HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use BREYANZI safely and effectively. See full prescribing information for
BREYANZI.
• The
dose is 50 to 110 × 106 CAR-positive viable T cells (consisting of CD8 and CD4 components) (2.1,
3).
• Administer
BREYANZI in a certified healthcare facility (2.2, 5.1, 5.2, 5.3).
BREYANZI® (lisocabtagene maraleucel) suspension for intravenous DOSAGE FORMS AND STRENGTHS
infusion
Initial U.S. Approval: 2021
WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES
See full prescribing information for complete boxed
warning.
• 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
•
BREYANZI is a cell suspension for infusion (3).
• 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 5 mL vials (3). Each mL contains 1.5 × 106 to
70 × 106 CAR-positive
viable T cells (3).
CONTRAINDICATIONS
None (4).
severe or life-threatening CRS with tocilizumab with or WARNINGS AND PRECAUTIONS
without corticosteroids (2.2, 2.3, 5.1).
• 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 (2.2, 2.3, 5.2).
• BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS (5.3).
INDICATIONS AND USAGE
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).
LimitationsofUse: BREYANZI is not indicated
for the treatment of patients with primary central nervous
system lymphoma (1, 14).
DOSAGE AND ADMINISTRATION
For
autologous use only. For intravenous use only.
•
Do NOT use a leukodepleting filter
(2.2).
• Administer
a lymphodepleting regimen of fludarabine and cyclophosphamide before infusion
of BREYANZI (2.2).
•
Verify the patient’s identity
prior to infusion (2.2).
•
Premedicate
with acetaminophen
and an H1 antihistamine (2.2).
•
Confirm availability of tocilizumab prior to infusion (2.2, 5.1).
• Dosing of BREYANZI is based on the number of chimeric antigen receptor (CAR)-positive viable T cells (2.1).
• Hypersensitivity Reactions: Monitor
for hypersensitivity reactions
during infusion (5.4).
• Serious Infections: Monitor
patients for signs and symptoms of infection; treat appropriately (5.5).
•
Prolonged Cytopenias: Patients
may exhibit Grade 3 or higher cytopenias for several weeks following BREYANZI
infusion. Monitor complete blood counts
(5.6).
• Hypogammaglobulinemia: Monitor and consider immunoglobulin replacement therapy (5.7).
• Secondary Malignancies: In the event that a secondary malignancy occurs after treatment with BREYANZI, contact Bristol-Myers Squibb at 1-888-805-4555 (5.8).
•
Effects on Ability to Drive and Use Machines: 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 after BREYANZI administration (5.9).
ADVERSE REACTIONS
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: 02/2021
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: CYTOKINE RELEASE
SYNDROME AND NEUROLOGIC TOXICITIES
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dose
2.2 Administration
2.3 Management of Severe Adverse
Reactions
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Cytokine Release
Syndrome (CRS)
5.2 Neurologic Toxicities
5.3 BREYANZI REMS
5.4 Hypersensitivity Reactions
5.5 Serious Infections
5.6 Prolonged Cytopenias
5.7 Hypogammaglobulinemia
5.8 Secondary Malignancies 5.9 EffectsonAbilitytoDriveandUseMachines
6 ADVERSE REACTIONS
6.1 Clinical Trials
Experience
6.2 Immunogenicity
7 DRUG INTERACTIONS
7.1 Drug-laboratory Test Interactions
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
11 DESCRIPTION
12 CLINICAL
PHARMACOLOGY
12.1 Mechanism of Action 12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections
omitted from the full prescribing information are not listed.
FULL PRESCRIBING
INFORMATION
WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC
TOXICITIES
• 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[see Dosage
and Administration (2.2, 2.3) and Warnings and Precautions (5.1)].
• 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[see Dosage and
Administration (2.2, 2.3) and
Warnings and Precautions (5.2)].
• BREYANZI
is available only through a restricted program under a Risk Evaluation and
Mitigation Strategy (REMS) called the BREYANZI REMS[see Warnings and Precautions (5.3)].
