ASH Clinical News ACN_4.7_FULL_ISSUE_DIGITAL | Página 3
patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly [see
Management of Severe Adverse Reactions (2.3); Neurologic Toxicities].
5.3 YESCARTA REMS: Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a
restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA REMS [see Boxed
Warning and Warnings and Precautions (5.1 and 5.2)]. The required components of the YESCARTA REMS are:
• Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS
requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and
ensure that a minimum of two doses of tocilizumab are available for each patient for infusion within
2 hours after YESCARTA infusion, if needed for treatment of CRS.
• Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer
YESCARTA are trained about the management of CRS and neurologic toxicities.
Further information is available at www.YescartaREMS.com or 1-844-454-KITE (5483).
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.
In Study 1, infections (all grades) occurred in 38% of patients. Grade 3 or higher infections occurred in
23% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients,
bacterial infections in 9%, and viral infections in 4%. YESCARTA should not be administered to patients with
clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before
and after YESCARTA infusion and treat appropriately. Administer prophylactic anti-microbials according to
local guidelines. Febrile neutropenia was observed in 36% of patients 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. Viral Reactivation: Hepatitis
B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can
occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in
accordance with clinical guidelines before collection of cells for manufacturing.
5.6 Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting
chemotherapy and YESCARTA infusion. In Study 1, Grade 3 or higher cytopenias not resolved by Day 30
following YESCARTA infusion occurred in 28% of patients and included thrombocytopenia (18%), neutropenia
(15%), and anemia (3%). Monitor blood counts after YESCARTA infusion.
Summary of Adverse Reactions Observed in at Least 10% of the Patients Treated with YESCARTA
in Study 1 (continued)
Adverse Reaction
Musculoskeletal and connective
tissue disorders
Nervous system disorders
Psychiatric disorders
Respiratory, thoracic and
mediastinal disorders
Renal and urinary disorders
Vascular disorders
Motor dysfunction
Pain in extremity
Back pain
Muscle pain
Arthralgia
Encephalopathy
Headache
Tremor
Dizziness
Aphasia
Delirium
Hypoxia
Cough
Dyspnea
Pleural effusion
Renal insufficiency
Any Grade
(%)
19
17
15
14
10
57
45
31
21
18
17
32
30
19
13
12 Grades 3 or
Higher (%)
1
2
1
1
0
29
1
2
1
6
6
11
0
3
2
5
57
15
10 15
6
1
Hypotension
Hypertension
Thrombosis
The following events were also counted in the incidence of CRS: tachycardia, arrhythmia, fever, chills, hypoxemia, renal insufficiency,
and hypotension. For a complete list of events that contributed to the incidence of certain adverse reactions, please see footnote
below Table 3 in Section 6.1 of the Full Prescribing Information.
5.7 Hypogammaglobulinemia: B-cell aplasia and hypogammaglobulinemia can occur in patients
receiving treatment with YESCARTA. In Study 1, hypogammaglobulinemia occurred in 15% of patients.
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. Other clinically important adverse reactions that occurred in less than 10% of patients treated with
YESCARTA include the following: blood and lymphatic system disorders: coagulopathy (2%); cardiac
disorders: cardiac failure (6%) and cardiac arrest (4%); immune system disorders: hemophagocytic
lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) (1%), hypersensitivity (1%); infections
and infestations disorders: fungal infections (5%); nervous system disorders: ataxia (6%), seizure (4%),
dyscalculia (2%), and myoclonus (2%); respiratory, thoracic and mediastinal disorders: pulmonary edema
(9%); skin and subcutaneous tissue disorders: rash (9%); vascular disorders: capillary leak syndrome (3%).
Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients in Study 1
Following Treatment with YESCARTA based on CTCAE (N=108)
5.8 Secondary Malignancies: Patients treated with YESCARTA may develop secondary malignancies. Monitor
life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at
1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing. Lymphopenia 100%, Leukopenia 96%, Neutropenia 93%, Anemia 66%, Thrombocytopenia 58%,
Hypophosphatemia 50%, Hyponatremia 19%, Uric acid increased 13%, Direct Bilirubin increased 13%,
Hypokalemia 10%, Alanine Aminotransferase increased 10%.
