6 ADVERSE REACTIONS

The following adverse reactions are described elsewhere in the labeling:

•: 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)]

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 the WARNINGS and PRECAUTIONS (N=702) and in this section reflect exposure to a single dose of BREYANZI in one randomized, open-label study with 89 patients (TRANSFORM) with relapsed or refractory LBCL, and five open-label, single-arm studies with 61 patients (PILOT) and 268 patients (TRANSCEND) with relapsed or refractory LBCL, 89 patients with relapsed or refractory CLL/SLL (TRANSCEND-CLL), 107 patients with relapsed or refractory FL (TRANSCEND-FL), and 88 patients with relapsed or refractory MCL (TRANSCEND-MCL Cohort).

Relapsed or Refractory LBCL After One Line of Therapy

TRANSFORM

The safety of BREYANZI was evaluated in the TRANSFORM, a randomized, open-label, multicenter study, in which patients with primary refractory LBCL or relapse within 1 year of first-line chemoimmunotherapy received BREYANZI (N=89) or standard therapy (N=91) [see Clinical Studies (14.1)]. Patients had not yet received treatment for relapsed or refractory lymphoma and were potential candidates for autologous HSCT. The trial excluded patients who were ineligible for transplant or who had age > 75 years, Eastern Cooperative Oncology Group (ECOG) performance status >1, history of central nervous system (CNS) disorders (such as seizures or cerebrovascular ischemia), uncontrolled infection, CrCl < 45 mL/min, alanine aminotransferase (ALT) > 5 times the upper limit of normal (ULN), left ventricular ejection fraction (LVEF) < 40%, or absolute neutrophil count (ANC) < 1.0 × 109 cells/L or platelets < 50 × 109 cells/L in the absence of bone marrow involvement.

The planned dose of BREYANZI was 100 × 106 CAR-positive viable T cells. The median age of the BREYANZI-treated population was 59 years (range: 20 to 74 years); 47% were male; 58% were White, 11% were Asian, and 5% were Black.

Serious adverse reactions occurred in 38% of patients. The most common nonlaboratory serious adverse reactions (> 2%) were CRS, sepsis, fever, febrile neutropenia, headache, aphasia, COVID-19 infection, and pulmonary embolism.

Table 4 presents selected nonlaboratory adverse reactions in patients treated with BREYANZI, and Table 5 describes selected new or worsening Grade 3 or 4 laboratory abnormalities.

The most common nonlaboratory adverse reactions (≥ 20%) were fever, CRS, musculoskeletal pain, headache, fatigue, nausea, constipation, and dizziness.

Table 4: Adverse Reactions in ≥ 10% of Patients Treated with BREYANZI in the TRANSFORM Study (N=89)
a Tachycardia includes atrial flutter, sinus tachycardia, supraventricular tachycardia, tachycardia.
b Abdominal pain includes abdominal pain, abdominal pain lower, abdominal tenderness.
c Fatigue includes asthenia, fatigue, malaise.
d Edema includes edema peripheral, localized edema, pleural effusion swelling.
e Infections and infestations are grouped per high-level grouped term.
f Sepsis includes bacteremia, bacterial sepsis, enterococcal bacteremia, Escherichia bacteremia, Klebsiella bacteremia, Klebsiella sepsis, sepsis, septic shock, staphylococcal bacteremia.
g Musculoskeletal pain includes arthralgia, back pain, bone pain, flank pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, osteoarthritis, pain in extremity.
h Headache includes headache, migraine, migraine with aura.
i Dizziness includes dizziness, dizziness postural, syncope, vertigo.
j Motor dysfunction includes fine motor skill dysfunction, muscle spasms, muscular weakness.
k Tremor includes resting tremor, tremor, essential tremor.
l Insomnia includes insomnia, sleep disorder.
m Cough includes cough, productive cough.
n Rash includes catheter site rash, dermatitis acneiform, dermatitis exfoliative generalized, erythema multiforme, rash, rash maculo-papular, rash pruritic.
o Hypotension includes hypotension, orthostatic hypotension.
p Hemorrhage includes conjunctival hemorrhage, cystitis hemorrhagic, epistaxis, gastrointestinal hemorrhage, hematoma, hematuria, retinal hemorrhage, vaginal hemorrhage.
Adverse Reaction	Any Grade (%)	Grade 3 or Higher (%)
Blood and lymphatic system disorders
Febrile neutropenia	10	10
Cardiac disorders
Tachycardiaa	15	1.1
Gastrointestinal disorders
Nausea	24	0
Constipation	20	2.2
Diarrhea	18	0
Abdominal painb	13	2.2
Vomiting	11	0
General disorders and administration site conditions
Fever	55	3.4
Fatiguec	28	1.1
Edemad	13	0
Immune system disorders
Cytokine release syndrome	49	1.1
Infections and infestationse
Bacterial infectious disorders	12	6
Infections with pathogen unspecified	12	6
Sepsisf	10	7
Metabolism and nutrition disorders
Decreased appetite	15	0
Musculoskeletal and connective tissue disorders
Musculoskeletal paing	36	3.4
Nervous system disorders
Headacheh	34	6
Dizzinessi	20	1.1
Motor dysfunctionj	12	3.4
Tremork	11	1.1
Psychiatric disorders
Insomnial	15	0
Respiratory, thoracic, and mediastinal disorders
Coughm	11	0
Skin and subcutaneous tissue disorders
Rashn	12	1.1
Vascular disorders
Hypotensiono	15	2.2
Hemorrhagep	12	0

