BREYANZI by is a Other medication manufactured, distributed, or labeled by Juno Therapeutics, Inc.. Drug facts, warnings, and ingredients follow.
BREYANZI is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B (1).
Limitations of Use: BREYANZI is not indicated for the treatment of patients with primary central nervous system lymphoma (1, 14).
For autologous use only. For intravenous use only.
None (4).
The most common nonlaboratory adverse reactions (incidence greater than or equal to 20%) in BREYANZI-treated patients were fatigue, cytokine release syndrome, musculoskeletal pain, nausea, headache, encephalopathy, infections (pathogen unspecified), decreased appetite, diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting, and edema (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-888-805-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 2/2021
BREYANZI is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.
Limitations of Use: BREYANZI is not indicated for the treatment of patients with primary central nervous system (CNS) lymphoma [see Clinical Studies (14)].
For autologous use only. For intravenous use only.
A single dose of BREYANZI contains 50 to 110 × 106 CAR-positive viable T cells (consisting of 1:1 CAR-positive viable T cells of the CD8 and CD4 components), with each component supplied separately in one to four single-dose vials.
See the respective Certificate of Release for Infusion (RFI Certificate) for each component, for the actual cell counts and volumes to be infused [see Dosage and Administration (2.2) and Dosage Forms and Strengths (3)].
BREYANZI is for autologous use only. The patient's identity must match the patient identifiers on the BREYANZI cartons, vials and syringe labels. Do not infuse BREYANZI if the information on the patient-specific labels does not match the intended patient.
Preparing the Patient for BREYANZI
Confirm the availability of BREYANZI before starting lymphodepleting chemotherapy.
Pretreatment
Administer the lymphodepleting chemotherapy regimen before infusion of BREYANZI: fludarabine 30 mg/m2/day intravenously (IV), and cyclophosphamide 300 mg/m2/day IV for 3 days. See the prescribing information for fludarabine and cyclophosphamide for information on dose adjustment in renal impairment.
Infuse BREYANZI 2 to 7 days after completion of lymphodepleting chemotherapy.
Delay the infusion of BREYANZI if the patient has unresolved serious adverse events from preceding chemotherapies, active uncontrolled infection, or active graft-versus-host disease (GVHD).
Premedication
To minimize the risk of infusion reactions, premedicate the patient with acetaminophen (650 mg orally) and diphenhydramine (25-50 mg, IV or orally), or another H1-antihistamine, 30 to 60 minutes prior to treatment with BREYANZI.
Avoid prophylactic use of systemic corticosteroids, as they may interfere with the activity of BREYANZI.
Receipt of BREYANZI
Preparing BREYANZI
Before thawing the vials
Thawing the vials
Dose preparation
Withdrawal of the required volume of cells from each vial into a separate syringe should be carried out using the following instructions:
![]() | ![]() |
![]() | ![]() |
a | b |
![]() |
![]() | ![]() | ![]() |
BREYANZI Administration
BREYANZI contains human blood cells that are genetically modified with replication-incompetent, self-inactivating lentiviral vector. Follow universal precautions and local biosafety guidelines applicable for the handling and disposal, to avoid potential transmission of infectious diseases.
Monitoring
Cytokine Release Syndrome
Identify cytokine release syndrome (CRS) based on clinical presentation [see Warnings and Precautions (5.1)]. Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in Table 1. Patients who experience Grade 2 or higher CRS (e.g., hypotension not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous cardiac telemetry and pulse oximetry. For patients experiencing severe CRS, consider performing an echocardiogram to assess cardiac function. For severe or life-threatening CRS, consider intensive-care supportive therapy.