1
INDICATIONS AND USAGE
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.
LimitationsofUse: BREYANZI
is not indicated for the treatment
of patients with primary central nervous system (CNS) lymphoma [see Clinical
Studies (14)].
2
DOSAGE AND ADMINISTRATION
For autologous
use only. For intravenous use only.
2.1 Dose
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)].
2.2
Administration
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.
PreparingthePatientforBREYANZI
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.
ReceiptofBREYANZI
• BREYANZI is shipped
directly to the cell-associated lab or
clinical pharmacy associated
with the infusion center in the vapor phase of a liquid nitrogen
shipper.
•
Confirm the
patient’s identity with the patient identifiers on the shipper.
• If the patient is not expected
to be ready for administration before the shipper
expires and the infusion site is qualified
for onsite storage, transfer
BREYANZI to onsite vapor phase of liquid nitrogen storage
prior
to preparation.
• If the patient is not expected to be ready for administration
before the shipper expires and the infusion site is not qualified for
onsite storage, contact Bristol-Myers
Squibb at 1-888-805-4555 to arrange for return shipment.
PreparingBREYANZI
Beforethawing
the vials
• Confirm the
patient’s identity with the
patient identifiers on the RFI Certificate.
• Read the RFI Certificate (affixed
inside the shipper) for information on the number of syringes you
will need to administer
the CD8 and CD4 components
(syringe labels are provided with the
RFI Certificate). There
is a separate RFI Certificate for each cell component.
• Confirm tocilizumab and
emergency equipment are available prior to infusion
and during the recovery period.
• Confirm the
infusion time in advance and
adjust the start time of BREYANZI thaw such that it will be available for infusion
when the patient is ready.
Thawing
the vials
1. Confirm the patient’s identity with the patient identifiers on the
outer carton and on the syringe labels.
Once the vials of CAR-positive viable T cells (CD8 component and
CD4 component) are removed from
frozen storage, the thaw must be carried to completion and the cells
administered
within 2 hours.
2. Remove the CD8
component carton and CD4
component carton from the outer carton.
3. Confirm the patient’s identity with the patient identifiers
on the inner carton.
4. Open each inner carton and visually inspect
the vial(s) for damage. If the vials are damaged, contact Bristol-Myers
Squibb at 1-888-805-4555.
5. Confirm the patient’s identity with the patient identifiers
on the vials.
6. Carefully remove the vials from the
cartons, place vials on a protective
barrier pad, and thaw at room temperature until
there is no visible ice in the vials. Thaw all of the vials at
the
same time. Keep the CD8 and
CD4 components separate.
Dose preparation
• Prepare BREYANZI
using sterile technique.
• Based on the concentration of CAR-positive viable T cells for each component,
more than one vial of each of
the CD8 and CD4 components may be required to complete a dose. A separate syringe should be prepared for each CD8
or CD4 component vial received.
Note: The volume
to be drawn up and infused may differ for each component as indicated
on the RFI Certificate. Do NOT draw up excess volume into the syringe.
• Each vial contains 5 mL
with a total extractable volume
of 4.6 mL of CD8 or CD4 component T cells. The RFI
Certificate for each component indicates
the volume (mL) of
cells to be drawn up into each syringe. Use the smallest Luer-lock tip
syringe necessary
(1, 3, or 5 mL) to draw up the specified volume
from each vial. A 5 mL syringe should not be used for volumes less than
3 mL.
7. Prepare the syringe(s) of the CD8
component first. Affix the CD8 syringe labels to the syringe(s) prior
to pulling the required volume
into the syringe(s).
Note: It is important
to confirm that the volume drawn
up for each component
matches the volume specified in the respective RFI Certificate. Do NOT
draw up excess volume into the syringe.