Other clinically important adverse reactions in < 10% of patients treated with BREYANZI included the following:

•: Immune system disorders: Hemophagocytic lymphohistiocytosis (1.1%)
•: Infections and infestations: Viral infection (9%), fungal infection (4.5%), pneumonia (2.2%)
•: Nervous system disorders: Encephalopathy (8%), aphasia (4.5%), peripheral neuropathy (4.5%), ataxia (3.4%), paresis (1.1%)
•: Psychiatric disorders: Delirium (2.2%)
•: Renal and urinary disorders: Renal failure (3.4%)
•: Respiratory, thoracic, and mediastinal disorders: Dyspnea (8%)
•: Vascular disorders: Thrombosis (8%), hypertension (7%)

Table 5: Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients Treated with BREYANZI in the TRANSFORM Study
a Baseline lab values were assessed prior to lymphodepleting chemotherapy.
b Based on 88 evaluable patients, defined as those with both a baseline grade and at least one post-baseline grade for the particular lab.
Laboratory Abnormalitya	Grade 3 or 4 (%)b
Lymphocyte count decreased	98
Neutrophil count decreased	89
Platelet count decreased	48
Hemoglobin decreased	32

Grade 4 laboratory abnormalities in ≥ 10% of patients were lymphocyte decrease (64%), neutrophil decrease (66%), and platelet decrease (34%).

PILOT

The safety of BREYANZI was evaluated in the PILOT study, a single-arm open-label study in transplant-ineligible patients with R/R LBCL after one line of chemoimmunotherapy [see Clinical Studies (14.1)]. The study enrolled patients who were ineligible for high-dose therapy and autologous HSCT due to organ function or age, but who had adequate organ function for CAR-T cell therapy. Patients with a history of relevant CNS disorders (such as seizures or cerebrovascular ischemia), ECOG performance status > 2, or uncontrolled infection were ineligible. The trial required LVEF ≥ 40%, adequate oxygen saturation on room air with ≤ Grade 1 dyspnea, AST, and ALT ≤ 5 x ULN, total bilirubin < 2.0 mg/dL, creatinine clearance > 30 mL/min, and adequate bone marrow function to receive lymphodepleting chemotherapy. The planned dose of BREYANZI was 100 × 106 CAR-positive viable T cells.

The median age was 74 years (range: 53 to 84 years), 90% were age ≥ 65 years, 61% were male. The ECOG performance status was 0 or 1 in 74% of patients and 2 in 26% of patients; 25% had CrCl < 60 ml/min; 20% had a baseline ANC < 1000/μL.

Serious adverse reactions occurred in 33% of patients. The most common nonlaboratory, serious adverse reactions (> 2%) were CRS, confusional state, gastrointestinal hemorrhage, muscular weakness, musculoskeletal pain, pulmonary embolism, and sepsis.

Table 6 presents selected nonlaboratory adverse reactions, and Table 7 describes selected new or worsening Grade 3 or 4 laboratory abnormalities.

The most common nonlaboratory adverse reactions (≥ 20%) were fatigue, CRS, fever, nausea, encephalopathy, hypotension, musculoskeletal pain, and edema.

