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Description for Breyanzi

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 and HOW SUPPLIED].

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).

INDICATIONS AND USAGE

Large B-cell Lymphoma (LBCL)

BREYANZI is indicated for the treatment of adult patients with large B-cell lymphoma (LBCL), 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 who have:

• refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or
• refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age; or
• relapsed or refractory disease after 2 or more lines of systemic therapy.

Limitations of Use: BREYANZI is not indicated for the treatment of patients with primary central nervous system (CNS) lymphoma [see Clinical Studies (14.1)].

Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

BREYANZI is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy including, a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor.

This indication is approved under accelerated approval based on response rate and duration of response [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Follicular Lymphoma (FL)

BREYANZI is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have received 2 or more prior lines of systemic therapy.

This indication is approved under accelerated approval based on response rate and duration of response [see Clinical Studies (14.3)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Mantle Cell Lymphoma (MCL)

BREYANZI is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least 2 prior lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor.

Marginal Zone Lymphoma (MZL)

BREYANZI is indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least 2 prior lines of systemic therapy.

Dosage for Breyanzi

Dose

For autologous use only. For intravenous use only.

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)].

A single dose of BREYANZI contains CAR-positive viable T cells (consisting of 1:1 CARpositive viable T cells of the CD8 and CD4 components), with each component supplied separately in one to four single-dose vials. See Table 1 for dose range per indication.

Table 1: Dose Range

Indication	BREYANZI dose range
LBCL after two or more lines of therapy (1.1)	50 to 110 × 106 CAR-positive viable T cells
LBCL after one line of therapy (1.1)	90 to 110 × 106 CAR-positive viable T cells
CLL or SLL (1.2)	90 to 110 × 106 CAR-positive viable T cells
FL (1.3)	90 to 110 × 106 CAR-positive viable T cells
MCL (1.4)	90 to 110 × 106 CAR-positive viable T cells
MZL (1.5)	90 to 110 × 106 CAR-positive viable T cells
Abbreviations: LBCL = large B-cell lymphoma; CLL = chronic lymphocytic leukemia; SLL = small lymphocytic lymphoma; FL = follicular lymphoma; MCL = mantle cell lymphoma; MZL = marginal zone lymphoma.

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.

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

• 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.

Preparing BREYANZI

Before thawing 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.
    1. Insert the needle into the septum at a 45°- 60° angle to puncture the retrieval port septum.
    2. Increase the angle of the needle gradually as the needle enters the vial.

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.

    BREYANZI Administration

    • Do NOT use a leukodepleting filter.
    • Confirm 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.
19. Use intravenous normal saline to flush all the infusion tubing prior to and after each CD8 or CD4 component administration.
20. 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.
21. 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).
22. 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.
23. 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

• Monitor patients daily for at least 7 days following BREYANZI infusion for signs and symptoms of CRS and neurologic toxicities.
• Instruct patients to remain within proximity of a healthcare facility for at least 2 weeks following infusion.
• Advise patients to avoid driving for at least 2 weeks following infusion.

Management of Severe Adverse Reactions

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 2. Physicians may also consider management per current practice guidelines.

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 intensivecare 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 2 and 3
• Tocilizumab according to the CRS grade in Table 2
• Antiseizure medication according to the neurologic toxicity in Table 3

Table 2: 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.
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.

Neurologic Toxicity

Monitor patients for signs and symptoms of neurologic toxicities (Table 3). 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 3. Physicians may also consider management per current practice guidelines.

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 2 and 3
• Tocilizumab according to the CRS grade in Table 2
• Antiseizure medication according to the neurologic toxicity in Table 3

Table 3: Neurologic Toxicity (NT) Grading and Management Guidance

NT Gradea	Corticosteroids and Antiseizure Medication
Grade 1	The infusion volume is calculated based on the concentration of cryopreserved drug product 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.
a NCI CTCAE criteria for grading neurologic toxicities, version 4.03.

HOW SUPPLIED

Dosage Forms And Strengths

BREYANZI is a cell suspension for infusion.

A single dose of BREYANZI contains CAR-positive viable T cells that consist of CD8 and CD4 components, with each component supplied separately in single-dose vials [see Dosage and Administration (2.1)].

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 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. The volume may differ for each component infused. See the RFI Certificate for details [see How Supplied/Storage and Handling (16)].

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)].

Manufactured by:

Juno Therapeutics Inc., a Bristol-Myers Squibb Company, Bothell, WA 98021. US License No.: 2156.

