Table 2. Selected Adverse Reactions Anytime After Infusion (≥ 10%) Following Treatment with KYMRIAH in
Pediatric and Young Adult r/r B-cell ALL (N = 68)
Adverse Reaction
All Grades
(%)
Grades 3 or Higher
(%)
Infections and infestations
Infections-pathogen unspecified
41
16
Viral infectious disorders
26
18
Bacterial infectious disorders
19
13
Fungal infectious disorders
13
7
Investigations
International normalized ratio increased
13
0
Metabolism and nutrition disorders
Decreased appetite
37
15
Fluid overload
10
7
Musculoskeletal and connective tissue disorders
Myalgia
15
0
Arthralgia
12
1
Back pain
10
3
Nervous system disorders
g
Headache
37
3
h
Encephalopathy
34
10
Psychiatric disorders
i
Delirium
21
4
Anxiety
13
3
j
Sleep disorders
10
0
Renal and urinary disorders
k
Acute kidney injury
24
15
Respiratory, thoracic and mediastinal disorders
Hypoxia
24
18
l
Cough
21
0
m
Dyspnea
16
12
Pulmonary edema
16
10
Tachypnea
12
6
Pleural effusion
10
4
Nasal congestion
10
0
Skin and subcutaneous tissue disorders
n
Rash
16
1
Vascular disorders
Hypotension
31
22
Hypertension
19
6
a
Tachycardia includes tachycardia and sinus tachycardia.
b
Abdominal pain includes abdominal pain, abdominal pain upper.
c
Fatigue includes fatigue and malaise.
d
Edema includes face edema, generalised edema, localised edema, edema peripheral.
e
Pain includes pain and pain in the extremity.
f
Hypogammaglobulinemia includes hypogammaglobulinemia, immunoglobulins decreased, blood immunoglobulin
G decreased, blood immunoglobulin A decreased, blood immunoglobulin M decreased.
g
Headache includes headache and migraine.
h
Encephalopathy includes encephalopathy, cognitive disorder, confusional state, depressed level of conscious-
ness, disturbance in attention, lethargy, mental status changes, somnolence, and automatism.
i
Delirium includes delirium, agitation, hallucination, hallucination visual, irritability, restlessness.
j
Sleep disorders includes sleep disorder, insomnia and nightmare.
k
Acute kidney injury includes acute kidney injury, anuria, azotemia, renal failure, renal tubular dysfunction, renal
tubular necrosis, and blood creatinine increased.
l
Cough includes cough and productive cough.
m
Dyspnea includes dyspnea and respiratory distress, respiratory failure.
n
Rash includes rash, rash maculo-papular, rash papular, and rash pruritic.
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: activated partial thromboplastin time prolonged (6%)
Nervous System: tremor (9%), dizziness (6%), seizure (3%), speech disorder a (3%), motor dysfunction b (1%)
Respiratory, thoracic, and mediastinal disorders: respiratory distress (6%), respiratory failure (6%), acute respi-
ratory distress syndrome (4%), oropharyngeal pain (6%)
Metabolism and nutrition disorders: tumor lysis syndrome (6%)
Vascular disorders: capillary leak syndrome (3%), thrombosis (3%)
Eye disorders: Visual impairment (3%)
a
Speech disorder includes aphasia and dysarthria.
b
Motor dysfunction includes muscle spasms.
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 (> 10%) from Baseline Grade 0-2 to Grade 3-4
Following Treatment with KYMRIAH in Pediatric and Young Adult r/r B-cell ALL based on CTCAE a (N = 68)
Laboratory Abnormality
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 prolonged thrombocytopenia and prolonged neutropenia in responding patients.
Table 4. Prolonged Cytopenias Following Treatment with KYMRIAH in Pediatric and Young Adult r/r B-cell ALL
Prolonged Cytopenia
N = 52 (%) N = 52 (%)
Day 28 Day 56
Prolonged neutropenia a 40 17
Prolonged thrombocytopenia a 27 12
a
≥ Grade 3 observed within 14 days after Day 28 or Day 56 in responding patients
Adult r/r Diffuse Large B-cell Lymphoma (DLBCL)
In the JULIET study (Study 2) 106 adults with r/r DLBCL received a single intravenous dose of KYMRIAH
[see Clinical Studies (14.2) in the full prescribing information]. The most common adverse reactions (inci-
dence > 20%) were cytokine release syndrome, infections-pathogen unspecified, diarrhea, nausea, pyrexia,
fatigue, hypotension, edema and headache.
The study population characteristics were: median age of 56 years (range: 22 to 76 years), 79% DLBCL; a
median of 3 prior lines of therapy (range: 1-6), 49% had a prior autologous hematopoietic stem cell transplan-
tation, and 33% had received prior radiation therapy. Ninety-nine patients (93%) received lymphodepleting
chemotherapy prior to KYMRIAH, that included fludarabine (n = 77) or bendamustine (n = 22).
The adverse reactions with greater than or equal to 10% incidence for any Grade are summarized in Table 5
below.
