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adverse reactions
6 ADVERSE REACTIONS The most common adverse reactions (incidence ≥ 30%) in: • LBCL are fever, CRS, fatigue, musculoskeletal pain, and nausea. The most common Grade 3-4 laboratory abnormalities include lymphocyte count decrease, neutrophil count decrease, platelet count decrease, and hemoglobin decrease. ( 6.1 ) • CLL/SLL are CRS, encephalopathy, fatigue, musculoskeletal pain, nausea, edema and diarrhea. The most common Grade 3-4 laboratory abnormalities include neutrophil count decrease, white blood cell decrease, hemoglobin decrease, platelet count decrease, and lymphocyte count decrease. ( 6.1 ) • FL are CRS. The most common Grade 3-4 laboratory abnormalities include lymphocyte count decreased, neutrophil count decreased, and white blood cell decreased. ( 6.1 ) • MCL are CRS, fatigue, musculoskeletal pain, and encephalopathy. The most common Grade 3-4 laboratory abnormalities include neutrophil count decrease, white blood cell decrease, and platelet count decrease. ( 6.1 ) • MZL are CRS. The most common Grade 3-4 laboratory abnormalities include lymphocyte count decreased, neutrophil count decreased, and white blood cell decreased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 and in this section reflects exposure to a single dose of BREYANZI in 769 patients in five clinical studies as described below. Study 1 (JCAR017-BCM-003; Relapsed or Refractory LBCL After One Line of Therapy) Study 1 was 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 stroke), 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 × 10 9 cells/L or platelets < 50 × 10 9 cells/L in the absence of bone marrow involvement. The planned dose of BREYANZI was 100 × 10 6 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 with Relapsed or Refractory LBCL Treated with BREYANZI in Study 1 (N=89) * Represents multiple related terms. a Dizziness includes dizziness, dizziness postural, syncope, vertigo. b Motor dysfunction includes fine motor skill dysfunction, muscle spasms, muscular weakness. c Tremor includes resting tremor, tremor, essential tremor. d 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 Tachycardia * 15 1.1 Gastrointestinal disorders Nausea 24 0 Constipation 20 2.2 Diarrhea 18 0 Abdominal pain * 13 2.2 Vomiting 11 0 General disorders and administration site conditions Fever 55 3.4 Fatigue * 28 1.1 Edema * 13 0 Immune system disorders Cytokine release syndrome 49 1.1 Infections and infestations Bacterial infectious disorders * 12 6 Infections with pathogen unspecified * 12 6 Sepsis * 10 7 Metabolism and nutrition disorders Decreased appetite 15 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain * 36 3.4 Nervous system disorders Headache * 34 6 Dizziness a 20 1.1 Motor dysfunction b 12 3.4 Tremor c 11 1.1 Psychiatric disorders Insomnia * 15 0 Respiratory, thoracic, and mediastinal disorders Cough * 11 0 Skin and subcutaneous tissue disorders Rash * 12 1.1 Vascular disorders Hypotension * 15 2.2 Hemorrhage d 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 with Relapsed or Refractory LBCL Treated with BREYANZI in Study 1 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 Abnormality a 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%). Study 2 (017006; Relapsed or Refractory LBCL After One Line of Therapy) Study 2 was 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 stroke), 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 × 10 6 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 with Relapsed or Refractory LBCL Treated with BREYANZI in Study 2 (N=61) * Represents multiple related terms. a Encephalopathy includes amnesia, apraxia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dyscalculia, encephalopathy, lethargy, memory impairment, mental status changes, somnolence. b Dizziness includes dizziness, dizziness postural, syncope, vertigo. c Tremor includes resting tremor, tremor. Adverse Reaction Any Grade (%) Grade 3 or Higher (%) Cardiac disorders Tachycardia * 10 0 Gastrointestinal disorders Nausea 25 1.6 Diarrhea 15 0 Constipation 11 0 General disorders and administration site conditions Fatigue * 44 1.6 Fever 38 1.6 Edema * 20 0 Immune system disorders Cytokine release syndrome 39 1.6 Infections and infestations Infections with pathogen unspecified * 13 4.9 Upper respiratory tract infection * 13 0 Bacterial infectious disorders * 10 3.3 Metabolism and nutrition disorders