The safety profile for Breyanzi® in R/R CLL and SLL builds on evidence seen in clinical trials and other lymphoma indications1

The primary safety analysis was conducted in the full safety set (N=702), which included all patients who received a single dose of CAR positive viable T cells.

The planned dose of BREYANZI was 100 × 106 CAR-positive viable T cells.

CRS events were primarily low-grade1
Rates of cytokine release syndrome (CRS) in patients of Breyanzi Transcend CLL 004 clinical trial Rates of cytokine release syndrome (CRS) in patients of Breyanzi Transcend CLL 004 clinical trial
CRS-related clinical trial details1
  • CRS resolved in 98% of patients, with a median duration of 5 days (range: 1 to 37 days)
  • One patient had fatal CRS and 5 patients had ongoing CRS at the time of death
Most common manifestations of CRS1
Among patients with CRS, the most common manifestations (≥10%) included fever, hypotension, chills, tachycardia, hypoxia, and headache.
Cytokine release syndrome warnings and precautions1
  • CRS, including life-threatening reactions, occurred following treatment with Breyanzi
  • Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome
  • Ensure that 2 doses of tocilizumab are available prior to infusion of Breyanzi
  • Monitor patients daily for at least 7 days at a REMS-certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated
  • Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time
CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; CRS, cytokine release syndrome; NT, neurologic toxicity; R/R, relapsed or refractory; SLL, small lymphocytic lymphoma.
NT events were primarily low-grade1
Rates of neurologic toxicities (NT) in patients of Breyanzi Transcend CLL 004 clinical trial Rates of neurologic toxicities (NT) in patients of Breyanzi Transcend CLL 004 clinical trial
Neurologic toxicity–related clinical trial details1
  • Median time to NT onset 8 days (range: 1 to 63 days)
  • Neurologic toxicities resolved in 88% of cases with a median duration of 7 days (range: 1 to 119 days)
  • 82% of patients with neurologic toxicity developed CRS
Most common neurologic toxicities1
Encephalopathy, tremor, aphasia, delirium, and headache
Neurologic toxicity warnings and precautions1
  • Neurologic toxicities that were fatal or life-threatening, including immune effector cell-associated neurotoxicity syndrome (ICANS), occurred following treatment with Breyanzi. Serious events including cerebral edema and seizures occurred with Breyanzi. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, also occurred
  • Monitor patients daily at least for at least 7 days following Breyanzi infusion at a REMS-certified healthcare facility for signs and symptoms of neurologic toxicities and assess for other causes of neurological symptoms. Monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after infusion and treat promptly. Manage neurologic toxicity with supportive care and/or corticosteroid as needed
  • Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time
NT, neurologic toxicity.
Most common adverse reactions observed in TRANSCEND CLL 0041
  • 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
  • The most common nonlaboratory adverse reactions (≥20%) were CRS, encephalopathy, fatigue, musculoskeletal pain, nausea, headache, diarrhea, fever, edema, dizziness, coagulopathy, decreased appetite, constipation, dyspnea, tremor, abdominal pain, transaminase elevation, infections (pathogen unspecified), renal failure, cough, delirium
This table includes adverse reactions observed in ≥10% of the full population (N=89) treated with Breyanzi1
Adverse reactions 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
aTachycardia includes atrial fibrillation, atrial flutter, sinus tachycardia, tachycardia, ventricular tachycardia.
bDiarrhea includes diarrhea.
cAbdominal pain includes abdominal pain, abdominal tenderness.
dFatigue includes asthenia, fatigue, malaise.
eEdema includes ascites, face edema, hypervolemia, edema peripheral, pleural effusion, pulmonary edema, scrotal edema.
fFever includes pyrexia.
gGrouped per high-level grouped term.
hUpper respiratory tract infection includes acute sinusitis, nasal congestion, nasopharyngitis, rhinitis, rhinovirus infection, sinusitis, upper respiratory tract infection.
iMusculoskeletal pain includes arthralgia, arthritis, back pain, bone pain, flank pain, musculoskeletal chest pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity.
jEncephalopathy includes cognitive disorder, confusional state, disturbance in attention, encephalopathy, lethargy, memory impairment, mental status changes, somnolence.
kHeadache includes headache, sinus headache.
lDizziness includes dizziness, presyncope, syncope, vertigo.
mMotor dysfunction includes asterixis, muscle spasms, muscular weakness, myoclonus.
nPeripheral neuropathy includes hyperaesthesia, hypoaesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy.
oTaste disorder includes dysgeusia, taste disorder.
pDelirium includes agitation, delirium, hallucination, hallucination visual, intensive care unit delirium, irritability, restlessness.
qRenal failure includes acute kidney injury, chronic kidney disease, renal failure.
rDyspnea includes dysponea, respiratory failure, tachypnoea, wheezing.
sCough includes cough, productive cough, upper-airway cough syndrome.
tRash includes dermatitis contact, erythema, petechiae, rash, rash macular, rash maculo-papular, scrotal erythema , seborrhoeic keratosis, urticaria.
uHypotension includes hypotension, orthostatic hypotension.
vHemorrhage includes epistaxis, haemorrhage intracranial, haematoma, haematuria, haemorrhoidal haemorrhage, intraventricular haemorrhage, lower gastrointestinal haemorrhage, traumatic haemothorax.
BCL-2i, B-cell lymphoma-2 inhibitor; BTKi, Bruton tyrosine kinase inhibitor; CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; CRS, cytokine release syndrome; NT, neurologic toxicity; R/R, relapsed or refractory; SLL, small lymphocytic lymphoma.
Important Safety Information
LESS
Indication
BREYANZI is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:
  • adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
Important Safety Information