Withdrawal of the required volume of cells from each vial into a
separate syringe should
be carried out using the
following instructions:
8. Hold the thawed vial(s) upright
and gently invert
the vial(s) 5 times
to mix
the cell product. If any clumping
is apparent, continue to invert
the vial(s) until clumps
have dispersed and cells appear to be evenly resuspended.
9. Visually inspect the thawed vial(s)
for damage or leaks. Do not use if the vial is damaged or if the clumps do not disperse;
contact Bristol-Myers Squibb at 1-888-805-4555. The liquid in the
vials should be slightly opaque
to opaque, colorless to yellow
or brownish-yellow.
10. Remove the polyaluminum
cover (if present) from the
bottom of the vial and swab the septum with an alcohol wipe. Allow to air dry before
proceeding.
NOTE: The absence of the
polyaluminum cover does not impact
the sterility of the vial.
11. Keeping the vial(s) upright, cut the seal on the tubing line on the top of the vial immediately
above the filter to open the
air vent on the vial.
NOTE: Be careful
to select the correct tubing
line with the filter. Cut ONLY the tubing with a
filter.
12. 
Hold a 20-gauge, 1-1 ½ inch needle, with the opening of the needle
tip away from the retrieval port septum.
a. Insert the needle into the
septum at a 45°- 60° angle
to puncture the retrieval port septum.
b. Increase the angle of the needle gradually as the
needle enters the vial.
a b
13.
WITHOUT drawing air into the syringe, slowly withdraw the target volume (as specified in the RFI Certificate). Carefully inspect
the syringe for signs of debris prior to proceeding. If there is debris, contact Bristol-Myers
Squibb at 1-888-805-4555.
14. Verify that the
volume of CD8/CD4 component matches the volume specified for the relevant component
in the RFI Certificate.
Once the volume is verified, remove the syringe/needle from the vial,
carefully detach the needle
from the syringe and cap the syringe.
15. 
Continue to keep the vial horizontal and return it to the carton to avoid
leaking from the vial.
16. Dispose of any unused portion of BREYANZI (according to local biosafety guidelines).
17. Repeat the process steps 7-16
for the CD4 Component.
18. Transport the labeled
CD8 and CD4 syringes to the
bedside by placing with protective barrier pad inside an
insulated room temperature container.
BREYANZIAdministration
• Do NOT use a leukodepleting filter.
• Ensure tocilizumab and emergency equipment are available prior to infusion
and during the recovery period.
•
Confirm the
patient’s identity matches the patient identifiers
on the syringe label.
• Once BREYANZI has been drawn into syringes, proceed with administration
as soon as possible. The total time
from removal from frozen
storage to patient administration should not exceed 2 hours as indicated
by the time entered on the syringe
label.
1. Use intravenous normal saline
to flush all the infusion
tubing prior to and after
each CD8
or CD4 component administration.
2. Administer the entire volume of the CD8 component intravenously at an infusion rate of
approximately 0.5 mL/minute,
using the closest port or Y-arm.
NOTE: The time for infusion will vary but will usually be less than
15 minutes for each component.
3. If more than one syringe is
required for a full cell dose of the
CD8 component, administer
the volume in each syringe consecutively
without any time between administering the contents
of the syringes (unless there is a clinical reason (e.g., infusion
reaction) to hold the dose).
4. After the CD8 component has
been administered, flush the tubing with normal saline, using enough volume to clear the tubing and the length of the IV catheter.
5. Administer the CD4
component
second, immediately after administration of the CD8
component is complete, using
steps 1-4, as described for
the CD8 component.
Following administration of the CD4 component, flush the tubing with normal
saline, using enough volume to clear the tubing and the length of the IV catheter.
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
• Administer BREYANZI at a
REMS-certified healthcare facility.
• Monitor patients daily at a certified healthcare facility during
the first week following
infusion for signs and symptoms of
CRS and neurologic toxicities.
• Instruct patients to remain
within proximity of the certified healthcare facility
for at least 4 weeks
following infusion.
• Refrain from driving or
hazardous activities for
8 weeks.