Celgene Corporation, a Bristol-Myers Squibb Company, Summit, NJ 07901. US License No.: 2252.

Bristol-Myers Squibb Company, Devens, MA 01434. US License No.: 1713.

BREYANZI® is a trademark of Juno Therapeutics, Inc., a Bristol-Myers Squibb Company.

Pat. https://www.bms.com/patient-and-caregivers/our-medicines.html

BREPI.010/MG.009

ADVERSE REACTIONS

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data described in the WARNINGS and PRECAUTIONS and in this section reflects exposure to a single dose of BREYANZI in 769 patients in five clinical studies as described below.

Study 1 (JCAR017-BCM-003; Relapsed or Refractory LBCL After One Line of Therapy)

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

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

Serious adverse reactions occurred in 38% of patients. The most common nonlaboratory serious adverse reactions (> 2%) were CRS, sepsis, fever, febrile neutropenia, headache, aphasia, COVID19 infection, and pulmonary embolism.

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

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

Table 4: Adverse Reactions in ≥ 10% of Patients with Relapsed or Refractory LBCL Treated with BREYANZI in Study 1 (N=89)

Adverse Reaction	Any Grade (%)	Grade 3 or Higher (%)
Blood and lymphatic system disorders
Febrile neutropenia	10	10
Cardiac disorders
Tachycardia*	15	1.1
Gastrointestinal disorders
Nausea	24	0
Constipation	20	2.2
Diarrhea	18	0
Abdominal pain*	13	2.2
Vomiting	11	0
General disorders and administration site conditions
Fever	55	3.4
Fatigue*	28	1.1
Edemaa	13	0
Immune system disorders
Cytokine release syndrome	49	1.1
Infections and infestations
Bacterial infectious disorders*	12	6
Infections with pathogen unspecified*	12	6
Sepsis*	10	7
Metabolism and nutrition disorders
Decreased appetite	15	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	36	3.4
Nervous system disorders
Headache*	34	6
Dizzinessb	20	1.1
Motor dysfunctionc	12	3.4
Tremord	11	1.1
Psychiatric disorders
Insomnia*	15	0
Respiratory, thoracic, and mediastinal disorders
Cough*	11	0
Skin and subcutaneous tissue disorders
Rashe	12	1.1
Vascular disorders
Hypotension*	15	2.2
Hemorrhagef	12	0
* Represents multiple related terms. a Edema includes edema peripheral, localized edema, pleural effusion swelling. b Dizziness includes dizziness, dizziness postural, syncope, vertigo. c Motor dysfunction includes fine motor skill dysfunction, muscle spasms, muscular weakness. d Tremor includes resting tremor, tremor, essential tremor. e Rash includes catheter site rash, dermatitis acneiform, dermatitis exfoliative generalized, erythema multiforme, rash, rash maculo-papular, rash pruritic. f Hemorrhage includes conjunctival hemorrhage, cystitis hemorrhagic, epistaxis, gastrointestinal hemorrhage, hematoma, hematuria, retinal hemorrhage, vaginal hemorrhage.

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

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

Table 5: Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients with Relapsed or Refractory LBCL Treated with BREYANZI in Study 1

Laboratory Abnormalitya	Grade 3 or 4 (%)b
Lymphocyte count decreased	98
Neutrophil count decreased	89
Platelet count decreased	48
Hemoglobin decreased	32
a Baseline lab values were assessed prior to lymphodepleting chemotherapy. b Based on 88 evaluable patients, defined as those with both a baseline grade and at least one post-baseline grade for the particular lab.

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

Study 2 (017006; Relapsed or Refractory LBCL After One Line of Therapy)

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

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

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

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

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

Table 6: Adverse Reactions in ≥ 10% of Patients with Relapsed or Refractory LBCL Treated with BREYANZI in Study 2 (N=61)

