the primary efficacy population was 1.0 month(range: 0.8 to 3.1 months).

Table 12.

Response Rate in Patients with Relapsed or Refractory FL in ZUMA-5
Primary Efficacy Analysis(N = 81)

All Leukapheresed
Patients(N = 123)

Objective Response Ratea, n(95% CI)74 (91%)(83, 96)110 (89%)(83, 94)

Complete Remissionb, n(95% CI)49 (60%)(49, 71)

76 (62%)(53, 70)

Partial Remission, n(95% CI)

25 (31%)(21, 42)34 (28%)(20, 36)

CI, confidence interval.
a. Per the International Working Group Lugano Classification (Cheson 2014), as assessed by the independent review committee.
b. Complete remission required documentation of a negative bone marrow biopsy after treatment, in patients who did not have a negative bonemarrow biopsy between their most recent disease progression prior to ZUMA-5 and initiation of lymphodepleting chemotherapy.

Table 13.

Duration of Response in Patients with Relapsed or Refractory FL in ZUMA-5

Number of Responders
DOR (Months)aMedianb(95% CI)
RangecRate of Continued Remissiona, b, d
At 12 months (95% CI), %At 18 months (95% CI), %Median Follow-up for DOR (Months)a, b

From N of 81
74
NE(20.8, NE)
0.0, 25.0+
76.2 (63.9, 84.7)
74.2 (61.5, 83.2)
14.5

CR, complete remission; DOR, duration of response; NE, not estimable; PR, partial remission.
a. Among all responders in the primary efficacy population. DOR is measured from the date of first objective response to the date ofprogression or death from any cause.
b. Kaplan-Meier estimate.
c. A “+” sign indicates a censored value.
d. Measured from the date of first objective response to the date of progression or death.

15

REFERENCES

1.

Lee DW et al (2014). Current concepts in the diagnosis and management of cytokine release syndrome. Blood.
2014 Jul 10; 124(2): 188-195.

16

HOW SUPPLIED/STORAGE AND HANDLINGYESCARTA is supplied in an infusion bag (NDC 71287-119-01) containing approximately 68 mL of frozen
suspension of genetically modified autologous T cells in 5% DMSO and 2.5% albumin (human).
Each YESCARTA infusion bag is individually packed in a metal cassette (NDC 71287-119-02). YESCARTA is stored
in the vapor phase of liquid nitrogen and supplied in a liquid nitrogen dry shipper.
•••

Match the identity of the patient with the patient identifiers on the cassette and infusion bag upon receipt.
Store YESCARTA frozen in the vapor phase of liquid nitrogen (less than or equal to minus 150 ºC).
Thaw before using [see Dosage and Administration (2)].

17

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Ensure that patients understand the risk of manufacturing failure (< 1% in clinical trials). In case of a manufacturing
failure, a second manufacturing of YESCARTA may be attempted. In addition, while the patient awaits the product,
additional chemotherapy (not the lymphodepletion) may be necessary and may increase the risk of adverse events
during the pre-infusion period.
Advise patients to seek immediate attention for any of the following:• Cytokine Release Syndrome (CRS) - Signs or symptoms associated with CRS, including fever, chills,
fatigue, tachycardia, nausea, hypoxia, and hypotension [see Warnings and Precautions (5.1) and Adverse
Reactions (6)].
• Neurologic Toxicities - Signs or symptoms associated with neurologic events, including encephalopathy,
seizures, changes in level of consciousness, speech disorders, tremors, and confusion [see Warnings andPrecautions (5.2) and Adverse Reactions (6)].
• Serious Infections - Signs or symptoms associated with infection [see Warnings and Precautions (5.5) and
Adverse Reactions (6)].
• Prolonged Cytopenia - Signs or symptoms associated with bone marrow suppression, including
neutropenia, anemia, thrombocytopenia, or febrile neutropenia [see Warnings and Precautions (5.6) and
Adverse Reactions (6)].
• Secondary Malignancies - Secondary malignancies, including T cell malignancies, have occurred [seeBoxed Warning, Warnings and Precautions (5.8), and Adverse Reactions (6.3)].
Advise patients of the need to:• Refrain from driving or operating heavy or potentially dangerous machinery after YESCARTA infusion for atleast 8 weeks after infusion [see Warnings and Precautions (5.9)].
• Have periodic monitoring of blood counts.
• Contact Kite at 1-844-454-KITE (5483) if they are diagnosed with a secondary malignancy [see Warnings andPrecautions (5.8)].
Manufactured by, Packed by, Distributed by:Kite Pharma, Inc.
Santa Monica, CA 90404
US License No 2064
YESCARTA is a trademark of Kite Pharma, Inc. All other trademarks referenced herein are the property of their respective
owners.
© 2024 Kite Pharma, Inc. All Rights Reserved.
125643-GS-013