If concurrent neurologic toxicity is suspected during CRS, administer:
CRS Grade* | Tocilizumab | Corticosteroids† |
---|---|---|
|
||
Grade 1
Fever | If less than 72 hours after infusion, consider tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). If 72 hours or more after infusion, treat symptomatically. | If less than 72 hours after infusion, consider dexamethasone 10 mg IV every 24 hours. If 72 hours or more after infusion, treat symptomatically. |
Grade 2
Symptoms require and respond to moderate intervention. Oxygen requirement less than 40% FiO2, or hypotension responsive to fluids or low dose of one vasopressor, or Grade 2 organ toxicity. | Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids or increasing supplemental oxygen. Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses. | If less than 72 hours after infusion, administer dexamethasone 10 mg IV every 12-24 hours. If 72 hours or more after infusion, consider dexamethasone 10 mg IV every 12-24 hours. |
If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (10-20 mg IV every 6 to 12 hours). If no improvement or continued rapid progression, maximize dexamethasone, switch to high-dose methylprednisolone 2 mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses tocilizumab in 24 hours, or 4 doses in total. |
||
Grade 3 | Per Grade 2. | Administer dexamethasone 10 mg IV every 12 hours. |
Symptoms require and respond to aggressive intervention. Oxygen requirement greater than or equal to 40% FiO2, or hypotension requiring high-dose or multiple vasopressors, or Grade 3 organ toxicity, or Grade 4 transaminitis. | If no improvement within 24 hours or rapid progression of CRS, repeat tocilizumab and escalate dose and frequency of dexamethasone (10-20 mg IV every 6 to 12 hours). If no improvement or continued rapid progression, maximize dexamethasone, switch to high-dose methylprednisolone 2 mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses tocilizumab in 24 hours, or 4 doses in total. |
|
Grade 4
Life-threatening symptoms Requirements for ventilator support or continuous veno-venous hemodialysis (CVVHD) or Grade 4 organ toxicity (excluding transaminitis). | Per Grade 2. | Administer dexamethasone 20 mg IV every 6 hours. |
If no improvement within 24 hours or rapid progression of CRS, escalate tocilizumab and corticosteroid use. If no improvement or continued rapid progression, maximize dexamethasone, switch to high-dose methylprednisolone 2 mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses tocilizumab in 24 hours, or 4 doses in total. | ||
Neurologic Toxicity
Monitor patients for signs and symptoms of neurologic toxicities (Table 2). Rule out other causes of neurologic symptoms. Provide intensive care supportive therapy for severe or life-threatening neurologic toxicities. If neurologic toxicity is suspected, manage according to the recommendations in Table 2.
If concurrent CRS is suspected during neurologic toxicity, administer:
NT Grade* | Corticosteroids and Antiseizure Medication |
---|---|
|
|
Grade 1 | Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. If 72 hours or more after infusion, observe. If less than 72 hours after infusion, consider dexamethasone 10 mg IV every 12 to 24 hours for 2 to 3 days. |
Grade 2 | Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. Dexamethasone 10 mg IV every 12 hours for 2-3 days, or longer for persistent symptoms. Consider taper for a total steroid exposure of greater than 3 days. If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency of dexamethasone up to a maximum of 20 mg IV every 6 hours. If no improvement after another 24 hours, rapidly progressing symptoms, or life-threatening complications arise, give methylprednisolone (2 mg/kg loading dose, followed by 2 mg/kg divided 4 times a day; taper within 7 days). |
Grade 3 | Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. Dexamethasone 10 to 20 mg IV every 8 to 12 hours. Steroids are not recommended for isolated Grade 3 headaches. If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (dose and frequency as per Grade 2). If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated) and cyclophosphamide 1.5 g/m2. |
Grade 4 | Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. Dexamethasone 20 mg IV every 6 hours. If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (dose and frequency as per Grade 2). If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated), and cyclophosphamide 1.5 g/m2. |
BREYANZI is a cell suspension for infusion.
A single dose of BREYANZI contains of 50 to 110 × 106 CAR-positive viable T cells, consisting of CD8 and CD4 components, with each component supplied separately in single-dose vials.
More than one vial of each of the CD8 component and/or CD4 component may be needed to achieve the dose of BREYANZI.
Each vial contains between 6.9 × 106 and 322 × 106 CAR-positive viable T cells in 4.6 mL cell suspension (between 1.5 × 106 and 70 × 106 CAR-positive viable T cells/mL).