Table 5. Selected Adverse Reactions Anytime After Infusion Reported in ≥ 10% Following Treatment with
KYMRIAH in Adult r/r DLBCL (N = 106)
Adverse Reaction
All Grades
(%)
Grades 3 or Higher
(%)
Blood and lymphatic system disorders
Febrile Neutropenia
17
17
Cardiac disorders
a
Tachycardia
13
3
Gastrointestinal disorders
Diarrhea
31
1
Nausea
27
1
Constipation
16
1
General disorders and administration site conditions
Pyrexia
34
6
b
Fatigue
26
7
c
Edema
23
2
d
Pain
15
3
Chills
13
0
Immune system disorders
Cytokine release syndrome
74
23
e
Hypogammaglobulinemia
14
4
Infections and infestations
Infections-pathogen unspecified
42
25
Investigations
Weight decreased
11
3
Metabolism and nutrition disorders
Decreased appetite
12
4
Musculoskeletal and connective tissue disorders
Arthralgia
10
0
Nervous system disorders
f
Headache
21
0
g
Encephalopathy
16
11
h
Dizziness
11
1
Renal and Urinary Disorders
i
Acute kidney injury
17
6
Respiratory, thoracic and mediastinal disorders
j
Cough
19
0
k
Dyspnea
18
6
Vascular disorders
l
Hypotension
26
8
a
Tachycardia includes tachycardia and sinus tachycardia.
b
Fatigue includes fatigue and malaise.
c
Edema includes face edema, generalised edema, localized edema, edema peripheral, peripheral swelling.
d
Pain includes pain and pain in the extremity.
e
Hypogammaglobulinemia includes blood immunoglobulin G decreased, immunoglobulins decreased and
hypogammaglobulinemia.
f
Headache includes headache and migraine.
g
Encephalopathy includes encephalopathy, cognitive disorder, confusional state, disturbance in attention,
lethargy, mental status changes, somnolence, memory impairment, metabolic encephalopathy and thinking
abnormal.
h
Dizziness includes dizziness, presyncope, and syncope.
i
Acute kidney injury includes acute kidney injury and blood creatinine increased.
j
Cough includes cough, productive cough, and upper-airway cough syndrome.
k
Dyspnea includes dyspnea, dyspnea exertional, respiratory distress, and respiratory failure.
l
Hypotension includes hypotension and orthostatic hypotension.
Additional important adverse reactions that did not meet the threshold criteria for inclusion in Table 5 were:
Blood and lymphatic system disorders: disseminated intravascular coagulation (3%), pancytopenia (2%), histio-
cytosis hematophagic (1%)
Cardiac Disorders: arrhythmia a (6%)
Gastrointestinal disorders: vomiting (9%), abdominal pain b (9%), anal incontinence (1%)
General disorders and administration site conditions: asthenia (7%), multiple organ dysfunction syndrome (3%)
Infections and infestations: fungal infectious disorders (9%), viral infectious disorders (9%), bacterial infectious
disorders (9%)
Musculoskeletal and connective tissue disorders: myalgia (7%), back pain (6%)
Nervous System: peripheral neuropathy c (8%), motor dysfunction d (6%), speech disorder e (3%), seizure f (3%),
ischemic cerebral infarction (1%), tremor (7%), ataxia (2%)
Psychiatric disorders: anxiety (9%), delirium g (6%), sleep disorders h (9%)
Respiratory, thoracic, and mediastinal disorders: hypoxia (8%), oropharyngeal pain i (8%), pleural effusion (5%)
pulmonary edema j (3%)
Metabolism and nutrition disorders: fluid overload (3%), tumor lysis syndrome (1%)
Vascular disorders: thrombosis k (7%), hypertension (2%), capillary leak syndrome (1%)
Skin and subcutaneous tissue disorders: rash l (8%), dermatitis m (4%)
Eye disorders: visual impairment n (7%)
a
Arrhythmia includes atrial fibrillation, supraventricular tachycardia, ventricular extrasystoles.
b
Abdominal pain includes abdominal pain and abdominal pain upper.
c
Peripheral Neuropathy includes paraethesia,hypoaesthesia, hyperaesthesia,peripheral sensory neuropathy, and
neuropathy peripheral.
d
Motor dysfunction includes muscle spasms, muscle twitching, myoclonus and myopathy.
e
Speech disorder includes speech disorder, aphasia.
f
Seizure includes PTs seizure and status epilepticus.
g
Delirium includes delirium, agitation, and irritability.
h
Sleep disorders includes sleep disorder, insomnia and nightmare.
i
Oropharyngeal pain includes oral pain and oropharyngeal pain.
j
Pulmonary edema includes acute pulmonary edema and pulmonary edema.
k
Thrombosis includes deep vein thrombosis, embolism, pulmonary embolism, thrombosis, vena cava thrombosis,
and venous thrombosis.
l
Rash includes rash, rash maculo-papular, rash papular and rash pruritic.
m
Dermatitis includes dermatitis, dermatitis acneiform and dermatitis contact.
n
Visual impairment includes vision blurred and visual impairment.