ASH Clinical News October 2017 | Page 25

Table 2 . Selected Adverse Reactions ( ≥ 10 %) Following Treatment with KYMRIAH ( N = 68 ) Adverse Reaction
All Grades
Grades 3 or Higher
(%)
(%)
Metabolism and nutrition disorders
Decreased appetite
37
15
Fluid overload
10
7
Musculoskeletal and connective tissue disorders Pain in extremity
16
1
Myalgia
15
0
Arthralgia
12
1
Back pain
10
3
Nervous system disorders d
Headache
37
3
e
Encephalopathy
34
10
Psychiatric disorders f
Delirium
21
4
Anxiety
13
3
Renal and urinary disorders Acute kidney injury
22
13
Respiratory , thoracic and mediastinal disorders Hypoxia
24
18
Cough
19
0
Pulmonary edema
16
10
Tachypnea
12
6
Pleural effusion
10
4
Nasal congestion
10
0
Vascular disorders Hypotension
31
22
Hypertension
19
6
a Tachycardia includes tachycardia and sinus tachycardia .
b Abdominal pain includes abdominal pain , abdominal pain upper , gastrointestinal pain , abdominal pain
lower .
c Hypogammaglobulinemia includes hypogammaglobulinemia , immunoglobulins decreased , blood
immunoglobulin G decreased , blood immunoglobulin A decreased , blood immunoglobulin M decreased ,
hypogammaglobulinemia .
d Headache includes headache and migraine .
e Encephalopathy includes encephalopathy , cognitive disorder , confusional state , depressed level of consciousness
, disturbance in attention , lethargy , mental status changes , posterior reversible encephalopathy
syndrome , somnolence , and automatism .
f Delirium includes delirium , agitation , hallucination , hallucination visual , irritability , restlessness .
g Acute kidney injury includes acute kidney injury , anuria , azotemia , renal failure , renal tubular dysfunction ,
renal tubular necrosis .
Additional important adverse reactions that did not meet the threshold criteria for inclusion in Table 2
were :
Blood and lymphatic system disorders : disseminated intravascular coagulation ( 9 %), histiocytosis
lymphocytic hemophagocytosis ( 7 %), coagulopathy ( 6 %), Grade 3 and Grade 4 hypofibrinogenemia
with Grade 3 and 4 CRS ( 16 %)
Cardiac Disorders : cardiac arrest ( 4 %), cardiac failure ( 7 %)
Gastrointestinal disorders : abdominal compartment syndrome ( 1 %)
General disorders and administration site conditions : multiple organ dysfunction syndrome ( 3 %)
Immune system disorders : graft versus host disease ( 1 %)
Investigations : blood creatinine increased ( 7 %), activated partial thromboplastin time prolonged ( 6 %)
Nervous System : intracranial hemorrhage ( 1 %), seizure ( 3 %)
Respiratory , thoracic , and mediastinal disorders : respiratory distress ( 6 %), respiratory failure ( 6 %),
acute respiratory distress syndrome ( 4 %)
Metabolism and nutrition disorders : tumor lysis syndrome ( 6 %)
Vascular disorders : capillary leak syndrome ( 3 %)
Laboratory Abnormalities
Selected laboratory abnormalities worsening from baseline Grade 0-2 to Grade 3-4 are shown in Table 3 .
Table 3 . Selected Other Laboratory Abnormalities Worsening from Baseline Grade 0-2 to Grade 3-4
Following Treatment with KYMRIAH based on CTCAE a ( N = 68 )
Grade 3 or 4
(%)
Increased Aspartate Aminotransferase
28
Hypokalemia
27
Increased Alanine Aminotransferase
21
Increased bilirubin
21
Hypophosphatemia
19
a
CTCAE = Common Terminology Criteria for Adverse Events version 4.03
All patients experienced neutropenia , anemia and thrombocytopenia . See Table 4 for the incidences of
Grade 3 and Grade 4 prolonged thrombocytopenia and prolonged neutropenia in responding patients .
Table 4 . Prolonged Cytopenias Following Treatment with KYMRIAH
N = 52
(%)
Day 28
Day 56
Prolonged neutropenia a
40
17
Prolonged thrombocytopenia a
27
12
a Grade 3 and 4 observed within 14 days after Day 28 or Day 56 in responding patients
7 DRUG INTERACTIONS HIV and the lentivirus used to make KYMRIAH have limited , short spans of identical genetic material ( RNA ). Therefore , some commercial HIV nucleic acid test ( NAT ) tests may yield false-positive results in patients who have received KYMRIAH .