2.3
Management of Severe Adverse
Reactions
CytokineReleaseSyndrome
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:
• Corticosteroids according to the more
aggressive intervention based on the CRS and neurologic toxicity grades in Tables 1 and 2
•
Tocilizumab according
to the CRS grade in Table 1
•
Antiseizure medication
according to the neurologic toxicity in Table
2
Table 1: CRS
Grading and Management Guidance
|
CRS Gradea
|
Tocilizumab
|
Corticosteroidsb
|
|
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.
|
|
CRS Gradea
|
Tocilizumab
|
Corticosteroidsb
|
|
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
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.
|
Per Grade 2.
|
Administer dexamethasone 10 mg IV every 12 hours.
|
|
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.
|
a
Lee
criteria for grading CRS
(Lee et al, 2014).
b
If
corticosteroids
are initiated, continue corticosteroids for at least
3 doses or until
complete resolution of symptoms, and consider corticosteroid
taper.
NeurologicToxicity
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:
• Corticosteroids according to the more
aggressive intervention based on the CRS and neurologic toxicity grades in Tables 1 and 2
• Tocilizumab according to the CRS grade in Table 1
• Antiseizure medication
according to the neurologic toxicity in Table 2
Table 2: Neurologic Toxicity (NT) Grading
and Management Guidance
|
NT Gradea
|
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.
|
|
NT Gradea
|
Corticosteroids and Antiseizure Medication
|
|
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.
|
a NCI CTCAE criteria
for grading neurologic toxicities version.
4.03.
3
DOSAGE FORMS AND STRENGTHS
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 x 106 CAR-positive viable T cells
in 4.6 mL cell suspension (between 1.5 × 106 and 70 x 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)].
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1 Cytokine
Release Syndrome
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)].
5.2
Neurologic Toxicities
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)].
5.3
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[see Boxed Warning and Warnings and Precautions (5.1,
5.2)]. 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.
• Certified healthcare facilities must
ensure that healthcare providers
who prescribe, dispense,
or administer BREYANZI are trained on the management of CRS and neurologic toxicities.
Further information is available at www.BreyanziREMS.com, or contact Bristol-Myers
Squibb at 1- 888-423-5436.
5.4
Hypersensitivity Reactions
Allergic reactions
may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including
anaphylaxis, may be due to dimethyl sulfoxide
(DMSO).
5.5
Serious Infections
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.
ViralReactivation
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.
5.6
Prolonged Cytopenias
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.
5.7
Hypogammaglobulinemia
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.
LiveVaccines
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.
5.8
Secondary Malignancies
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.
5.9
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 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.
6
ADVERSE REACTIONS
The following
adverse reactions are described elsewhere in the labeling:
•
Cytokine
Release Syndrome[see Warnings and Precautions (5.1, 5.3)]
•
Neurologic
Toxicities[see Warnings and
Precautions (5.2, 5.3)]
•
Hypersensitivity Reactions[see Warnings and Precautions (5.4)]
•
Serious
Infections[see Warnings and Precautions (5.5)]
•
Prolonged
Cytopenias[see Warnings and
Precautions (5.6)]
•
Hypogammaglobulinemia[see Warnings and Precautions (5.7)]
6.1
Clinical Trials
Experience
Because clinical trials
are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly
compared to rates in the
clinical trials of another
drug and may not reflect the
rates observed in practice.
The safety data described in 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.
Table 3:
Summary of Adverse Reactions Observed in at Least 10% of the Patients Treated with BREYANZI
in the TRANSCEND Study (N=268)
|
Adverse Reaction
|
Any Grade (%)
|
Grade 3 or Higher (%)
|
|
Cardiac disorders
|
|
Tachycardiaa
|
25
|
0
|
|
Gastrointestinal disorders
|
|
Nausea
|
33
|
1.5
|
|
Diarrhea
|
26
|
0.4
|
|
Constipation
|
23
|
0
|
|
Abdominal painb
|
21
|
3.0
|
|
Vomiting
|
21
|
0.4
|
|
Adverse Reaction
|
Any Grade (%)
|
Grade 3 or Higher (%)
|
|
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
|
|
Adverse Reaction
|
Any Grade (%)
|
Grade 3 or Higher (%)
|
|
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
|
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.