Decreased appetite 13 1.6 Musculoskeletal and connective tissue disorders Musculoskeletal pain * 23 4.9 Nervous system disorders Encephalopathy a 23 4.9 Dizziness b 16 1.6 Tremor c 16 0 Headache 11 1.6 Psychiatric disorders Insomnia 11 0 Respiratory, thoracic, and mediastinal disorders Cough * 18 0 Dyspnea * 16 4.9 Vascular disorders Hypotension * 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 with Relapsed or Refractory LBCL Treated with BREYANZI in Study 2 (N=61) a Baseline lab values were assessed prior to lymphodepleting chemotherapy. Laboratory Abnormality a 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%). Study 3 (017001; Relapsed or Refractory LBCL After Two or More Lines of Therapy) Study 3 was an open-label, single-arm study which evaluated 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 stroke) 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 with Relapsed or Refractory LBCL Treated with BREYANZI in Study 3 (N=268) * Represents multiple related terms. a 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. b Dizziness includes dizziness, presyncope, syncope, vertigo. c Tremor includes essential tremor, resting tremor, tremor. d Peripheral neuropathy includes hyperesthesia, hypoesthesia, meralgia paresthetica, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, sciatica, sensory loss. e Aphasia includes aphasia, disorganized speech, dysarthria, dysphemia, dysphonia, slow speech, speech disorder. f Motor dysfunction includes eyelid ptosis, motor dysfunction, muscle rigidity, muscle spasms, muscle spasticity, muscle tightness, muscle twitching, muscular weakness, myoclonus, myopathy. g Delirium includes agitation, delirium, delusion, disorientation, hallucination, hallucination, visual, irritability, restlessness. h 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 Tachycardia * 25 0 Gastrointestinal disorders Nausea 33 1.5 Diarrhea 26 0.4 Constipation 23 0 Abdominal pain * 21 3.0 Vomiting 21 0.4 General disorders and administration site conditions Fatigue * 48 3.4 Edema * 21 1.1 Fever 16 0 Chills 12 0 Immune system disorders Cytokine release syndrome 46 4.1 Infections and infestations * Infection with pathogen unspecified * 29 16 Bacterial infection * 13 5 Upper respiratory tract infection * 13 0.7 Viral infection 10 1.5 Metabolism and nutrition disorders Decreased appetite 28 2.6 Musculoskeletal and connective tissue disorders Musculoskeletal pain * 37 2.2 Nervous system disorders Headache * 30 1.1 Encephalopathy a 29 9 Dizziness b 24 2.6 Tremor c 16 0 Peripheral neuropathy d 11 0 Aphasia e 10 2.2 Motor dysfunction f 10 1.1 Psychiatric disorders Insomnia * 14 0.4 Anxiety * 10 0 Delirium g 10 2.2 Renal and urinary disorders Renal failure * 11 3.0 Respiratory, thoracic, and mediastinal disorders Cough * 23 0 Dyspnea * 16 2.6 Skin and subcutaneous tissue disorders Rash * 13 0.4 Vascular disorders Hypotension * 26 3.4 Hypertension 14 4.5 Hemorrhage h 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 with Relapsed or Refractory LBCL Treated with BREYANZI in Study 3 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 Abnormality a 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 Study 4 (017004; Relapsed or Refractory CLL/SLL) Study 4 was an open-label, single-arm study which evaluated 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 stroke) 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 with Relapsed or Refractory CLL/SLL Treated with BREYANZI in Study 4 (N=89) * Represents multiple related terms. a Encephalopathy includes cognitive disorder, confusional state, disturbance in attention, encephalopathy, lethargy, memory impairment, mental status changes, somnolence. b Dizziness includes dizziness, presyncope, syncope, vertigo. c Motor dysfunction includes asterixis, muscle spasms, muscular weakness, myoclonus. d Peripheral neuropathy includes hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy. e Delirium includes agitation, delirium, hallucination, hallucination visual, intensive care unit delirium, irritability, restlessness. f 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 Tachycardia * 21 0 Gastrointestinal disorders Nausea 35 0 Diarrhea * 30 1.1 Constipation 24 0 Abdominal pain * 18 0 Vomiting 15 0 General disorders and administration site conditions Fatigue * 40 4.5 Edema * 30 4.5 Fever * 27 1.1 Chills 17 1.1 Immune system disorders Cytokine release syndrome 83 9 Infections and infestations Infection