Adverse Reaction	Any Grade (%)	Grade 3 or Higher (%)
Cardiac disorders
Tachycardia*	10	0
Gastrointestinal disorders
Nausea	25	1.6
Diarrhea	15	0
Constipation	11	0
General disorders and administration site conditions
Fatigue*	44	1.6
Fever	38	1.6
Edema*	20	0
Immune system disorders
Cytokine release syndrome	39	1.6
Infections and infestations
Infections with pathogen unspecified*	13	4.9
Upper respiratory tract infection*	13	0
Bacterial infectious disorders*	10	3.3
Metabolism and nutrition disorders
Decreased appetite	13	1.6
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	23	4.9
Nervous system disorders
Encephalopathya	23	4.9
Dizzinessb	16	1.6
Tremorc	16	0
Headache	11	1.6
Psychiatric disorders
Insomnia	11	0
Respiratory, thoracic, and mediastinal disorders
Cough*	18	0
Dyspnea*	16	4.9
Vascular disorders
Hypotension*	23	1.6
Hypertension	10	4.9
* Represents multiple related terms. a Encephalopathy includes amnesia, apraxia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dyscalculia, encephalopathy, lethargy, memory impairment, mental status changes, somnolence. b Dizziness includes dizziness, dizziness postural, syncope, vertigo. c Tremor includes resting tremor, tremor.

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

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

Table 7: Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients with Relapsed or Refractory LBCL Treated with BREYANZI in Study 2 (N=61)

Laboratory Abnormalitya	Grade 3 or 4 (%)
Lymphocyte count decreased	97
Neutrophil count decreased	80
Hemoglobin decreased	30
Platelet count decreased	26
a Baseline lab values were assessed prior to lymphodepleting chemotherapy.

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

Study 3 (017001; Relapsed or Refractory LBCL After Two or More Lines of Therapy)

Study 3 was an open-label, single-arm study which evaluated 268 adult patients with R/R LBCL after 2 or more prior lines of therapy received a single dose of CAR-positive viable T cells [see Clinical Studies (14.1)]. Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) or autoimmune disease requiring systemic immunosuppression were ineligible. The median age of the study population was 63 years (range: 18 to 86 years); 65% were male. The ECOG performance status at screening was 0 in 41% of patients, 1 in 58% of patients, and 2 in 1.5% of patients.

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

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

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

Table 8: Adverse Reactions in ≥ 10% of Patients with Relapsed or Refractory LBCL Treated with BREYANZI in Study 3 (N=268)

Adverse Reaction	Any Grade (%)	Grade 3 or Higher (%)
Cardiac disorders
Tachycardia*	25	0
Gastrointestinal disorders
Nausea	33	1.5
Diarrhea	26	0.4
Constipation	23	0
Abdominal pain*	21	3.0
Vomiting	21	0.4
General disorders and administration site conditions
Fatigue*	48	3.4
Edemaa	21	1.1
Fever	16	0
Chills	12	0
Immune system disorders
Cytokine release syndrome	46	4.1
Infections and infestations*
Infection with pathogen unspecified*	29	16
Bacterial infection*	13	5
Upper respiratory tract infection*	13	0.7
Viral infection	10	1.5
Metabolism and nutrition disorders
Decreased appetite	28	2.6
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	37	2.2
Nervous system disorders
Headache*	30	1.1
Encephalopathyb	29	9
Dizzinessc	24	2.6
Tremord	16	0
Peripheral neuropathye	11	0
Aphasiaf	10	2.2
Motor dysfunctiong	10	1.1
Psychiatric disorders
Insomnia*	14	0.4
Anxiety*	10	0
Deliriumh	10	2.2
Renal and urinary disorders
Renal failure*	11	3.0
Respiratory, thoracic, and mediastinal disorders
Cough*	23	0
Dyspnea*	16	2.6
Skin and subcutaneous tissue disorders
Rashi	13	0.4
Vascular disorders
Hypotension*	26	3.4
Hypertension	14	4.5
Hemorrhagej	10	1.5
* Represents multiple related terms. a Edema includes edema, edema peripheral, fluid overload, fluid retention, generalized edema, hypervolemia, peripheral swelling, pulmonary congestion, pulmonary edema, swelling. b 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. c Dizziness includes dizziness, presyncope, syncope, vertigo. d Tremor includes essential tremor, resting tremor, tremor. e Peripheral neuropathy includes hyperesthesia, hypoesthesia, meralgia paresthetica, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, sciatica, sensory loss. f Aphasia includes aphasia, disorganized speech, dysarthria, dysphemia, dysphonia, slow speech, speech disorder. g Motor dysfunction includes eyelid ptosis, motor dysfunction, muscle rigidity, muscle spasms, muscle spasticity, muscle tightness, muscle twitching, muscular weakness, myoclonus, myopathy. h Delirium includes agitation, delirium, delusion, disorientation, hallucination, ‘hallucination, visual’, irritability, restlessness. i Rash includes erythema, dermatitis acneiform, perineal rash, rash, rash erythematous, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, rash pustular. j Hemorrhage includes catheter site hemorrhage, conjunctival hemorrhage, epistaxis, hematoma, hematuria, hemorrhage, hemorrhage intracranial, pulmonary hemorrhage, retinal hemorrhage, vaginal hemorrhage.