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, AND SECONDARY HEMATOLOGICAL MALIGNANCIES

  • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving BREYANZI. Do not administer BREYANZI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids.
  • Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving BREYANZI, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with BREYANZI. Provide supportive care and/or corticosteroids as needed.
  • T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI.
  • BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.
Cytokine Release Syndrome
Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. In clinical trials of BREYANZI, which enrolled a total of 702 patients with non-Hodgkin lymphoma (NHL), CRS occurred in 54% of patients, including ≥ Grade 3 CRS in 3.2% of patients. The median time to onset was 5 days (range: 1 to 63 days). CRS resolved in 98% of patients with a median duration of 5 days (range: 1 to 37 days). One patient had fatal CRS and 5 patients had ongoing CRS at the time of death. The most common manifestations of CRS (≥10%) were fever, hypotension, tachycardia, chills, hypoxia, and headache.
Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).
Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI.
Neurologic Toxicities
Neurologic toxicities that were fatal or life-threatening, including immune effector cell-associated neurotoxicity syndrome (ICANS), occurred following treatment with BREYANZI. Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, also occurred.
In clinical trials of BREYANZI, CAR T cell-associated neurologic toxicities occurred in 31% of patients, including ≥ Grade 3 cases in 10% of patients. The median time to onset of neurotoxicity was 8 days (range: 1 to 63 days). Neurologic toxicities resolved in 88% of patients with a median duration of 7 days (range: 1 to 119 days). Of patients developing neurotoxicity, 82% also developed CRS.
The most common neurologic toxicities (≥5%) included encephalopathy, tremor, aphasia, headache, dizziness, and delirium
CRS and Neurologic Toxicities Monitoring
Monitor patients daily for at least 7 days following BREYANZI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS and neurologic toxicities and assess for other causes of neurological symptoms. Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion and treat promptly. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated. Manage neurologic toxicity with supportive care and/or corticosteroid as needed. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time.
BREYANZI REMS
Because of the risk of CRS and neurologic toxicities, BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS. The required components of the BREYANZI REMS are:
  • Healthcare facilities that dispense and administer BREYANZI must be enrolled and comply with the REMS requirements.
  • Certified healthcare facilities must have on-site, immediate access to tocilizumab.
  • Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after BREYANZI infusion, if needed for treatment of CRS.
Further information is available at www.BreyanziREMS.com, or contact Bristol-Myers Squibb at 1-866-340-7332.
Hypersensitivity Reactions
Allergic reactions may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO).
Serious Infections
Severe infections, including life-threatening or fatal infections, have occurred in patients after BREYANZI infusion. In clinical trials of BREYANZI, infections of any grade occurred in 34% of patients, with Grade 3 or higher infections occurring in 12% of all patients. Grade 3 or higher infections with an unspecified pathogen occurred in 7%, bacterial infections in 3.7%, viral infections in 2%, and fungal infections in 0.7% of patients. One patient who received 4 prior lines of therapy developed a fatal case of John Cunningham (JC) virus progressive multifocal leukoencephalopathy 4 months after treatment with BREYANZI. One patient who received 3 prior lines of therapy developed a fatal case of cryptococcal meningoencephalitis 35 days after treatment with BREYANZI.
Febrile neutropenia developed after BREYANZI infusion in 8% of patients. Febrile neutropenia may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.
Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines. Avoid administration of BREYANZI in patients with clinically significant, active systemic infections.
Viral reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. In clinical trials of BREYANZI, 35 of 38 patients with a prior history of HBV were treated with concurrent antiviral suppressive therapy. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. In patients with prior history of HBV, consider concurrent antiviral suppressive therapy to prevent HBV reactivation per standard guidelines.
Prolonged Cytopenias
Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion. In clinical trials of BREYANZI, Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 35% of patients, and included thrombocytopenia in 25%, neutropenia in 22%, and anemia in 6% of patients. Monitor complete blood counts prior to and after BREYANZI administration.
Hypogammaglobulinemia
B-cell aplasia and hypogammaglobulinemia can occur in patients receiving BREYANZI. In clinical trials of BREYANZI, hypogammaglobulinemia was reported as an adverse reaction in 10% of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 30% of patients. Monitor immunoglobulin levels after treatment with BREYANZI and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated.

Live vaccines: The safety of immunization with live viral vaccines during or following BREYANZI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during BREYANZI treatment, and until immune recovery following treatment with BREYANZI.
Secondary Malignancies
Patients treated with BREYANZI may develop secondary malignancies. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes. Monitor lifelong for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol-Myers Squibb at 1- 888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing.
Effects on Ability to Drive and Use Machines
Due to the potential for neurologic events, including altered mental status or seizures, patients receiving BREYANZI are at risk for developing altered or decreased consciousness or impaired coordination in the 8 weeks following BREYANZI administration. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 8 weeks.
Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS)
Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. Three of 89 (3%) safety evaluable patients with R/R CLL/SLL developed IEC-HS. Time to onset of IEC-HS ranged from 7 to 18 days. Two of the 3 patients developed IEC-HS in the setting of ongoing CRS and 1 in the setting of ongoing neurotoxicity. IEC-HS was fatal in 2 of 3 patients. One patient had fatal IEC-HS and one had ongoing IEC-HS at time of death. IEC-HS is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of IEC-HS should be administered per current practice guidelines.
Adverse Reactions
The most common adverse reactions (incidence ≥30%) in CLL/SLL are cytokine release syndrome, 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.
Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide.
Reference
  1. Breyanzi [package insert]. Summit, NJ: Bristol-Myers Squibb Company; 2024.

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Reference
  1. Breyanzi [package insert]. Summit, NJ: Bristol-Myers Squibb Company; 2024.