with pathogen unspecified * 23 10 Upper respiratory tract infection * 19 1.1 Viral infection * 10 1.1 Metabolism and nutrition disorders Decreased appetite 27 4.5 Tumor lysis syndrome 11 11 Musculoskeletal and connective tissue disorders Musculoskeletal pain * 42 1.1 Nervous system disorders Encephalopathy a 44 18 Headache * 28 1.1 Tremor 24 2.2 Dizziness b 21 1.1 Motor dysfunction c 14 2.2 Peripheral neuropathy d 12 0 Taste disorder * 10 0 Psychiatric disorders Delirium e 20 3.4 Insomnia 16 1.1 Anxiety 12 1.1 Renal and urinary disorders Renal failure * 15 3.4 Respiratory, thoracic, and mediastinal disorders Dyspnea * 27 8 Cough * 20 0 Skin and subcutaneous tissue disorders Rash * 23 2.2 Vascular disorders Hypotension * 17 0 Hemorrhage f 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 with Relapsed or Refractory CLL/SLL Treated with BREYANZI in Study 4 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 Abnormality a 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%). Study 5 (JCAR017-FOL-001; Relapsed or Refractory FL Cohort) Study 5 was an open-label, single-arm study which evaluated 107 adult patients with relapsed or refractory FL after two or more prior lines of therapy received a single dose of CAR-positive viable T cells [see Clinical Studies ( 14.3 )]. Patients with a history of CNS disorders (such as seizures or stroke) 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 with Relapsed or Refractory FL Treated with BREYANZI in Study 5 (N=107) * Represents multiple related terms. ** Includes adverse reactions up to 90 days following treatment with BREYANZI. Adverse Reaction Any Grade (%) Grade 3 or Higher (%) Gastrointestinal disorders Constipation 21 0 Diarrhea 15 0 General disorders and administration site conditions Fatigue * 23 0 Fever * 20 0 Immune system disorders Cytokine release syndrome 59 0.9 Infections and infestations Infection with pathogen unspecified * 16 4.7 Musculoskeletal and connective tissue disorders Musculoskeletal pain * 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 with Relapsed or Refractory FL Treated with BREYANZI in Study 5 (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 Abnormality a 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%). Study 3 (017001; Relapsed or Refractory MCL Cohort) Study 3 was an open-label, single-arm study which evaluated 88 adult patients with relapsed or refractory MCL who 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 stroke) 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 with Relapsed or Refractory MCL Treated with BREYANZI in Study 3 (N=88) * Represents multiple related terms. ** Includes adverse reactions up to 90 days following treatment with BREYANZI. a Encephalopathy includes confusional state, depressed level of consciousness, encephalopathy, lethargy, memory impairment, mental status changes, somnolence. b Dizziness includes dizziness, dizziness postural, syncope, vertigo. c Motor dysfunction includes fine motor skill dysfunction, muscle spasms, muscle tightness, muscular weakness. d Hemorrhage includes catheter site hemorrhage, epistaxis, hematoma, hematuria, hemorrhage, hemorrhoidal hemorrhage, rectal hemorrhage. Adverse Reaction Any Grade (%) Grade 3 or Higher (%) Cardiac disorders Tachycardia * 17 3.4 Gastrointestinal disorders Nausea 18 2.3 Diarrhea 17 0 Abdominal pain * 15 3.4 Constipation 14 0 General disorders and administration site conditions Fatigue * 39 2.3 Edema * 25 1.1 Fever * 17 0 Chills 11 0 Immune system disorders Cytokine release syndrome 61 1.1 Infections and infestations Infection with pathogen unspecified * 16 6 Upper respiratory tract infection * 13 2.3 Metabolism and nutrition disorders Decreased appetite 21 4.5 Musculoskeletal and connective tissue disorders Musculoskeletal pain * 38 2.3 Nervous system disorders Encephalopathy a 30 9 Headache 23 0 Dizziness b 11 2.3 Motor dysfunction c 11 0 Tremor 11 0 Psychiatric disorders Insomnia * 14 0 Anxiety 13 1.1 Renal and urinary disorders Renal failure * 15 0 Respiratory, thoracic, and mediastinal disorders Dyspnea * 11 0 Cough 10 0 Skin and subcutaneous tissue disorders Rash * 11 1.1 Vascular disorders Hypotension * 15 0 Hemorrhage d 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 with Relapsed or Refractory MCL Treated with BREYANZI in Study 3 * 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 Abnormality a 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%). Study 5 (JCAR017-FOL-001; Relapsed or Refractory MZL Cohort) Study 5 was a an open-label, single-arm study which evaluated 67 adult patients with relapsed or refractory MZL after two or more prior lines of therapy or relapsed after hematopoietic stem cell transplant (HSCT) received a single dose of CAR-positive viable T cells [see Clinical Studies ( 14.5 )] . Patients who had previously received CD19-directed therapy had to have biopsy proven CD19 positive lymphoma [see Clinical Studies ( 14 )] . Patients with a history of CNS disorders (such as seizures or stroke) and active autoimmune disease requiring immunosuppressive therapy were ineligible. The median age was 62 years (range: 37 to 81 years), 58% were male, ECOG performance status was 0 in 55% and 1 in 45% of patients; 57% were White, 6% were Asian, 2% were Black; race was not reported in 36% of patients; and 2% were Hispanic. Serious adverse reactions occurred in 39% of patients. The most common nonlaboratory serious adverse reactions (> 2%) were CRS, encephalopathy, aphasia, sepsis, tremor, delirium, dizziness, infusion related hypersensitivity reaction, and transient ischemic attack. Fatal adverse reactions occurred in 3% of patients. Table 16 presents nonlaboratory adverse reactions reported in ≥ 10% of patients treated with BREYANZI, and Table 17 describes selected new or worsening Grade 3 or 4 laboratory abnormalities. The most common nonlaboratory adverse reactions (≥ 20%) were CRS, diarrhea, fatigue, musculoskeletal pain, and headache. Table 16: Adverse Reactions** in ≥ 10% of Patients with Relapsed or Refractory MZL Treated with BREYANZI in Study 5 (N=67) * Represents multiple related terms. ** Includes adverse reactions up to 90 days following treatment with BREYANZI. a Encephalopathy includes brain fog, cognitive disorder, confusional state, disturbance in attention, dyscalculia, dysgraphia, memory impairment, somnolence. b Delirium includes delirium, disorientation, hallucination, irritability, restlessness. Adverse Reaction Any Grade (%) Grade 3 or Higher (%) Gastrointestinal disorders Diarrhea 28 1.5 Nausea 18 1.5 Abdominal pain * 10 0 General disorders and administration site conditions Fatigue * 27 3 Edema * 18 3 Fever * 10 0 Immune system disorders Cytokine release syndrome 76 4.5 Infections and infestations Infection with pathogen unspecified * 16 6 Metabolism and nutrition disorders Decreased appetite 10 3 Musculoskeletal and connective tissue disorders Musculoskeletal pain * 22 0 Nervous system disorders Headache 21 1.5 Tremor 21 0 Encephalopathy a 21 1.5 Dizziness 16 0 Aphasia 10 0 Psychiatric disorders Delirium b 10 3 Renal and urinary disorders Renal failure * 10 1.5 Vascular disorders Hypotension 10 0 Other clinically important adverse reactions in < 10% of patients included the following: • Blood and lymphatic system disorders: Febrile neutropenia (3%). • Cardiac disorders: Tachycardia (7.5%). • Gastrointestinal disorders: Vomiting (9%), constipation (3%), dyspepsia (3%). • General disorders and administration site conditions: Chills (7.5%), infusion related hypersensitivity reactions (3%). • Immune system disorders: Hemophagocytic lymphohistiocytosis (4.5%). • Infections and infestations: Bacterial infections (6%), viral infections (6%), fungal infections (3%). • Metabolism and nutrition disorders: Tumor lysis syndrome (1.5%). • Nervous system disorders: Motor dysfunction (4.5%), ataxia (3%), neuropathy peripheral (3%), transient ischaemic attack (3.0%). • Psychiatric disorders: Insomnia (9%), affective disorder (7.5%). • Respiratory, thoracic and mediastinal disorders: Dyspnea (6%), cough (4.5%), hypoxia (4.5%). • Skin and subcutaneous tissue disorders: Rash (4.5%). • Vascular disorders: Hemorrhage (9%), hypertension (6%), thrombosis (6%). Table 17: Grade 3 or 4 Laboratory Abnormalities * Occurring in ≥ 10% of Patients with Relapsed or Refractory MZL Treated with BREYANZI in Study 5 (N=67) * 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 Abnormality a Grade 3 or 4 (%) b Lymphocyte count decreased 99 Neutrophil count decreased 84 White blood cell decreased 84 Platelet count decreased 28 Hemoglobin decreased 25 Fibrinogen decreased 10 Grade 4 laboratory abnormalities in ≥ 10% of patients were lymphocyte count decreased (85%), neutrophil count decreased (64%), white blood cell decreased (49%), and platelet count decreased (19%). 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 Eye disorders: Blindness