The infusion volume is calculated based on the concentration of cryopreserved drug product CAR-positive viable T cells concentration. The volume may differ for each component infused. See the RFI Certificate for details [see How Supplied/Storage and Handling (16)].
Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. CRS occurred in 46% (122/268) of patients receiving BREYANZI, including ≥ Grade 3 (Lee grading system1) CRS in 4% (11/268) of patients. One patient had fatal CRS and 2 had ongoing CRS at time of death. The median time to onset was 5 days (range: 1 to 15 days). CRS resolved in 119 of 122 patients (98%) with a median duration of 5 days (range: 1 to 17 days). Median duration of CRS was 5 days (range 1 to 30 days) in all patients, including those who died or had CRS ongoing at time of death.
Among patients with CRS, the most common manifestations of CRS include fever (93%), hypotension (49%), tachycardia (39%), chills (28%), and hypoxia (21%) [see Adverse Reactions (6.1)]. 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) [see Adverse Reactions (6.1)].
Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI.
Sixty-one of 268 (23%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of BREYANZI. Twenty-seven (10%) patients received tocilizumab only, 25 (9%) received tocilizumab and a corticosteroid, and 9 (3%) received corticosteroids only.
Monitor patients daily at a certified healthcare facility during the first week following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Patient Counseling Information (17)]. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated [see Dosage and Administration (2.3)].
Neurologic toxicities that were fatal or life-threatening, occurred following treatment with BREYANZI. CAR T cell-associated neurologic toxicities occurred in 35% (95/268) of patients receiving BREYANZI, including ≥ Grade 3 in 12% (31/268) of patients. Three patients had fatal neurologic toxicity and 7 had ongoing neurologic toxicity at time of death. The median time to onset of the first event was 8 days (range: 1 to 46 days). The onset of all neurologic events occurred within the first 8 weeks following BREYANZI infusion. Neurologic toxicities resolved in 81 of 95 patients (85%) with a median duration of 12 days (range: 1 to 87 days). Three of four patients with ongoing neurologic toxicity at data cutoff had tremor and one subject had encephalopathy. Median duration of neurologic toxicity was 15 days (range: 1 to 785 days) in all patients, including those with ongoing neurologic events at the time of death or at data cutoff.
Seventy-eight (78) of 95 (82%) patients with neurologic toxicity experienced CRS. Neurologic toxicity overlapped with CRS in 57 patients. The onset of neurologic toxicity was after onset of CRS in 30 patients, before CRS onset in 13 patients, same day as CRS onset in 7 patients, and same day as CRS resolution in 7 patients. Neurologic toxicity resolved in three patients before the onset of CRS. Eighteen patients experienced neurologic toxicity after resolution of CRS.
The most common neurologic toxicities included encephalopathy (24%), tremor (14%), aphasia (9%), delirium (7%), headache (7%), ataxia (6%), and dizziness (6%). Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, have occurred in patients treated with BREYANZI.
Monitor patients daily at a certified healthcare facility during the first week following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after infusion; evaluate and treat promptly [see Dosage and Administration (2.3)]. Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time [see Patient Counseling Information (17)].
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 [see Boxed Warning and Warnings and Precautions (5.1, 5.2)]. The required components of the BREYANZI REMS are:
Further information is available at www.BreyanziREMS.com, or contact Bristol-Myers Squibb at 1-888-423-5436.
Allergic reactions may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO).
Severe infections, including life-threatening or fatal infections, have occurred in patients after BREYANZI infusion. Infections (all grades) occurred in 45% (121/268) of patients. Grade 3 or higher infections occurred in 19% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections occurred in 5%, and viral and fungal infections occurred in 1.5% and 0.4% of patients, respectively. Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines.
Febrile neutropenia has been observed in 9% (24/268) of patients after BREYANZI infusion and 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.
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.
Ten of the 11 patients in the TRANSCEND study with a prior history of HBV were treated with concurrent antiviral suppressive therapy to prevent HBV reactivation during and after treatment with BREYANZI.
Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.
Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion.
Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 31% (84/268) of patients, and included thrombocytopenia (26%), neutropenia (14%), and anemia (3.0%). Monitor complete blood counts prior to and after BREYANZI administration.
B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with BREYANZI. The adverse event of hypogammaglobulinemia was reported as an adverse reaction in 14% (37/268) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 21% (56/268) of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 32% (85/268) 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.
Patients treated with BREYANZI may develop secondary malignancies. 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.
Due to the potential for neurologic events, including altered mental status or seizures, patients receiving BREYANZI are at risk for 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, during this initial period.
The following adverse reactions are described elsewhere in the labeling:
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 this section reflect exposure to BREYANZI in the TRANSCEND study, in which 268 adult patients with R/R large B-cell lymphoma received a flat dose of CAR-positive viable T cells [see Clinical Studies (14)]. Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) or autoimmune disease requiring systemic immunosuppression were ineligible. The median duration of follow-up was 9 months. The median age of the study population was 63 years (range: 18 to 86 years); 65% were male. The Eastern Cooperative Oncology Group (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 3 presents the adverse reactions reported in at least 10% of patients treated with BREYANZI, and Table 4 describes the laboratory abnormalities of Grade 3 or 4 that occurred in at least 10% of patients.
The most common nonlaboratory adverse reactions of any grade (≥ 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.
Adverse Reaction | Any Grade (%) | Grade 3 or Higher (%) |
---|---|---|
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 Hypogammaglobulinemia includes subjects with adverse events of hypogammaglobulinemia (14%) and/or laboratory IgG levels that fell below 500 mg/dL after infusion (21%). | ||
f Infections and infestations are grouped by pathogen type and selected clinical syndromes. | ||
g Infections – pathogen unspecified contains febrile neutropenia (9%). | ||
h Bacterial infection includes infections by pathogen type plus appendicitis, diverticulitis, peritonitis, skin infection, tooth infection. | ||
i Upper respiratory tract infections include nasopharyngitis, pharyngitis, rhinitis, rhinovirus infection, sinusitis, upper respiratory tract congestion, upper respiratory tract infection. | ||
j 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. | ||
k Motor dysfunction includes eyelid ptosis, motor dysfunction, muscle rigidity, muscle spasms, muscle spasticity, muscle tightness, muscle twitching, muscular weakness, myoclonus, myopathy. | ||
l Headache includes headache, head discomfort, migraine, sinus headache. | ||
m 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. | ||
n Dizziness includes dizziness, presyncope, syncope, vertigo. | ||
o Tremor includes essential tremor, resting tremor, tremor. | ||
p Peripheral neuropathy includes hyperesthesia, hypoesthesia, meralgia paresthetica, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, sciatica, sensory loss. | ||
q Aphasia includes aphasia, disorganized speech, dysarthria, dysphemia, dysphonia, slow speech, speech disorder. | ||
r Insomnia includes insomnia, somnambulism. | ||
s Anxiety includes anxiety, panic attack. | ||
t Delirium includes agitation, delirium, delusion, disorientation, hallucination, 'hallucination, visual', irritability, restlessness. | ||
u Renal failure includes acute kidney injury, blood creatinine increased, chronic kidney disease, renal failure, renal injury. | ||
v Cough includes cough, productive cough, upper-airway cough syndrome. | ||
w Dyspnea includes acute respiratory failure, dyspnea, dyspnea exertional, respiratory failure. | ||
x Rash includes erythema, dermatitis acneiform, perineal rash, rash, rash erythematous, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, rash pustular. | ||
y Hypotension includes hypotension, orthostatic hypotension. | ||