Table 6: Adverse Reactions in ≥ 10% of Patients Treated with BREYANZI in the PILOT Study (N=61)
a Tachycardia includes atrial fibrillation, sinus tachycardia, tachycardia.
b Fatigue includes asthenia, fatigue, malaise.
c Edema includes edema peripheral, pleural effusion, swelling.
d Grouped per high-level grouped term.
e Upper respiratory tract infection includes nasal congestion, paranasal sinus hypersecretion, rhinitis, rhinorrhea, upper respiratory tract infection.
f Musculoskeletal pain includes arthralgia, back pain, bone pain, flank pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, osteoarthritis, pain in extremity, spinal pain.
g Encephalopathy includes amnesia, apraxia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dyscalculia, encephalopathy, lethargy, memory impairment, mental status changes, somnolence.
h Dizziness includes dizziness, dizziness postural, syncope, vertigo.
i Tremor includes resting tremor, tremor.
j Cough includes cough, productive cough.
k Dyspnea includes acute respiratory distress syndrome, dyspnea, tachypnea, wheezing.
l Hypotension includes hypotension, orthostatic hypotension.
Adverse Reaction	Any Grade (%)	Grade 3 or Higher (%)
Cardiac disorders
Tachycardiaa	10	0
Gastrointestinal disorders
Nausea	25	1.6
Diarrhea	15	0
Constipation	11	0
General disorders and administration site conditions
Fatigueb	44	1.6
Fever	38	1.6
Edemac	20	0
Immune system disorders
Cytokine release syndrome	39	1.6
Infections and infestations
Infections with pathogen unspecifiedd	13	4.9
Upper respiratory tract infectione	13	0
Bacterial infectious disorders	10	3.3
Metabolism and nutrition disorders
Decreased appetite	13	1.6
Musculoskeletal and connective tissue disorders
Musculoskeletal painf	23	4.9
Nervous system disorders
Encephalopathyg	23	4.9
Dizzinessh	16	1.6
Tremori	16	0
Headache	11	1.6
Psychiatric disorders
Insomnia	11	0
Respiratory, thoracic, and mediastinal disorders
Coughj	18	0
Dyspneak	16	4.9
Vascular disorders
Hypotensionl	23	1.6
Hypertension	10	4.9

Other clinically important adverse reactions in < 10% of patients included the following:

•: Blood and lymphatic system disorders: Febrile neutropenia (1.6%)
•: Eye disorders: Vision blurred (3.3%)
•: Gastrointestinal disorders: Vomiting (8%), abdominal pain (7%), gastrointestinal hemorrhage (4.9%)
•: Infections and infestations: Fungal infection (4.9%), sepsis (3.3%), viral infection (3.3%)
•: Nervous system disorders: Motor dysfunction (7%), aphasia (4.9%), ataxia (4.9%), peripheral neuropathy (4.9%)
•: Psychiatric disorders: Delirium (3.3%)
•: Renal and urinary disorders: Renal failure (7%)
•: Respiratory, thoracic, and mediastinal disorders: Hypoxia (4.9%)
•: Skin and subcutaneous tissue disorders: Rash (7%)
•: Vascular disorders: Thrombosis (7%)

Table 7: Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients Treated with BREYANZI in the PILOT Study (N=61)
a Baseline lab values were assessed prior to lymphodepleting chemotherapy.
Laboratory Abnormalitya	Grade 3 or 4 (%)
Lymphocyte count decreased	97
Neutrophil count decreased	80
Hemoglobin decreased	30
Platelet count decreased	26

Grade 4 laboratory abnormalities in ≥ 10% of patients were lymphocyte decrease (95%), neutrophil decrease (57%), and platelet decrease (20%).

Relapsed or Refractory LBCL After Two or More Lines of Therapy

TRANSCEND

The safety of BREYANZI was evaluated in the TRANSCEND study, in which 268 adult patients with R/R LBCL after 2 or more prior lines of therapy received a single dose of CAR-positive viable T cells [see Clinical Studies (14.1)]. Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) or autoimmune disease requiring systemic immunosuppression were ineligible. The median age of the study population was 63 years (range: 18 to 86 years); 65% were male. The ECOG performance status at screening was 0 in 41% of patients, 1 in 58% of patients, and 2 in 1.5% of patients.

Serious adverse reactions occurred in 46% of patients. The most common nonlaboratory serious adverse reactions (> 2%) were CRS, encephalopathy, sepsis, febrile neutropenia, aphasia, pneumonia, fever, hypotension, dizziness, and delirium. Fatal adverse reactions occurred in 4% of patients.

Table 8 presents selected nonlaboratory adverse reactions reported in patients treated with BREYANZI, and Table 9 describes selected new or worsening Grade 3 or 4 laboratory abnormalities.

The most common nonlaboratory adverse reactions (≥ 20%) were fatigue, CRS, musculoskeletal pain, nausea, headache, encephalopathy, infections (pathogen unspecified), decreased appetite, diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting, and edema.