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

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

Table 9: Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients with Relapsed or Refractory LBCL Treated with BREYANZI in Study 3

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

Study 4 (017004; Relapsed or Refractory CLL/SLL)

Study 4 was an open-label, single-arm study which evaluated 89 adult patients with R/R CLL/SLL who had received at least 2 prior lines of therapy including a BTK inhibitor and a BCL-2 inhibitor before receiving a single dose of CAR positive viable T cells [see Clinical Studies (14.2)]. Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) or autoimmune disease requiring systemic immunosuppression, Richter’s transformation, ECOG performance status >1 were ineligible. The trial required LVEF ≥ 40%, adequate oxygen saturation on room air with ≤ Grade 1 dyspnea, ALT ≤ 5 x ULN, total bilirubin < 2.0 mg/dL, creatinine clearance > 30 mL/min, and adequate bone marrow function to receive lymphodepleting chemotherapy.

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

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

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

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

Table 10: Adverse Reactions in ≥ 10% of Patients with Relapsed or Refractory CLL/SLL Treated with BREYANZI in Study 4 (N=89)

Adverse Reaction	Any Grade (%)	Grade 3 or Higher (%)
Blood and lymphatic system disorders
Febrile neutropenia	12	12
Cardiac disorders
Tachycardia*	21	0
Gastrointestinal disorders
Nausea	35	0
Diarrhea*	30	1.1
Constipation	24	0
Abdominal pain*	18	0
Vomiting	15	0
General disorders and administration site conditions
Fatigue*	40	4.5
Edemaa	30	4.5
Fever*	27	1.1
Chills	17	1.1
Immune system disorders
Cytokine release syndrome	83	9
Infections and infestations
Infection with pathogen unspecified*	23	10
Upper respiratory tract infection*	19	1.1
Viral infection*	10	1.1
Metabolism and nutrition disorders
Decreased appetite	27	4.5
Tumor lysis syndrome	11	11
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	42	1.1
Nervous system disorders
Encephalopathyb	44	18
Headache*	28	1.1
Tremor	24	2.2
Dizzinessc	21	1.1
Motor dysfunctiond	14	2.2
Peripheral neuropathye	12	0
Taste disorder*	10	0
Psychiatric disorders
Deliriumf	20	3.4
Insomnia	16	1.1
Anxiety	12	1.1
Renal and urinary disorders
Renal failure*	15	3.4
Respiratory, thoracic, and mediastinal disorders
Dyspnea*	27	8
Cough*	20	0
Skin and subcutaneous tissue disorders
Rashg	23	2.2
Vascular disorders
Hypotension*	17	0
Hemorrhageh	16	1.1
Hypertension	10	4.5
* Represents multiple related terms. a Edema includes ascites, face edema, hypervolemia, edema peripheral, pleural effusion, pulmonary edema, scrotal edema. b Encephalopathy includes cognitive disorder, confusional state, disturbance in attention, encephalopathy, lethargy, memory impairment, mental status changes, somnolence. c Dizziness includes dizziness, presyncope, syncope, vertigo. d Motor dysfunction includes asterixis, muscle spasms, muscular weakness, myoclonus. e Peripheral neuropathy includes hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy. f Delirium includes agitation, delirium, hallucination, hallucination visual, intensive care unit delirium, irritability, restlessness. g Rash includes dermatitis contact, erythema, petechiae, rash, rash macular, rash maculo-papular, scrotal erythema, seborrheic keratosis, urticaria. h Hemorrhage includes epistaxis, hemorrhage intracranial, hematoma, hematuria, hemorrhoidal hemorrhage, intraventricular hemorrhage, lower gastrointestinal hemorrhage, traumatic hemothorax.