Other clinically important adverse reactions that
occurred in less than 10% of
patients treated with BREYANZI
include the following:
• Blood and lymphatic system
disorders:Coagulopathy (1.5%)
• Cardiac disorders:Arrhythmia
(6%), cardiomyopathy (1.5%)
• Gastrointestinal disorders:Gastrointestinal
hemorrhage (4.1%)
• Infections and infestations:Pneumonia
(8%), fungal infections
(8%), sepsis (4.5%),
urinary tract infection
(4.1%)
• Injury, poisoning, and procedural
complications:Infusion-related reaction (1.9%)
• Metabolism and nutrition disorders:Tumor lysis
syndrome (0.7%)
• Nervous system disorders:Ataxia/gait disturbance (7%), visual
disturbance (5%), paresis (2.6%), cerebrovascular
events (1.9%), seizure (1.1%), brain
edema (0.4%)
• Respiratory, thoracic, and mediastinal disorders:Pleural effusion (7%), hypoxia (6%)
• Vascular disorder:Thrombosis
(7%)
Table 4: Grade
3 or 4 Treatment Emergent Laboratory
Abnormalities Occurring in
≥ 10% of Patients Following Treatment
with BREYANZI in the TRANSCEND Studya (N=268)
|
Laboratory Abnormality
|
Grade 3 or 4 (%)
|
|
Neutropenia
|
76
|
|
Thrombocytopenia
|
39
|
|
Anemia
|
23
|
|
Hypofibrinogenemia
|
15
|
|
Hypophosphatemia
|
13
|
a NCI CTCAE
= Common Terminology
Criteria
for Adverse Events version 4.03.
6.2
Immunogenicity
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.
7
DRUG INTERACTIONS
7.1 Drug-laboratory Test Interactions
HIV and the lentivirus used to make BREYANZI
have limited, short spans of
identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests may yield false-positive results
in patients who have received BREYANZI.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
RiskSummary
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.
8.2
Lactation
RiskSummary
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.
8.3
Females and Males of Reproductive Potential
PregnancyTesting
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.
20
Infertility
There are no data on the effects
of BREYANZI on fertility.
8.4
Pediatric Use
The safety and efficacy of BREYANZI have not been established in pediatric patients.
8.5
Geriatric Use
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.
11
DESCRIPTION
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).
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
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.
12.2
Pharmacodynamics
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.
12.3
Pharmacokinetics
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.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis,
Mutagenesis, Impairment of Fertility
No carcinogenicity or genotoxicity studies
have been conducted with BREYANZI. No studies have
been conducted to evaluate the effects of BREYANZI
on fertility. In vitrostudies 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.
14
CLINICAL STUDIES
RelapsedorRefractoryLargeB-CellLymphoma
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:
• 44 (15%) did not receive
CAR-positive T cells either due to manufacturing failures (n=2), death
(n=29),
disease complications (n=6), or other
reasons (n=7)
• 204 (68%) received BREYANZI
in the intended dose range, of whom 192 were
evaluable for efficacy (main
efficacy population); 12
were not evaluable due to absence
of PET positive disease at study baseline or after bridging therapy
• 51 (17%) either received BREYANZI
outside of the intended dose range (n=26) or received CAR-positive T cells that did
not meet
the product specifications for BREYANZI (manufacturing
failures; n=25).
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).