Table 8: Adverse Reactions in ≥ 10% of Patients Treated with BREYANZI in the TRANSCEND Study (N=268)
a Tachycardia includes heart rate increased, sinus tachycardia, tachycardia.
b Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness.
c Fatigue includes asthenia, fatigue, malaise.
d Edema includes edema, edema peripheral, fluid overload, fluid retention, generalized edema, hypervolemia, peripheral swelling, pulmonary congestion, pulmonary edema, swelling.
e Infections and infestations are grouped by pathogen type and selected clinical syndromes.
f Infections with pathogen unspecified contains febrile neutropenia (9%).
g Bacterial infection includes infections by pathogen type plus appendicitis, diverticulitis, peritonitis, skin infection, tooth infection.
h Upper respiratory tract infections include nasopharyngitis, pharyngitis, rhinitis, rhinovirus infection, sinusitis, upper respiratory tract congestion, upper respiratory tract infection.
i Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, pain in extremity, spinal pain.
j Headache includes headache, head discomfort, migraine, sinus headache.
k Encephalopathy includes amnesia, bradyphrenia, cognitive disorder, confusional state, depersonalization/derealization disorder, depressed level of consciousness, disturbance in attention, encephalopathy, flat affect, hypersomnia, incoherent, lethargy, leukoencephalopathy, loss of consciousness, memory impairment, mental impairment, mental status changes, somnolence.
l Dizziness includes dizziness, presyncope, syncope, vertigo.
m Tremor includes essential tremor, resting tremor, tremor.
n Peripheral neuropathy includes hyperesthesia, hypoesthesia, meralgia paresthetica, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, sciatica, sensory loss.
o Aphasia includes aphasia, disorganized speech, dysarthria, dysphemia, dysphonia, slow speech, speech disorder.
p Motor dysfunction includes eyelid ptosis, motor dysfunction, muscle rigidity, muscle spasms, muscle spasticity, muscle tightness, muscle twitching, muscular weakness, myoclonus, myopathy.
q Insomnia includes insomnia, somnambulism.
r Anxiety includes anxiety, panic attack.
s Delirium includes agitation, delirium, delusion, disorientation, hallucination, ‘hallucination, visual’, irritability, restlessness.
t Renal failure includes acute kidney injury, blood creatinine increased, chronic kidney disease, renal failure, renal injury.
u Cough includes cough, productive cough, upper-airway cough syndrome.
v Dyspnea includes acute respiratory failure, dyspnea, dyspnea exertional, respiratory failure.
w Rash includes erythema, dermatitis acneiform, perineal rash, rash, rash erythematous, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, rash pustular.
x Hypotension includes hypotension, orthostatic hypotension.
y Hemorrhage includes catheter site hemorrhage, conjunctival hemorrhage, epistaxis, hematoma, hematuria, hemorrhage, hemorrhage intracranial, pulmonary hemorrhage, retinal hemorrhage, vaginal hemorrhage.
Adverse Reaction	Any Grade (%)	Grade 3 or Higher (%)
Cardiac disorders
Tachycardiaa	25	0
Gastrointestinal disorders
Nausea	33	1.5
Diarrhea	26	0.4
Constipation	23	0
Abdominal painb	21	3.0
Vomiting	21	0.4
General disorders and administration site conditions
Fatiguec	48	3.4
Edemad	21	1.1
Fever	16	0
Chills	12	0
Immune system disorders
Cytokine release syndrome	46	4.1
Infections and infestationse
Infection with pathogen unspecifiedf	29	16
Bacterial infectiong	13	5
Upper respiratory tract infectionh	13	0.7
Viral infection	10	1.5
Metabolism and nutrition disorders
Decreased appetite	28	2.6
Musculoskeletal and connective tissue disorders
Musculoskeletal paini	37	2.2
Nervous system disorders
Headachej	30	1.1
Encephalopathyk	29	9
Dizzinessl	24	2.6
Tremorm	16	0
Peripheral neuropathyn	11	0
Aphasiao	10	2.2
Motor dysfunctionp	10	1.1
Psychiatric disorders
Insomniaq	14	0.4
Anxietyr	10	0
Deliriums	10	2.2
Renal and urinary disorders
Renal failuret	11	3.0
Respiratory, thoracic, and mediastinal disorders
Coughu	23	0
Dyspneav	16	2.6
Skin and subcutaneous tissue disorders
Rashw	13	0.4
Vascular disorders
Hypotensionx	26	3.4
Hypertension	14	4.5
Hemorrhagey	10	1.5

Other clinically important adverse reactions in < 10% of patients included the following:

•: Cardiac disorders: Arrhythmia (6%), cardiomyopathy (1.5%)
•: Gastrointestinal disorders: Gastrointestinal hemorrhage (4.1%)
•: Infections and infestations: Pneumonia (8%), fungal infection (8%), sepsis (4.5%), urinary tract infection (4.1%)
•: Metabolism and nutrition disorders: Tumor lysis syndrome (0.7%)
•: Nervous system disorders: Ataxia or gait disturbance (7%), visual disturbance (5%), paresis (2.6%), cerebrovascular events (1.9%), seizure (1.1%), brain edema (0.4%)
•: Procedural complications: Infusion-related reaction (1.9%)
•: Respiratory, thoracic, and mediastinal disorders: Pleural effusion (7%), hypoxia (6%)
•: Vascular disorder: Thrombosis (7%)

Table 9: Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients Treated with BREYANZI in the TRANSCEND Study
a Baseline lab values were assessed prior to lymphodepleting chemotherapy.
b The denominator varied from 239 to 268, based on the number of patients with a baseline value and at least one post-treatment value for the particular lab.
Laboratory Abnormalitya	Grade 3 or 4 (%)b
Lymphocyte count decreased	95
Neutrophil count decreased	88
Platelet count decreased	41
Hemoglobin decreased	32
Phosphate decreased	16
Fibrinogen decreased	14