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

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

Table 11: Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients with Relapsed or Refractory CLL/SLL Treated with BREYANZI in Study 4

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

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

Study 5 (JCAR017-FOL-001; Relapsed or Refractory FL Cohort)

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

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

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

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

Table 12: Adverse Reactions** in ≥ 10% of Patients with Relapsed or Refractory FL Treated with BREYANZI in Study 5 (N=107)

Adverse Reaction	Any Grade (%)	Grade 3 or Higher (%)
Gastrointestinal disorders
Constipation	21	0
Diarrhea	15	0
General disorders and administration site conditions
Fatigue*	23	0
Fever*	20	0
Immune system disorders
Cytokine release syndrome	59	0.9
Infections and infestations
Infection with pathogen unspecified*	16	4.7
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	28	0
Nervous system disorders
Headache	28	0
Tremor	15	0
* Represents multiple related terms. ** Includes adverse reactions up to 90 days following treatment with BREYANZI.

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

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

Table 13: Grade 3 or 4 Laboratory Abnormalities* Occurring in ≥ 10% of Patients with Relapsed or Refractory FL Treated with BREYANZI in Study 5 (N=107)

Laboratory Abnormalitya	Grade 3 or 4 (%)b
Lymphocyte count decreased	94
Neutrophil count decreased	79
White blood cell decreased	74
Platelet count decreased	17
* Includes laboratory abnormalities up to 90 days following treatment with BREYANZI. a Baseline lab values were assessed prior to lymphodepleting chemotherapy. b Based on the number of patients with a baseline value and at least one post treatment value for the particular lab.

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

Study 3 (017001; Relapsed or Refractory MCL Cohort)

Study 3 was an open-label, single-arm study which evaluated 88 adult patients with relapsed or refractory MCL received a single dose of CAR-positive viable T cells [see Clinical Studies (14.4)]. Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) or autoimmune disease requiring systemic immunosuppression were ineligible. The trial required left ventricular ejection fraction ≥ 40%, adequate oxygen saturation on room air with ≤ Grade 1 dyspnea, ALT ≤ 5 x ULN, total bilirubin < 2.0 mg/dL, creatinine clearance > 30 mL/min, and adequate bone marrow function to receive lymphodepleting chemotherapy. The median age of the study population was 69 years (range: 36 to 86 years); 76% were male, 88% were White, 6% were Asian and 2.3% were Black. Four percent were Hispanic, and 92% were non-Hispanic. The ECOG performance status at screening was 0 in 54% of patients, and 1 in 46% of patients.

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

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

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

Table 14: Adverse Reactions** in ≥ 10% of Patients with Relapsed or Refractory MCL Treated with BREYANZI in Study 3 (N=88)

Adverse Reaction	Any Grade (%)	Grade 3 or Higher (%)
Cardiac disorders
Tachycardia*	17	3.4
Gastrointestinal disorders
Nausea	18	2.3
Diarrhea	17	0
Abdominal pain*	15	3.4
Constipation	14	0
General disorders and administration site conditions
Fatigue*	39	2.3
Edemaa	25	1.1
Fever*	17	0
Chills	11	0
Immune system disorders
Cytokine release syndrome	61	1.1
Infections and infestations
Infection with pathogen unspecified*	16	6
Upper respiratory tract infection*	13	2.3
Metabolism and nutrition disorders
Decreased appetite	21	4.5
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	38	2.3
Nervous system disorders
Encephalopathyb	30	9
Headache	23	0
Dizzinessc	11	2.3
Motor dysfunctiond	11	0
Tremor	11	0
Psychiatric disorders
Insomnia*	14	0
Anxiety	13	1.1
Renal and urinary disorders
Renal failure*	15	0
Respiratory, thoracic, and mediastinal disorders
Dyspnea*	11	0
Cough	10	0
Skin and subcutaneous tissue disorders
Rashe	11	1.1
Vascular disorders
Hypotension*	15	0
Hemorrhagef	10	0
Hypertension	10	3.4
* Represents multiple related terms. ** Includes adverse reactions up to 90 days following treatment with BREYANZI. a Edema includes hypervolemia, localized edema, edema, edema peripheral, peripheral swelling, pleural effusion, pulmonary edema. b Encephalopathy includes confusional state, depressed level of consciousness, encephalopathy, lethargy, memory impairment, mental status changes, somnolence. c Dizziness includes dizziness, dizziness postural, syncope, vertigo. d Motor dysfunction includes fine motor skill dysfunction, muscle spasms, muscle tightness, muscular weakness. e Rash includes dermatitis contact, rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic. f Hemorrhage includes catheter site hemorrhage, epistaxis, hematoma, hematuria, hemorrhage, hemorrhoidal hemorrhage, rectal hemorrhage.