z Hemorrhage includes catheter site hemorrhage, conjunctival hemorrhage, epistaxis, hematoma, hematuria, hemorrhage, hemorrhage intracranial, pulmonary hemorrhage, retinal hemorrhage, vaginal hemorrhage. | ||
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 |
Hypogammaglobulinemiae | 32 | 0 |
Infections and infestationsf | ||
Infections - pathogen unspecifiedg | 29 | 16 |
Bacterial infectious disordersh | 13 | 5 |
Upper respiratory tract infectioni | 13 | 0.7 |
Viral infectious disorders | 10 | 1.5 |
Metabolism and nutrition disorders | ||
Decreased appetite | 28 | 2.6 |
Musculoskeletal and connective tissue disorders | ||
Musculoskeletal pain j | 37 | 2.2 |
Motor dysfunctionk | 10 | 1.1 |
Nervous system disorders | ||
Headachel | 30 | 1.1 |
Encephalopathym | 29 | 9 |
Dizzinessn | 24 | 2.6 |
Tremoro | 16 | 0 |
Peripheral neuropathyp | 11 | 0 |
Aphasiaq | 10 | 2.2 |
Psychiatric disorders | ||
Insomniar | 14 | 0.4 |
Anxietys | 10 | 0 |
Deliriumt | 10 | 2.2 |
Renal and urinary disorders | ||
Renal failureu | 11 | 3.0 |
Respiratory, thoracic, and mediastinal disorders | ||
Coughv | 23 | 0 |
Dyspneaw | 16 | 2.6 |
Skin and subcutaneous tissue disorders | ||
Rashx | 13 | 0.4 |
Vascular disorders | ||
Hypotensiony | 26 | 3.4 |
Hypertension | 14 | 4.5 |
Hemorrhagez | 10 | 1.5 |
Other clinically important adverse reactions that occurred in less than 10% of patients treated with BREYANZI include the following:
Laboratory Abnormality | Grade 3 or 4 (%) |
---|---|
|
|
Neutropenia | 76 |
Thrombocytopenia | 39 |
Anemia | 23 |
Hypofibrinogenemia | 15 |
Hypophosphatemia | 13 |
BREYANZI has the potential to induce anti-product antibodies. The immunogenicity of BREYANZI has been evaluated using an electrochemiluminescence (ECL) immunoassay for the detection of binding antibodies against the extracellular CD19-binding domain of BREYANZI. Pre-existing anti-product antibodies were detected in 11% (28/261) of patients. Treatment-induced or treatment-boosted anti-product antibodies were detected in 11% (27/257) of patients. Due to the small number of patients who had anti-product antibodies, the relationship between anti-product antibody status and efficacy, safety, or pharmacokinetics was not conclusive.
Risk Summary
There are no available data with BREYANZI use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with BREYANZI to assess whether it can cause fetal harm when administered to a pregnant woman.
It is not known if BREYANZI has the potential to be transferred to the fetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia and hypogammaglobulinemia. Therefore, BREYANZI is not recommended for women who are pregnant, and pregnancy after BREYANZI infusion should be discussed with the treating physician.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Risk Summary
There is no information regarding the presence of BREYANZI in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BREYANZI and any potential adverse effects on the breastfed infant from BREYANZI or from the underlying maternal condition.
Pregnancy Testing
Pregnancy status of females with reproductive potential should be verified. Sexually active females of reproductive potential should have a pregnancy test prior to starting treatment with BREYANZI.
Contraception
See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive lymphodepleting chemotherapy.
There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with BREYANZI.
The safety and efficacy of BREYANZI have not been established in pediatric patients.
In clinical trials of BREYANZI, 111 (41%) of the 268 patients in TRANSCEND were 65 years of age or older, and 27 (10%) were 75 years of age or older. No clinically important differences in safety or effectiveness of BREYANZI were observed between these patients and younger patients.
BREYANZI (lisocabtagene maraleucel) is a CD19-directed genetically modified autologous T cell immunotherapy administered as a defined composition of CAR-positive viable T cells (consisting of CD8 and CD4 components). The CAR is comprised of the FMC63 monoclonal antibody-derived single-chain variable fragment (scFv), IgG4 hinge region, CD28 transmembrane domain, 4-1BB (CD137) costimulatory domain, and CD3 zeta activation domain. In addition, BREYANZI includes a nonfunctional truncated epidermal growth factor receptor (EGFRt) that is co-expressed on the cell surface with the CD19-specific CAR.
