ASH Clinical News ACN_4.1_FULL_ISSUE_DIGITAL | Page 25

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 .
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 .
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 .
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 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
Cardiac disorders
Gastrointestinal disorders
General disorders and administration site conditions
Immune system disorders
Infections and infestations
Investigations
Adverse Reaction
Tachycardia Arrhythmia
Diarrhea Nausea Vomiting Constipation Abdominal pain Dry mouth
Fever Fatigue Chills Edema
Cytokine release syndrome Hypogammaglobulinemia
Infections-pathogen unspecified Viral infections Bacterial infections
Decreased appetite Weight decreased Dehydration
Any Grade (%)
57 23
38 34 26 23 14 11
86 46 40 19
94 15
26 16 13
44 16 11
Grades 3 or Higher (%)
2 7
4 0 1 0 1 0
16 3 0 1
13 0
16 4 9
2 0 3
Summary of Adverse Reactions Observed in at Least 10 % of the Patients Treated with YESCARTA in Study 1 ( continued )
Musculoskeletal and connective tissue disorders
Nervous system disorders
Adverse Reaction
Motor dysfunction Pain in extremity Back pain Muscle pain Arthralgia
Encephalopathy Headache Tremor Dizziness Aphasia
Any Grade (%)
19 17 15 14 10
57 45 31 21 18
Grades 3 or Higher (%)
1 2 1 1 0
29 1 2 1 6
Psychiatric disorders Delirium 17 6
Respiratory , thoracic and mediastinal disorders
Hypoxia Cough Dyspnea Pleural effusion
Renal and urinary disorders Renal insufficiency 12 5
Vascular disorders
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 .
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 )
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 %.
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 .
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 known 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 .
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 )].
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Manufactured by , Packed by , Distributed by : Kite Pharma , Inc ., Santa Monica , CA 90404 US License No 2064 YESCARTA is a trademark of Kite Pharma . © 2017 Kite Pharma | PRC-00104 11 / 2017
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