Relapsed or Refractory CLL/SLL

TRANSCEND-CLL

The safety of BREYANZI was evaluated in the TRANSCEND-CLL study, which included 89 adult patients with R/R CLL/SLL who had received at least 2 prior lines of therapy including a BTK inhibitor and a BCL-2 inhibitor before receiving a single dose of CAR‑positive viable T cells [see Clinical Studies (14.2)]. Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) or autoimmune disease requiring systemic immunosuppression, Richter’s transformation, ECOG performance status >1 were ineligible. The trial required LVEF ≥ 40%, adequate oxygen saturation on room air with ≤ Grade 1 dyspnea, ALT ≤ 5 x ULN, total bilirubin < 2.0 mg/dL, creatinine clearance > 30 mL/min, and adequate bone marrow function to receive lymphodepleting chemotherapy.

The median age of the study population was 66 years (range: 49 to 82 years); 69% were male, 84% were White, 3% were Black, 1% were Asian. Two percent were Hispanic, and 89% were non-Hispanic. The ECOG performance status at screening was 0 in 40% of patients, and 1 in 60% of patients.

Serious adverse reactions occurred in 60% of patients. The most common nonlaboratory serious adverse reactions (> 2%) were CRS, encephalopathy, febrile neutropenia, pneumonia, hemorrhage, fever, renal failure, aphasia, abdominal pain, delirium, tumor lysis syndrome, upper respiratory tract infection, and hemophagocytic lymphohistiocytosis [IEC-HS]. Fatal adverse reactions occurred in 1.1% of patients.

Table 10 presents selected nonlaboratory adverse reactions reported in patients treated with BREYANZI, and Table 11 describes selected new or worsening Grade 3 or 4 laboratory abnormalities.

The most common nonlaboratory adverse reactions (≥ 20%) were CRS, encephalopathy, fatigue, musculoskeletal pain, nausea, edema, diarrhea, dyspnea, headache, fever, decreased appetite, constipation, tremor, dizziness, Infection with pathogen unspecified, rash, tachycardia, cough, and delirium.

Table 10: Adverse Reactions in ≥ 10% of Patients Treated with BREYANZI in the TRANSCEND-CLL Study (N=89)
a Tachycardia includes atrial fibrillation, atrial flutter, sinus tachycardia, tachycardia, ventricular tachycardia.
b Diarrhea includes diarrhea
c Abdominal pain includes abdominal pain, abdominal tenderness.
d Fatigue includes asthenia, fatigue, malaise.
e Edema includes ascites, face edema, hypervolemia, edema peripheral, pleural effusion, pulmonary edema, scrotal edema.
f Fever includes pyrexia.
g Grouped per high-level grouped term.
h Upper respiratory tract infection includes acute sinusitis, nasal congestion, nasopharyngitis, rhinitis, rhinovirus infection, sinusitis, upper respiratory tract infection.
i Musculoskeletal pain includes arthralgia, arthritis, back pain, bone pain, flank pain, musculoskeletal chest pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity.
j Encephalopathy includes cognitive disorder, confusional state, disturbance in attention, encephalopathy, lethargy, memory impairment, mental status changes, somnolence.
k Headache includes headache, sinus headache.
l Dizziness includes dizziness, presyncope, syncope, vertigo.
m Motor dysfunction includes asterixis, muscle spasms, muscular weakness, myoclonus.
n Peripheral neuropathy includes hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy.
o Taste disorder includes dysgeusia, taste disorder.
p Delirium includes agitation, delirium, hallucination, hallucination visual, intensive care unit delirium, irritability, restlessness.
q Renal failure includes acute kidney injury, chronic kidney disease, renal failure.
r Dyspnea includes dyspnea, respiratory failure, tachypnea, wheezing.
s Cough includes cough, productive cough, upper-airway cough syndrome.
t Rash includes dermatitis contact, erythema, petechiae, rash, rash macular, rash maculo-papular, scrotal erythema, seborrheic keratosis, urticaria.
u Hypotension includes hypotension, orthostatic hypotension.
v Hemorrhage includes epistaxis, hemorrhage intracranial, hematoma, hematuria, hemorrhoidal hemorrhage, intraventricular hemorrhage, lower gastrointestinal hemorrhage, traumatic hemothorax.
Adverse Reaction	Any Grade (%)	Grade 3 or Higher (%)
Blood and lymphatic system disorders
Febrile neutropenia	12	12
Cardiac disorders
Tachycardiaa	21	0
Gastrointestinal disorders
Nausea	35	0
Diarrheab	30	1.1
Constipation	24	0
Abdominal painc	18	0
Vomiting	15	0
General disorders and administration site conditions
Fatigued	40	4.5
Edemae	30	4.5
Feverf	27	1.1
Chills	17	1.1
Immune system disorders
Cytokine release syndrome	83	9
Infections and infestations
Infection with pathogen unspecifiedg	23	10
Upper respiratory tract infectionh	19	1.1
Viral infectiong	10	1.1
Metabolism and nutrition disorders
Decreased appetite	27	4.5
Tumor lysis syndrome	11	11
Musculoskeletal and connective tissue disorders
Musculoskeletal paini	42	1.1
Nervous system disorders
Encephalopathyj	44	18
Headachek	28	1.1
Tremor	24	2.2
Dizzinessl	21	1.1
Motor dysfunctionm	14	2.2
Peripheral neuropathyn	12	0
Taste disordero	10	0
Psychiatric disorders
Deliriump	20	3.4
Insomnia	16	1.1
Anxiety	12	1.1
Renal and urinary disorders
Renal failureq	15	3.4
Respiratory, thoracic, and mediastinal disorders
Dyspnear	27	8
Coughs	20	0
Skin and subcutaneous tissue disorders
Rasht	23	2.2
Vascular disorders
Hypotensionu	17	0
Hemorrhagev	16	1.1
Hypertension	10	4.5