BREYANZI is a T-cell product. BREYANZI is prepared from the patient's T cells, which are obtained from the product of a standard leukapheresis procedure. The purified CD8-positive and CD4-positive T cells are separately activated and transduced with the replication-incompetent lentiviral vector containing the anti-CD19 CAR transgene. The transduced T cells are expanded in cell culture, washed, formulated into a suspension, and cryopreserved as separate CD8 and CD4 component vials that together constitute a single dose of BREYANZI. The product must pass a sterility test before release for shipping as a frozen suspension in patient-specific vials. The product is thawed prior to administration [see Dosage and Administration (2.2) and How Supplied/Storage and Handling (16)].
The BREYANZI formulation contains 75% (v/v) Cryostor® CS10 [containing 7.5% dimethylsulfoxide (v/v)], 24% (v/v) Multiple Electrolytes for Injection, Type 1, 1% (v/v) of 25% albumin (human).
BREYANZI is a CD19-directed genetically modified autologous cell immunotherapy administered as a defined composition to reduce variability in CD8-positive and CD4-positive T cell dose. The CAR is comprised of an FMC63 monoclonal antibody-derived single chain variable fragment (scFv), IgG4 hinge region, CD28 transmembrane domain, 4-1BB (CD137) costimulatory domain, and CD3 zeta activation domain. CD3 zeta signaling is critical for initiating activation and antitumor activity, while 4-1BB (CD137) signaling enhances the expansion T cell and persistence of BREYANZI.
CAR binding to CD19 expressed on the cell surface of tumor and normal B cells induces activation and proliferation of CAR T cells, release of pro-inflammatory cytokines, and cytotoxic killing of target cells.
Following BREYANZI infusion, pharmacodynamic responses were evaluated over a 4-week period by measuring transient elevation of soluble biomarkers such as cytokines, chemokines, and other molecules. Peak elevation of soluble biomarkers was observed within the first 14 days after BREYANZI infusion and returned to baseline levels within 28 days.
B-cell aplasia, defined as CD19+ B cells comprising less than 3% of peripheral blood lymphocytes, is an on-target effect of BREYANZI. B-cell aplasia was observed in the majority of patients for up to 1 year following BREYANZI infusion.
Following infusion, BREYANZI exhibited an initial expansion followed by a bi-exponential decline. The median time of maximal expansion in peripheral blood occurred 12 days after the first infusion. BREYANZI was present in peripheral blood for up to 2 years.
Responders (N=135) had a 2.28-fold higher median Cmax than nonresponders (N=37) (35,335 vs. 15,527 copies/µg). Responders had a 1.76-fold higher median AUC0-28d than nonresponders (273,552 vs. 155,240 day*copies/µg).
Some patients required tocilizumab and corticosteroids for the management of CRS and neurologic toxicities. Patients treated with tocilizumab (N=49) had a 3.63-fold and 3.69-fold higher median Cmax and AUC0-28d, respectively, compared to patients who did not receive tocilizumab (N=189). Similarly, patients who received corticosteroids (N=50) had a 3.76-fold and 3.69-fold higher median Cmax and AUC0-28d, respectively, compared to patients who did not receive corticosteroids (N=188).
Patients < 65 years old (N=142) had a 3.06-fold and 2.30-fold higher median Cmax and AUC0-28d, respectively, compared to patients ≥ 65 years old (N=96). Sex, race, ethnicity, and body weight did not show clear relationships to Cmax and AUC0-28d.
No carcinogenicity or genotoxicity studies have been conducted with BREYANZI. No studies have been conducted to evaluate the effects of BREYANZI on fertility. In vitro studies with BREYANZI manufactured from healthy donors and patients showed no evidence for transformation and/or immortalization and no preferential integration near genes associated with oncogenic transformation.