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. 6.2 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. Three patients tested positive
for pre-dose anti-FMC63 antibodies at baseline and Months 1, 3, or 6 in Study 1. There is no evidence that
the kinetics of initial expansion and persistence of YESCARTA, or the safety or effectiveness of YESCARTA, was
altered in these patients.
6 ADVERSE REACTIONS: The following adverse reactions are described in Warnings and Precautions:
Cytokine Release Syndrome, Neurologic Toxicities, Hypersensitivity Reactions, Serious Infections, Prolonged
Cytopenias, Hypogammaglobulinemia.
6.1 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 safety data described
in this section reflect exposure to YESCARTA in the clinical trial (Study 1) in which 108 patients with relapsed/
refractory B-cell NHL received CAR-positive T cells based on a recommended dose which was weight-based
[see Clinical Trials (14)] . Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia)
or autoimmune disease requiring systemic immunosuppression were ineligible. The median duration of
follow up was 8.7 months. The median age of the study population was 58 years (range: 23 to 76 years); 68%
were men. The baseline ECOG performance status was 43% with ECOG 0, and 57% with ECOG 1. The most
common adverse reactions (incidence ≥ 20%) include CRS, fever, hypotension, encephalopathy, tachycardia,
fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified,
nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias. Serious adverse
reactions occurred in 52% of patients. The most common serious adverse reactions (> 2%) include
encephalopathy, fever, lung infection, febrile neutropenia, cardiac arrhythmia, cardiac failure, urinary tract
infection, renal insufficiency, aphasia, cardiac arrest, Clostridium difficile infection, delirium, hypotension,
and hypoxia. The most common (≥ 10%) Grade 3 or higher reactions include febrile neutropenia, fever,
CRS, encephalopathy, infections-pathogen unspecified, hypotension, hypoxia, and lung infections. Forty-five
percent (49/108) of patients received tocilizumab after infusion of YESCARTA.
Summary of Adverse Reactions Observed in at Least 10% of the Patients Treated with YESCARTA
in Study 1
Adverse Reaction
Any Grade
(%) Grades 3 or
Higher (%)
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 to a pregnant woman. It is not kno wn if YESCARTA has
the potential to be transferred to the fetus. Based on the mechanism 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 clinically recognized 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, and the effects on milk production. The developmental and health benefits
of breastfeeding should be considered along with the mother’s clinical need for YESCARTA and any potential
adverse effects on the breastfed infant from YESCARTA 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: Clinical trials of YESCARTA did not include sufficient numbers of patients aged 65 years
and older to determine whether they respond differently or have different safety outcomes as compared to
younger patients.
Cardiac disorders Tachycardia
Arrhythmia 57
23 2
7 Gastrointestinal disorders Diarrhea
Nausea
Vomiting
Constipation
Abdominal pain
Dry mouth 38
34
26
23
14
11 4
0
1
0
1
0 General disorders and
administration site conditions Fever
Fatigue
Chills
Edema 86
46
40
19 16
3
0
1 Immune system disorders Cytokine release syndrome
Hypogammaglobulinemia 94
15 13
0 Manufactured by, Packed by, Distributed by: Kite Pharma, Inc., Santa Monica, CA 90404
Infections and infestations Infections-pathogen unspecified
Viral infections
Bacterial infections 26
16
13 16
4
9 YESCARTA and KITE are trademarks of Kite Pharma, Inc.
Decreased appetite
Weight decreased
Dehydration 44
16
11 2
0
3
Investigations
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 trial). 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, Neurologic Toxicities, Serious Infections, Prolonged Cytopenia [see
Warnings and Precautions (5.1, 5.2, 5.3, 5.5) and Adverse Reactions (6) for more information and signs
and symptoms]. Advise patients for the need to: Refrain from driving or operating heavy or potentially
dangerous machinery after YESCARTA infusion until at least 8 weeks after infusion [see Warnings and
Precautions (5.2)], Have periodic monitoring of blood counts. Contact Kite at 1-844-454-KITE (5483) if
they are diagnosed with a secondary malignancy [see Warnings and Precautions (5.8)].
US License No 2064
© 2018 Kite Pharma | PRC-00428 03/2018