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

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

Table 15: Grade 3 or 4 Laboratory Abnormalities* Occurring in ≥ 10% of Patients with Relapsed or Refractory MCL Treated with BREYANZI in Study 3

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

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

Study 5 (JCAR017-FOL-001; Relapsed or Refractory MZL Cohort)

Study 5 was a an open-label, single-arm study which evaluated 67 adult patients with relapsed or refractory MZL after two or more prior lines of therapy or relapsed after hematopoietic stem cell transplant (HSCT) received a single dose of CAR-positive viable T cells [see Clinical Studies (14.5)]. Patients who had previously received CD19-directed therapy had to have biopsy proven CD19 positive lymphoma [see Clinical Studies (14)]. Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) and active autoimmune disease requiring immunosuppressive therapy were ineligible. The median age was 62 years (range: 37 to 81 years), 58% were male, ECOG performance status was 0 in 55% and 1 in 45% of patients; 57% were White, 6% were Asian, 2% were Black; race was not reported in 36% of patients; and 2% were Hispanic.

Serious adverse reactions occurred in 39% of patients. The most common nonlaboratory serious adverse reactions (> 2%) were CRS, encephalopathy, aphasia, sepsis, tremor, delirium, dizziness, infusion related hypersensitivity reaction, and transient ischemic attack. Fatal adverse reactions occurred in 3% of patients.

Table 16 presents nonlaboratory adverse reactions reported in ≥ 10% of patients treated with BREYANZI, and Table 17 describes selected new or worsening Grade 3 or 4 laboratory abnormalities.

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

Table 16: Adverse Reactions** in ≥ 10% of Patients with Relapsed or Refractory MZL Treated with BREYANZI in Study 5 (N=67)

Adverse Reaction	Any Grade (%)	Grade 3 or Higher (%)
Gastrointestinal disorders
Diarrhea	28	1.5
Nausea	18	1.5
Abdominal pain*	10	0
General disorders and administration site conditions
Fatigue*	27	3
Edemaa	18	3
Fever*	10	0
Immune system disorders
Cytokine release syndrome	76	4.5
Infections and infestations
Infection with pathogen unspecified*	16	6
Metabolism and nutrition disorders
Decreased appetite	10	3
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	22	0
Nervous system disorders
Headache	21	1.5
Tremor	21	0
Encephalopathyb	21	1.5
Dizziness	16	0
Aphasia	10	0
Psychiatric disorders
Deliriumc	10	3
Renal and urinary disorders
Renal failure*	10	1.5
Vascular disorders
Hypotension	10	0
* Represents multiple related terms. ** Includes adverse reactions up to 90 days following treatment with BREYANZI. a Edema includes ascites, fluid retention, hypervolaemia, oedema peripheral, peripheral swelling, pleural effusion, pulmonary oedema. b Encephalopathy includes brain fog, cognitive disorder, confusional state, disturbance in attention, dyscalculia, dysgraphia, memory impairment, somnolence. c Delirium includes delirium, disorientation, hallucination, irritability, restlessness.

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

• Blood and lymphatic system disorders: Febrile neutropenia (3%).
• Cardiac disorders: Tachycardia (7.5%).
• Gastrointestinal disorders: Vomiting (9%), constipation (3%), dyspepsia (3%).
• General disorders and administration site conditions: Chills (7.5%), infusion related hypersensitivity reactions (3%).
• Immune system disorders: Hemophagocytic lymphohistiocytosis (4.5%).
• Infections and infestations Bacterial infections (6%), viral infections (6%), fungal infections (3%).
• Metabolism and nutrition disorders: Tumor lysis syndrome (1.5%).
• Nervous system disorders: Motor dysfunction (4.5%), ataxia (3%), neuropathy peripheral (3%), transient ischaemic attack (3.0%).
• Psychiatric disorders: Insomnia (9%), affective disorder (7.5%).
• Respiratory, thoracic and mediastinal disorders: Dyspnea (6%); cough (4.5%), hypoxia (4.5%).
• Skin and subcutaneous tissue disorders: Rash (4.5%).
• Vascular disorders: Hemorrhage (9%), hypertension (6%), thrombosis (6%).

Table 17: Grade 3 or 4 Laboratory Abnormalities* Occurring in ≥ 10% of Patients with Relapsed or Refractory MZL Treated with BREYANZI in Study 5 (N=67)

Laboratory Abnormalitya	Grade 3 or 4 (%)b
Lymphocyte count decreased	99
Neutrophil count decreased	84
White blood cell decreased	84
Platelet count decreased	28
Hemoglobin decreased	25
Fibrinogen decreased	10
* Includes laboratory abnormalities up to 90 days following treatment with BREYANZI. a Baseline lab values were assessed prior to lymphodepleting chemotherapy. b Based on the number of patients with a baseline value and at least one post treatment value for the particular lab.