Relapsed or Refractory Large B-Cell Lymphoma
The efficacy of BREYANZI was evaluated in an open-label, multicenter, single-arm trial (TRANSCEND; NCT02631044) in adult patients with relapsed or refractory large B-cell non-Hodgkin lymphoma after at least 2 lines of therapy. The study included patients with ECOG performance status ≤ 2, prior autologous and/or allogeneic hematopoietic stem cell transplant (HSCT), and secondary CNS lymphoma involvement. The study excluded patients with a creatinine clearance of less than 30 mL/min, alanine aminotransferase > 5 times the upper limit of normal, or left ventricular ejection fraction < 40%. There was no prespecified threshold for blood counts; patients were eligible to enroll if they were assessed by the investigator to have adequate bone marrow function to receive lymphodepleting chemotherapy. Bridging therapy for disease control was permitted between apheresis and the start of lymphodepleting chemotherapy, including intrathecal chemotherapy or radiation therapy for treatment of CNS involvement with lymphoma.
BREYANZI was administered two to seven days following completion of lymphodepleting chemotherapy. The lymphodepleting chemotherapy regimen consisted of fludarabine 30 mg/m2/day and cyclophosphamide 300 mg/m2/day concurrently for 3 days. BREYANZI was administered in the inpatient and outpatient setting.
Of 299 patients who underwent leukapheresis for whom BREYANZI was manufactured in the dose range of 50 to 110 × 106 CAR-positive viable T cells:
Of the 192 patients in the main efficacy population, the median age was 63 years (range: 18 to 86 years), 69% were male, 84% were white, 6% were black, and 4.7% were Asian. The median number of prior therapies was 3 (range: 1 to 8). Diagnoses were de novo DLBCL (53%), DLBCL transformed from indolent lymphoma (25%), high-grade B-cell lymphoma (14%), primary mediastinal large B-cell lymphoma (7%), follicular lymphoma, grade 3B (1.0%). Of these patients, 64% had disease refractory to last therapy, 53% had primary refractory disease, 37% had prior HSCT and 2.6% had CNS involvement.
Efficacy was based on complete response (CR) rate and duration of response (DOR), as determined by an independent review committee (IRC) using 2014 Lugano criteria (Tables 5 and 6). The median time to first response (CR or partial response [PR]) was 1.0 month (range: 0.7 to 8.9 months). The median time to first CR was 1.0 month (range 0.8 to 12.5 months). Of the 104 patients who achieved CR, 23 initially had stable disease (6 patients) or PR (17 patients), with a median time to improvement of 2.2 months (range: 0.7 to 11.6 months).
BREYANZI-treated N=192 |
||
---|---|---|
CI=confidence interval. | ||
|
||
Overall Response Rate*, n
[95% CI] | 141 (73%) [67%, 80%] |
|
Complete Response, n
[95% CI] | 104 (54%) [47%, 61%] |
|
Partial Response, n
[95% CI] | 37 (19%) [14%, 26%] |
BREYANZI-treated*
N=192 |
||
---|---|---|
Number of Responders | 141 | |
DOR=duration of response; CI=confidence interval; CR=complete response; PR=partial response; NR=not reached. | ||
|
||
DOR (Months) | ||
Median | 16.7 | |
[95% CI]† | [5.3, NR] | |
Range‡ | 0.0+ to 23.5+ | |
DOR if Best Response is CR (Months) | ||
Median | NR | |
[95% CI]† | [16.7, NR] | |
Range‡ | 0.7+ to 23.5+ | |
DOR if Best Response is PR (Months) | ||
Median | 1.4 | |
[95% CI]† | [1.1, 2.2] | |
Range‡ | 0.0+ to 22.8+ |
Response durations were longer in patients who achieved a CR, as compared to patients with a best response of PR (Table 6). Of the 104 patients who achieved CR, 68 (65%) had remission lasting at least 6 months and 64 (62%) had remission lasting at least 9 months.
Of the 287 patients who underwent leukapheresis and had radiographically evaluable disease, 27 additional patients achieved a response, apart from the responses noted in Table 5. The IRC-assessed overall response rate in the leukapheresed population (n=287) was 59% (95% CI: 53, 64), with a CR rate of 43% (95% CI: 37, 49) and PR rate of 15% (95% CI: 11, 20). These efficacy results include responses that may have been contributed solely by bridging therapy, responses after receipt of product outside of the intended dose range, and responses to product that did not meet release specifications.