Table 5: Response Rate in Main Efficacy Population
|
|
BREYANZI-treated N=192
|
|
Overall Response Ratea, n
|
141 (73%)
|
|
[95% CI]
|
[67%, 80%]
|
|
Complete Response, n
|
104 (54%)
|
|
[95% CI]
|
[47%, 61%]
|
|
Partial Response, n
|
37 (19%)
|
|
[95% CI]
|
[14%, 26%]
|
CI=confidence interval.
a Per the Lugano
criteria, as assessed by an IRC.
|
BREYANZI-treateda
|
|
N=192
|
|
Number
|
of Responders
|
141
|
|
DOR (Months)
Median
|
16.7
|
|
[95% CI]b
Range†
|
[5.3, NR]
0.0+ to 23.5+
|
|
DOR if Best Response is CR (Months)
Median [95% CI]b
Range†
|
NR [16.7, NR]
0.7+ to 23.5+
|
|
DOR if Best Response is PR (Months)
Median [95% CI]b
Range†
|
1.4
[1.1, 2.2]
0.0+ to 22.8+
|
|
DOR=duration of response; CI=confidence interval; CR=complete response; PR=partial response; NR=not reached.
|
|
|
Table
6: Duration of Response
a Evaluable for
efficacy.
b KM method
was used to obtain 2-sided 95% confidence intervals.
† A +
sign indicates a censored
value.
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.
15
REFERENCES
1. Lee DW, Gardner R, Porter DL,
et al. Current concepts in
the diagnosis and management of cytokine release syndrome. Blood2014;124:188-195.
16
HOW SUPPLIED/STORAGE AND HANDLING
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.
• Confirm patient identity upon receipt.
• Store vials in the vapor phase of liquid
nitrogen (less than or equal to minus 130°C) in a temperature-monitored
system.
•
Thaw BREYANZI
prior to infusion[see Dosage and Administration
(2.2)].
17
PATIENT COUNSELING
INFORMATION
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:
• CytokineReleaseSyndrome(CRS) – Signs and symptoms of
CRS (fever, chills, hypotension,
tachycardia, hypoxia, and fatigue). Counsel
patients to seek immediate
medical attention should signs or symptoms
of CRS
occur at any time[see Warnings and
Precautions (5.1) and Adverse Reactions (6.1)].
• NeurologicToxicities – Signs or symptoms associated with neurologic events including encephalopathy,
confusion, decreased consciousness,
speech disorders, tremor,
and seizures. Counsel patients to seek immediate
medical attention should signs or symptoms
of neurologic toxicity occur
at any time [see Warnings and Precautions (5.2) and Adverse
Reactions (6.1)].
• SeriousInfections – Signs or symptoms
associated with infection[see
Warnings and Precautions (5.5)
and Adverse Reactions (6.1)].
• ProlongedCytopenias – Signs or symptoms associated with bone marrow suppression including neutropenia, anemia,
thrombocytopenia,
or febrile neutropenia[see
Warnings and Precautions (5.6) and Adverse Reactions (6.1)].
Advise patients of the need to:
• Contact Bristol-Myers Squibb
at 1-888-805-4555 if they
are diagnosed with a secondary
malignancy[see Warnings and
Precautions (5.8)].
• Refrain
from driving or operating heavy or potentially dangerous machines until at
least 8 weeks after BREYANZI administration[see
Warnings and Precautions (5.9)].
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
|
MEDICATION GUIDE
BREYANZI® (pronounced braye an' zee) (lisocabtagene
maraleucel)
|
|
Read this Medication Guide before you
start your BREYANZI
treatment. The more you know about your treatment, the more active
you can be in your care. Talk with
your healthcare provider if you have questions about your health
condition or treatment. Reading this Medication Guide does not take the place of talking with your healthcare provider about your treatment.
|
|
What is the most important information I should know about BREYANZI?
BREYANZI may cause side effects that are life-threatening and can lead to
death. Call your healthcare
provider or get emergency help right away
if you get any of the following:
• difficulty
breathing
• fever (100.4°F/38°C or higher)
• chills/shaking
chills
• confusion
• severe
nausea, vomiting, diarrhea
• fast or irregular
heartbeat
• dizziness/lightheadedness
• severe
fatigue or weakness
It is important that you tell
your healthcare providers that you
have received BREYANZI and
to show them your BREYANZI Patient Wallet Card. Your
healthcare provider may give you other medicines to treat your side effects.
|
|
What is BREYANZI?