Other clinically important adverse reactions in < 10% of patients included the following:

•: Cardiac disorders: Chest discomfort (4.5%), Arrhythmia (2.2%).
•: Eye disorders: Vision blurred (4.5%).
•: Gastrointestinal disorders: Dyspepsia (9%), abdominal distension (7%).
•: Immune system disorders: Hemophagocytic lymphohistiocytosis [IEC-HS] (3.4%).
•: Infections and infestations: Fungal infection (9%), pneumonia (7%), urinary tract infection (7%), bacterial infectious disorders (4.5%), sepsis (2.2%).
•: Injury, poisoning and procedural complications: Infusion related reaction (1.1%).
•: Nervous system disorders: Aphasia (8%), Ataxia (3.4%), Paresis (3.4%), Seizure (1.1%).
•: Psychiatric disorders: Affective disorder (7%).
•: Respiratory, thoracic, and mediastinal disorders: Oral pain (8%), hypoxia (8%).
•: Skin and subcutaneous tissue disorders: Ecchymosis (8%), xerosis (7%), pruritus (6%).
•: Vascular disorder: Thrombosis (6%).

Table 11: Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients Treated with BREYANZI in the TRANSCEND-CLL Study
a Baseline lab values were assessed prior to lymphodepleting chemotherapy.
b The denominator ranged from 85 to 89 for other measurements, based on the number of patients with a baseline value and at least one post-treatment value for the particular lab.
Laboratory Abnormalitya	Grade 3 or 4 (%)b
Neutrophil count decreased	94
Lymphocyte count decreased	87
White blood cell decreased	85
Platelet count decreased	53
Hemoglobin decreased	49
Hypophosphatemia	24
Hyponatremia	18
Hypocalcemia	11

Grade 4 laboratory abnormalities in ≥ 10% of patients were neutrophil count decreased (81%), lymphocyte count decreased (73%), white blood cell decreased (72%), and platelet count decreased (30%).

Relapsed or Refractory FL

TRANSCEND-FL

The safety of BREYANZI was evaluated in the TRANSCEND-FL study, in which 107 adult patients with relapsed or refractory FL after two or more prior lines of therapy received a single dose of BREYANZI [see Clinical Studies (14.3)]. Patients with a history of CNS disorders and active autoimmune disease requiring immunosuppressive therapy were ineligible. The median age was 62 years (range: 23 to 80 years), 38 % were female, and ECOG performance status was 0 in 61% and 1 in 39% of patients; 56% were White, 3% were Black, 9% were Asian; 5% were Hispanic and 69% were non-Hispanic.

Serious adverse reactions occurred in 26% of patients. The most common nonlaboratory serious adverse reactions (> 2%) were CRS, aphasia, febrile neutropenia, fever, and tremor.

Table 12 presents selected nonlaboratory adverse reactions reported in patients treated with BREYANZI, and Table 13 describes selected new or worsening Grade 3 or 4 laboratory abnormalities.

The most common nonlaboratory adverse reactions (≥ 20%) were CRS, headache, musculoskeletal pain, fatigue, constipation, and fever.