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary
There are no available data with KYMRIAH use in pregnant women . No animal reproductive and developmental toxicity studies have been conducted with KYMRIAH to assess whether it can cause fetal harm when administered to a pregnant woman . It is not known if KYMRIAH 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 , KYMRIAH is not recommended for women who are pregnant , and pregnancy after KYMRIAH administration should be discussed with the treating physician . Report pregnancies to Novartis Pharmaceuticals Corporation at 1-888-669-6682 .
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 KYMRIAH 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 KYMRIAH and any potential adverse effects on the breastfed infant from KYMRIAH 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 KYMRIAH .
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 KYMRIAH .
Infertility There are no data on the effect of KYMRIAH on fertility .
8.4 Pediatric Use The safety and efficacy of KYMRIAH have been established in pediatric patients . Use of KYMRIAH is supported by a single-arm trial [ see Clinical Studies ( 14 ) in the full prescribing information ] that included 52 pediatric patients with relapsed or refractory B-cell precursor ALL in the following age groups : 33 children ( age 3 years to less than 12 years ) and 19 adolescents ( age 12 years to less than 17 years ). No differences in efficacy or safety were observed between the different age subgroups or in comparison to the young adults in the trial .
8.5 Geriatric Use The safety and effectiveness of KYMRIAH have not been established in geriatric patients . Clinical studies of KYMRIAH for this indication did not include patients age 65 years and over .
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 . This has been reported in up to 9 % of manufacturing attempts . In case of a manufacturing failure , a second manufacturing of KYMRIAH 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 preinfusion period .
Prior to infusion , advise patients of the following risks :
• Cytokine Release Syndrome ( CRS ) -- Report signs and symptoms of CRS ( high fever , difficulty breathing , chills / shaking chills , severe nausea , severe vomiting , severe diarrhea , severe muscle pain , severe joint pain , very low blood pressure , or dizziness / lightheadedness ) to their healthcare professional [ see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.1 )].
• Neurological Toxicities -- Report altered or decreased consciousness , delirium , confusion , agitation , seizures , difficulty speaking and understanding , or loss of balance to their healthcare professional [ see Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6.1 )].
• Serious Infections -- KYMRIAH may cause serious infections . Advise patients that they will be screened for HBV , HCV , and HIV before collection of cells [ see Warnings and Precautions ( 5.5 ), Adverse Reactions ( 6.1 )].
• Hypogammaglobulinemia -- Patients may need to receive immunoglobulin replacement for an indefinite amount of time following treatment with KYMRIAH . Patients should tell their physician about their treatment with KYMRIAH before receiving a live virus vaccine [ see Warnings and Precautions ( 5.7 ), Adverse Reactions ( 6.1 )].
• Driving and Engaging in Hazardous Occupations -- Patients should refrain from driving and engaging in hazardous occupations or activities , such as operating heavy or potentially dangerous machinery , for at least 8 weeks after treatment [ see Warnings and Precautions ( 5.9 )].
Patients should be instructed to contact Novartis Pharmaceuticals Corporation at 1-844-4KYMRIAH if they get secondary malignancies [ see Warnings and Precautions ( 5.8 )].
Distributed by : Novartis Pharmaceuticals Corporation East Hanover , New Jersey 07936
© Novartis T2017-78
6.2 Immunogenicity In clinical studies , humoral immunogenicity of KYMRIAH was measured by determination of anti-murine CAR19 antibodies ( anti-m CAR19 ) in serum pre- and post-administration . The majority of patients ( 86 %) tested positive for pre-dose anti-m CAR19 antibodies in Study 1 ; however , the preexisting and treatment-induced antibodies were not associated with an impact on clinical response and did not have an impact on the initial expansion and persistence of KYMRIAH . Persistence of KYMRIAH was similar between patients with positive post-infusion anti-m CAR19 antibodies compared with patients with negative post-infusion anti-m CAR19 antibodies . There is no evidence that the presence of preexisting and treatment-induced anti-mCAR19 antibodies impact the safety or effectiveness of KYMRIAH .