BREYANZI consists of genetically modified autologous T cells, supplied in vials as separate frozen suspensions of each CD8 component (NDC: 73153-901-08) and CD4 component (NDC: 73153-902-04). Each CD8 or CD4 component is packed in a carton containing up to 4 vials, depending upon the concentration of the cryopreserved drug product CAR-positive viable T cells. The cartons for each CD8 component and CD4 component are in an outer carton (NDC: 73153-900-01). BREYANZI is shipped directly to the cell lab or clinical pharmacy associated with the infusion center in the vapor phase of a liquid nitrogen shipper. A Release for Infusion (RFI) Certificate for each component and patient-specific syringe labels are affixed inside the shipper.
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Ensure that patients understand the risk (11%) of manufacturing failure. In case of a manufacturing failure, a second manufacturing of BREYANZI may be attempted. While the patient awaits the product, additional bridging therapy (not the lymphodepletion) may be necessary. This bridging therapy may be associated with adverse events during the pre-infusion period, which could delay or prevent the administration of BREYANZI.
Prior to infusion, advise patients of the following risks:
Advise patients of the need to:
Manufactured by Juno Therapeutics Inc., a Bristol-Myers Squibb Company, Bothell, WA 98021.
BREYANZI® is a trademark of Juno Therapeutics, Inc., a Bristol-Myers Squibb Company.
Pat. https://www.bms.com/patient-and-caregivers/our-medicines.html
© 2021 Juno Therapeutics, Inc., a Bristol-Myers Squibb Company. All rights reserved.
BREPI.001/MG.001
lisocabtagene maraleucel
Breyanzi™
lisocabtagene maraleucel
Breyanzi®
NDC: 73153-900-01
Rx only
FOR AUTOLOGOUS & INTRAVENOUS USE ONLY
Dispense with Medication Guide
Dosage: 50 to 110 x 106 CAR-positive viable T cells.
See Release for Infusion Certificate (inside shipper).
Contains DMSO 7.5% v/v.
1 to 4 single-dose vials/component. Each vial
contains 1.5 to 70 x 106 CAR-positive viable T cells/mL.
4.6 mL per vial.
Store at ≤ -130°C; vapor phase of liquid nitrogen.
Do not filter or irradiate.
Not evaluated for infectious substances.
Discard unused portion.
Manufactured by:
Juno Therapeutics, Inc., a Bristol-Myers Squibb Company
Bothell, WA 98021
Phone: 1-888-805-4555
US License #: 2156
111633
VERIFY
PATIENT
ID
First: FIRST NAME
Last: LAST NAME
Date of birth: DD-MMM-YYYY
JOIN: XXXX-XXXXX
Aph ID/DIN: XXX XXX XXX XXX
CD8
component
CD4
component
Lot
XXXX-XXXXXY
XXXX-XXXXXY
Expiration
DD-MMM-YYYY
DD-MMM-YYYY
STOP
Confirm patient ID
prior to infusion
BREYANZI
lisocabtagene maraleucel kit |
|||||||||||||||
|
|||||||||||||||
|
|||||||||||||||
|
|||||||||||||||
|
|||||||||||||||
|
|||||||||||||||
|
|||||||||||||||
|
|||||||||||||||
|
|||||||||||||||
|
|||||||||||||||
|
|||||||||||||||
|
|||||||||||||||
|
|||||||||||||||
|
|||||||||||||||
|
|||||||||||||||
|
|||||||||||||||
|
Labeler - Juno Therapeutics, Inc. (079290042) |
Mark Image Registration | Serial | Company Trademark Application Date |
---|---|
![]() BREYANZI 90300948 not registered Live/Pending |
JUNO THERAPEUTICS, INC. 2020-11-05 |
![]() BREYANZI 90300931 not registered Live/Pending |
JUNO THERAPEUTICS, INC. 2020-11-05 |
![]() BREYANZI 88569196 not registered Live/Pending |
JUNO THERAPEUTICS, INC. 2019-08-07 |
![]() BREYANZI 88077381 not registered Live/Pending |
Celgene Corporation 2018-08-14 |