BREYANZI is for the treatment
of large B-cell lymphoma in patients when at least 2 previous treatments have not worked or have
stopped working. BREYANZI is a medicine made from your
own white blood cells;
the cells are genetically modified to recognize and attack your lymphoma cells.
|
|
How will I receive BREYANZI?
• BREYANZI is made from your own white blood cells, so
your blood will be collected by a process called
“leukapheresis” (LOO-kuh-feh-REE-sis).
• It takes about 3-4 weeks
from the time your cells
are received at the manufacturing
site and are available to be shipped back to your healthcare provider, but the time
may vary.
• Before you get BREYANZI, you will get 3 days of
chemotherapy to prepare your body.
|
|
• When your BREYANZI is
ready, your healthcare provider will give it to you through a catheter (tube)
placed into your vein (intravenous
infusion). BREYANZI is given as infusions of 2 different cell types.
o You will receive infusions of one cell type,
immediately followed by the other cell type.
o The time for
infusion will vary, but will
usually be less than 15 minutes
for each of the 2 cell types.
• During the first week, you will be monitored daily
by the facility where
you received your treatment.
• You should plan to stay close to this location for at
least 4 weeks after
getting BREYANZI. Your
healthcare provider will check to
see that your treatment is working and help you with any
side effects that may occur.
• You may be hospitalized for side effects and your healthcare provider will discharge
you if your side effects are under control, and it is safe for you
to leave the hospital.
• Your healthcare provider will
want to do blood tests to follow your progress. It is important that you do have your blood
tested. If you miss an appointment, call your healthcare provider as soon as possible to reschedule.
|
|
What should I avoid after receiving BREYANZI?
• Do not drive, operate heavy machinery, or do other activities that could be dangerous if you are not
mentally alert, for at least 8 weeks after you get BREYANZI. This
is because the treatment can cause temporary memory and
coordination problems, including
sleepiness, confusion, dizziness,
and seizures.
• Do not donate
blood, organs, tissues, or cells for transplantation.
|
|
What are the possible or reasonably likely side effects of BREYANZI?
The most common side effects of BREYANZI are:
• fatigue
• difficulty
breathing
• fever (100.4°F/38°C or higher)
• chills/shaking
chills
• confusion
• difficulty speaking
or slurred speech
• severe
nausea, vomiting, diarrhea
• headache
• dizziness/lightheadedness
• fast or irregular
heartbeat
• swelling
|
BREYANZI can increase the risk of life-threatening
infections that may lead to death. Tell
your healthcare provider right away
if you develop fever, chills, or
any signs or symptoms of an infection.
BREYANZI can lower one or more types of your blood cells (red blood cells, white blood cells, or platelets). After treatment, your healthcare provider will test your blood to check for this. Tell your healthcare
provider right away if you get a
fever, are feeling
tired, or have bruising or
bleeding.
Having BREYANZI in your blood
may cause a false-positive HIV test
result by some commercial tests.
These are not all the possible
side effects of BREYANZI. Call your doctor for medical advice about side effects. You may report
side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use
of BREYANZI
Medicines are sometimes prescribed
for purposes other than those listed in
a Medication Guide. If you would
like more information about BREYANZI, talk
with your healthcare provider.
You can ask your healthcare provider for
information about BREYANZI that is written for health
professionals.
For more information, go
to BREYANZI.com
or call 1-888-805-4555. 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
BREMG.001
02/2021 © 2021Juno
Therapeutics, Inc., a Bristol-Myers Squibb Company.
All rights reserved.
This Medication Guide
has
been approved by the U.S. Food
and Drug Administration. Issued: FEB 2021