MEDICATION GUIDEYESCARTA (pronounced yes-kar-ta)(axicabtagene ciloleucel)
Read this Medication Guide before you start your YESCARTA treatment. The more you know about yourtreatment, the more active you can be in your care. Talk with your healthcare provider if you have questions about
your health condition or treatment. Reading this Medication Guide does not take the place of talking with yourhealthcare provider about your treatment.
What is the most important information I should know about YESCARTA?
YESCARTA may cause side effects that are life-threatening and can lead to death. Call or see your healthcare
provider or get emergency help right away if you get any of the following:
•
•
•
•
•
•
•
•

Fever (100.4°F/38°C or higher)
Difficulty breathing
Chills or shaking chills
Confusion
Dizziness or lightheadedness
Severe nausea, vomiting, or diarrhea
Fast or irregular heartbeat
Severe fatigue or weakness

It is important to tell your healthcare provider that you received YESCARTA and to show them your YESCARTA
Patient Wallet Card. Your healthcare provider may give you other medicines to treat your side effects.
What is YESCARTA?
YESCARTA is a prescription medicine used to treat two types of non-Hodgkin lymphoma:••

large B-cell lymphoma when your first treatment did not work or your cancer returned within a year of firsttreatment, OR when at least two kinds of treatment have failed to control your cancer.
follicular lymphoma when at least two kinds of treatment have failed to control your cancer.

YESCARTA is different than other cancer medicines because it is made from your own white blood cells, whichhave been modified to recognize and attack your lymphoma cells.
Before getting YESCARTA, tell your healthcare provider about all your medical problems, including if you
have or have had:
•
•
•
•
•
•

Neurologic problems (such as seizures, stroke, or memory loss)
Lung or breathing problems
Heart problems
Liver problems
Kidney problems
A recent or active infection

Tell your healthcare provider about all the medications you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements.

How will I receive YESCARTA?
•
•
•
•
•
•
•
•

Since YESCARTA is made from your own white blood cells, your blood will be collected by a process
called “leukapheresis” (loo-kah-fur-ee-sis), which will concentrate your white blood cells.
Your blood cells will be sent to a manufacturing center to make your YESCARTA.
Before you get YESCARTA, you will get 3 days of chemotherapy to prepare your body.
When your YESCARTA is ready, your healthcare provider will give it to you through a catheter placed
into your vein (intravenous infusion). The infusion usually takes less than 30 minutes.
You will be monitored where you received your treatment daily for at least 7 days after the infusion.
You should plan to stay close to a certified healthcare facility for at least 4 weeks after getting
YESCARTA. Your healthcare provider will help you with any side effects that may occur.
You may be hospitalized for side effects and your healthcare provider will discharge you if your side
effects are under control, and it is safe for you to leave the hospital.
Your healthcare provider will want to do blood tests to follow your progress. It is important that you dohave your blood tested. If you miss an appointment, call your healthcare provider as soon as possible toreschedule.

What should I avoid after receiving YESCARTA?
••

Do not drive, operate heavy machinery, or do other dangerous things for 8 weeks after you get
YESCARTA because the treatment can cause sleepiness, confusion, weakness, and temporary memory andcoordination problems.
Do not donate blood, organs, tissues, or cells for transplantation.

What are the possible or reasonably likely side effects of YESCARTA?
The most common side effects of YESCARTA include:
•
•
•
•
•
•
•
•
•

Fever (100.4°F/38°C or higher)
Low white blood cells (can occur with a fever)Low red blood cells
Low blood pressure (dizziness or lightheadedness, headache, feeling tired, short of breath)
Fast heartbeat
Confusion
Difficulty speaking or slurred speech
NauseaDiarrhea

YESCARTA may increase your risk of getting cancers including certain types of blood cancers. Your healthcare
provider should monitor you for this.
These are not all the possible side effects of YESCARTA. Call your healthcare provider about any side effects thatconcern you. You may report side effects to the FDA at 1-800-FDA-1088.
General information about the safe and effective use of YESCARTA
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would likemore information about YESCARTA, talk with your healthcare provider. You can ask your healthcare provider for
information about YESCARTA that is written for health professionals. You can get additional information bycontacting Kite at 1-844-454-KITE (5483) or at www.Yescarta.com.

What are the ingredients in YESCARTA?
Active ingredients: axicabtagene ciloleucel.
Inactive ingredients: albumin (human); DMSO.
YESCARTA is a trademark of Kite Pharma, Inc. All other trademarks referenced herein are the property of their respective
owners.
© 2024 Kite Pharma, Inc. All Rights Reserved.
This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: June 2024