Table 12: Adverse Reactions* in ≥ 10% of Patients Treated with BREYANZI in the TRANSCEND-FL Study (N=107)
*Includes adverse reactions up to 90 days following treatment with BREYANZI.
a Fatigue includes asthenia, fatigue, somnolence.
b Fever includes pyrexia.
c Grouped per high-level grouped term.
d Musculoskeletal pain includes arthralgia, back pain, bone pain, muscle spasms, flank pain, pain in extremity, myalgia, musculoskeletal pain, neck pain, muscle tightness, groin pain, tendonitis, and ligament sprain.
Adverse Reaction	Any Grade (%)	Grade 3 or Higher (%)
Gastrointestinal disorders
Constipation	21	0
Diarrhea	15	0
General disorders and administration site conditions
Fatiguea	23	0
Feverb	20	0
Immune system disorders
Cytokine release syndrome	59	0.9
Infections and infestations
Infection with pathogen unspecifiedc	16	4.7
Musculoskeletal and connective tissue disorders
Musculoskeletal paind	28	0
Nervous system disorders
Headache	28	0
Tremor	15	0

Other clinically important adverse reactions in < 10% of patients included the following:

•: Blood and lymphatic system disorders: Febrile neutropenia (6%).
•: Cardiac disorders: Tachycardia (2.8%).
•: Eye disorders: Vision blurred (1.9%).
•: Gastrointestinal disorders: Nausea (9%), abdominal pain (4.7%), vomiting (3.7%).
•: General disorders and administration site conditions: Edema (4.7%), chills (3.7%).
•: Infections and infestations: Upper respiratory tract infection (8%), bacterial infectious disorders (6%), urinary tract infection (4.7%), viral infectious disorders (1.9%), pneumonia (1.9%), sepsis (0.9%).
•: Nervous system disorders: Encephalopathy (7%), aphasia (8%), dizziness (4.7%), motor dysfunction (3.7%), ataxia (3.7%), neuropathy peripheral (4.7%).
•: Psychiatric disorders: Insomnia (4.7%), delirium (4.7%), anxiety (1.9%).
•: Renal and urinary disorders: Acute kidney injury (0.9%).
•: Respiratory, thoracic and mediastinal disorders: Cough (7%), dyspnea (1.9%), hypoxia (1.9%).
•: Vascular disorders: Hypotension (8%), hypertension (6%), thrombosis (4.7%).
•: Skin and subcutaneous tissue disorders: Rash (7%).

Table 13: Grade 3 or 4 Laboratory Abnormalities* Occurring in ≥ 10% of Patients Treated with BREYANZI in the TRANSCEND-FL Study (N=107)
*Includes laboratory abnormalities up to 90 days following treatment with BREYANZI.
a Baseline lab values were assessed prior to lymphodepleting chemotherapy.
b Based on the number of patients with a baseline value and at least one post treatment value for the particular lab.
Laboratory Abnormalitya	Grade 3 or 4 (%)b
Lymphocyte count decreased	94
Neutrophil count decreased	79
White blood cell decreased	74
Platelet count decreased	17

Grade 4 laboratory abnormalities in ≥ 10% of patients were lymphocyte count decreased (78%), neutrophil count decreased (61%), white blood cell decreased (41%), and platelet count decreased (11%).

Relapsed or Refractory MCL

TRANSCEND-MCL Cohort

The safety of BREYANZI was evaluated in the TRANSCEND Study-MCL Cohort, in which 88 adult patients with relapsed or refractory MCL received a single dose of CAR-positive viable T cells [see Clinical Studies (14.4)]. Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) or autoimmune disease requiring systemic immunosuppression were ineligible. The trial required left ventricular ejection fraction ≥ 40%, adequate oxygen saturation on room air with ≤ Grade 1 dyspnea, ALT ≤ 5 x ULN, total bilirubin < 2.0 mg/dL, creatinine clearance > 30 mL/min, and adequate bone marrow function to receive lymphodepleting chemotherapy. The median age of the study population was 69 years (range: 36 to 86 years); 76% were male, 88% were White, 6% were Asian and 2.3% were Black. Four percent were Hispanic, and 92% were non-Hispanic. The ECOG performance status at screening was 0 in 54% of patients, and 1 in 46% of patients.

Serious adverse reactions occurred in 53% of patients. The most common nonlaboratory serious adverse reactions (> 2%) were CRS, confusional state, fever, encephalopathy, mental status changes, pleural effusion, upper respiratory tract infection, and decreased appetite. Fatal adverse reactions occurred in 4.5% of patients.

Table 14 presents selected nonlaboratory adverse reactions reported in patients treated with BREYANZI, and Table 15 describes selected new or worsening Grade 3 or 4 laboratory abnormalities.

The most common nonlaboratory adverse reactions (≥ 20%) were CRS, fatigue, musculoskeletal pain, encephalopathy, edema, headache, and decreased appetite.