Grade 4 laboratory abnormalities in ≥ 10% of patients were lymphocyte count decreased (85%), neutrophil count decreased (64%), white blood cell decreased (49%), and platelet count decreased (19%).

Postmarketing Experience

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

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

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

Neoplasms: T cell malignancies

Eye disorders: Blindness

Drug Interactions for Breyanzi

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.

Warnings for Breyanzi

Included as part of the PRECAUTIONS section.

Precautions for Breyanzi

Cytokine Release Syndrome

Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI.

In clinical trials of BREYANZI, which included a total of 769 patients with non-Hodgkin lymphoma (NHL) exposed to BREYANZI, CRS occurred in 56% of patients, including ≥ Grade 3 CRS (Lee grading system1) in 3.4% of patients. The median time to onset was 5 days (range: 1 to 63 days). CRS resolved in 99% of patients with a median duration of 5 days (range: 1 to 37 days). One patient had fatal CRS and 5 patients had ongoing CRS at the time of death. The most common manifestations of CRS (≥ 10%) included fever, hypotension, chills, tachycardia, hypoxia, and headache

Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) [see Adverse Reactions (6.1)].

Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI.

Monitor patients daily for at least 7 days following BREYANZI infusion for signs and symptoms of CRS. Continue to monitor patients for signs or symptoms of CRS for at least 2 weeks after infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated [see Dosage and Administration (2.2, 2.3)].

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Patient Counseling Information (17)].

Neurologic Toxicities

Neurologic toxicities that were fatal or life-threatening, including immune effector cell-associated neurotoxicity syndrome (ICANS), occurred following treatment with BREYANZI. Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, also occurred.

In clinical trials of BREYANZI, CAR T cell-associated neurologic toxicities occurred in 32% of patients, including ≥ Grade 3 cases in 10% of patients. The median time to onset of neurotoxicity was 8 days (range: 1 to 63 days). Neurologic toxicities resolved in 88% of patients with a median duration of 7.5 days (range: 1 to 119 days). Of patients developing neurotoxicity, 83% also developed CRS.

The most common neurologic toxicities (≥ 5%) included encephalopathy, tremor, aphasia, delirium, and headache.

Monitor patients daily for at least 7 days following BREYANZI infusion for signs and symptoms of neurologic toxicities and assess for other causes of neurological symptoms. Continue to monitor patients for signs or symptoms of neurologic toxicities for at least 2 weeks after infusion and treat promptly. Manage neurologic toxicity with supportive care and/or corticosteroid as needed [see Dosage and Administration (2.2, 2.3)]. Advise patients to avoid driving for at least 2 weeks following infusion.

Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time [see Patient Counseling Information (17)].

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO).

Serious Infections

Severe infections, including life-threatening or fatal infections, have occurred in patients after BREYANZI infusion.

In clinical trials of BREYANZI, infections of any grade occurred in 33% of patients, with Grade 3 or higher infections occurred in 12% of all patients. Grade 3 or higher infections with an unspecified pathogen occurred in 7%, bacterial infections in 3.5%, viral infections in 2%, and fungal infections in 0.7% of patients. One patient with FL, who received four prior lines of therapy developed a fatal case of John Cunningham (JC) virus progressive multifocal leukoencephalopathy four months after treatment with BREYANZI. One patient with MCL, who received three prior lines of therapy, developed a fatal case of cryptococcal meningoencephalitis 35 days after treatment with BREYANZI.

Febrile neutropenia developed after BREYANZI infusion in 8% of patients. Febrile neutropenia may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines.

Avoid administration of BREYANZI in patients with clinically significant, active systemic infections.

Viral Reactivation

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells.

In clinical trials of BREYANZI, 35 of 38 patients with a prior history of HBV were treated with concurrent antiviral suppressive therapy. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. In patients with prior history of HBV, consider concurrent antiviral suppressive therapy to prevent HBV reactivation per standard guidelines.

Prolonged Cytopenias

Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion.

In clinical trials of BREYANZI, Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 35% of patients, and included thrombocytopenia in 25%, neutropenia in 22%, and anemia in 6% of patients.

Monitor complete blood counts prior to and after BREYANZI administration.