Table 14: Adverse Reactions* in ≥ 10% of Patients Treated with BREYANZI in the TRANSCEND-MCL Cohort (N=88)
*Includes adverse reactions up to 90 days following treatment with BREYANZI.
a Tachycardia includes atrial fibrillation, sinus tachycardia, tachycardia, ventricular tachycardia.
b Abdominal pain includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain upper.
c Fatigue includes asthenia, fatigue, malaise.
d Edema includes hypervolemia, localized edema, edema, edema peripheral, peripheral swelling, pleural effusion, pulmonary edema.
e Fever includes pyrexia.
f Grouped per high-level grouped term.
g Upper respiratory tract infection includes nasal congestion, rhinitis, rhinorrhea, rhinovirus infection, upper respiratory tract infection.
h Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal pain, myalgia, neck pain, pain in extremity.
i Encephalopathy includes confusional state, depressed level of consciousness, encephalopathy, lethargy, memory impairment, mental status changes, somnolence.
j Dizziness includes dizziness, dizziness postural, syncope, vertigo.
k Motor dysfunction includes fine motor skill dysfunction, muscle spasms, muscle tightness, muscular weakness.
l Insomnia includes insomnia, sleep disorder.
m Renal failure includes acute kidney injury, blood creatinine increased.
n Dyspnea includes dyspnea, tachypnea, wheezing.
o Rash includes dermatitis contact, rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic.
p Hypotension includes hypotension, orthostatic hypotension.
q Hemorrhage includes catheter site hemorrhage, epistaxis, hematoma, hematuria, hemorrhage, hemorrhoidal hemorrhage, rectal hemorrhage.
Adverse Reaction	Any Grade (%)	Grade 3 or Higher (%)
Cardiac disorders
Tachycardiaa	17	3.4
Gastrointestinal disorders
Nausea	18	2.3
Diarrhea	17	0
Abdominal painb	15	3.4
Constipation	14	0
General disorders and administration site conditions
Fatiguec	39	2.3
Edemad	25	1.1
Fevere	17	0
Chills	11	0
Immune system disorders
Cytokine release syndrome	61	1.1
Infections and infestations
Infection with pathogen unspecifiedf	16	6
Upper respiratory tract infectiong	13	2.3
Metabolism and nutrition disorders
Decreased appetite	21	4.5
Musculoskeletal and connective tissue disorders
Musculoskeletal painh	38	2.3
Nervous system disorders
Encephalopathyi	30	9
Headache	23	0
Dizzinessj	11	2.3
Motor dysfunctionk	11	0
Tremor	11	0
Psychiatric disorders
Insomnial	14	0
Anxiety	13	1.1
Renal and urinary disorders
Renal failurem	15	0
Respiratory, thoracic, and mediastinal disorders
Dyspnean	11	0
Cough	10	0
Skin and subcutaneous tissue disorders
Rasho	11	1.1
Vascular disorders
Hypotensionp	15	0
Hemorrhageq	10	0
Hypertension	10	3.4

Other clinically important adverse reactions in < 10% of patients included the following:

•: Blood and lymphatic system disorders: Febrile neutropenia (6%).
•: Cardiac disorders: Arrhythmia (2.3%).
•: Eye disorders: Vision blurred (3.4%).
•: Gastrointestinal disorders: Vomiting (6%).
•: Infections and infestations: Bacterial infection (9%), viral infection (9%), fungal infection (8%), urinary tract infection (6%), sepsis (3.4%), pneumonia (2.3%).
•: Injury, poisoning and procedural complications: Infusion related reaction (4.5%).
•: Metabolism and nutrition disorders: Tumor lysis syndrome (2.3%).
•: Nervous system disorders: Neuropathy peripheral (9%), aphasia (8%), ataxia (4.5%), cerebral infarction (1.1%), seizure (1.1%).
•: Psychiatric disorders: Delirium (7%).
•: Respiratory, thoracic, and mediastinal disorders: Hypoxia (3.4%).
•: Vascular disorder: Thrombosis (4.5%).

Table 15: Grade 3 or 4 Laboratory Abnormalities* Occurring in ≥ 10% of Patients Treated with BREYANZI in the TRANSCEND-MCL Cohort
*Includes lab abnormalities up to 90 days following treatment with BREYANZI.
a Baseline lab values were assessed prior to lymphodepleting chemotherapy.
b The denominator ranged from 87 to 88 for laboratory measurements, based on the number of patients with a baseline value and at least one post-treatment value for the particular lab.
Laboratory Abnormalitya	Grade 3 or 4 (%)b
Lymphocyte count decreased	89
Neutrophil count decreased	85
White blood cell decreased	83
Platelet count decreased	39
Hemoglobin decreased	33
Uric acid increased	10
Sodium decreased	10

Grade 4 laboratory abnormalities in ≥ 10% of patients were lymphocyte count decreased (84%), neutrophil count decreased (52%), white blood cell decreased (52%), and platelet count decreased (22%).

6.2 Postmarketing Experience

Because adverse events to marketed products are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure.

The following adverse events have been identified during postmarketing use of BREYANZI.

Nervous System Disorder: Immune effector cell-associated neurotoxicity syndrome (ICANS).

Neoplasms: T cell malignancies