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving BREYANZI.

In clinical trials of BREYANZI, hypogammaglobulinemia was reported as an adverse reaction in 9% of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 30% of patients.

Monitor immunoglobulin levels after treatment with BREYANZI and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated.

Live Vaccines

The safety of immunization with live viral vaccines during or following BREYANZI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during BREYANZI treatment, and until immune recovery following treatment with BREYANZI.

Secondary Malignancies

Patients treated with BREYANZI may develop secondary malignancies. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes [see Boxed Warning, Adverse Reactions (6.2), Patient Counseling Information (17)]. 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.

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS)

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IECHS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. Seven out of 769 (0.9%) patients with R/R NHL exposed to BREYANZI developed IEC-HS (1 LBCL; 3 CLL/SLL; 3 MZL). Time to onset of IEC-HS ranged from 7 to 32 days. Of the 7 patients, 3 patients developed IEC-HS with overlapping occurrence of CRS and neurotoxicity, 2 patients developed IEC-HS with overlapping occurrence of neurotoxicity, and 1 patient developed IECHS with overlapping occurrence of CRS. IEC-HS was fatal in 2 of 7 patients. One patient had fatal IEC-HS and one had ongoing IEC-HS at time of death.

IEC-HS is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of IEC-HS should be administered per current practice guidelines.

NONCLINICAL TOXICOLOGY

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 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.

Patient Information for Breyanzi

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.

Advise patients that they will be monitored daily for at least 7 days following the BREYANZI infusion and instruct patients to remain close to a healthcare facility for at least 2 weeks following the infusion.

Prior to infusion, advise patients of the following risks:

• Cytokine Release Syndrome (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)].
• Neurologic Toxicities – 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)].
• Serious Infections – Signs or symptoms associated with infection [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
• Prolonged Cytopenias – Signs or symptoms associated with bone marrow suppression including neutropenia, anemia, thrombocytopenia, or febrile neutropenia [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].
• Secondary Malignancies: Secondary malignancies, including T cell malignancies, have occurred [see Boxed Warning, Warnings and Precautions (5.7), Adverse Reactions (6.2)].

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 (5.7)].
• Avoid driving for at least 2 weeks after BREYANZI administration.

Overdose Information for Breyanzi

No Information Provided

Contraindications for Breyanzi

None.

Clinical Pharmacology for Breyanzi

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 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.

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.

Pharmacokinetics

Following infusion, BREYANZI exhibited an initial expansion followed by a bi-exponential decline.

Relapsed or Refractory LBCL

The median time of maximal expansion in peripheral blood occurred 10-12 days after infusion. BREYANZI was present in peripheral blood for an estimated median of 12.1 months (range: 0.1+ to 24.2+ months).

Among patients who received two or more prior lines of therapy for LBCL (Study 3 – LBCL Cohort), responders (N=135) had a 2.3-fold higher median Cmax than nonresponders (N=37) (35,335 vs. 15,527 copies/µg). Responders had a 1.8-fold higher median AUC0-28d than nonresponders (273,552 vs. 155,240 day*copies/µg).

Patients < 65 years old (N=142) had a 3.1-fold and 2.3-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.

Relapsed or Refractory CLL/SLL

The median time of maximal expansion in peripheral blood occurred 14 days after infusion. BREYANZI was present in peripheral blood for an estimated median of 12.0 months (range: 0.1+ to 30.1+ months).

Among patients who received prior therapy for CLL/SLL (Study 4), responders (N=27) had a 2.0 fold higher median Cmax than nonresponders (N=25) (99,559 vs. 48,948 copies/µg). Responders had a 1.9-fold higher median AUC0-28d than nonresponders (793,893 vs. 408,307 day*copies/µg).

Relapsed or Refractory FL

The median time of maximal expansion in peripheral blood occurred 10 days after infusion. Median Cmax and AUC0-28d are 30,530 copies/µg and 253,400 day*copies/µg, respectively. BREYANZI was present in peripheral blood for an estimated median of 12.0 months (range: 0.3+ to 24.0+ months).

Relapsed or Refractory MCL

The median time of maximal expansion in peripheral blood occurred 10 days after infusion. Median Cmax and AUC0-28d were 30,968 copies/µg and 375,006 day*copies/µg, respectively. BREYANZI was present in peripheral blood for an estimated median of 17.9 months (range: 0.1+ to 24.2+ months).

Relapsed or Refractory MZL

The median time of maximal expansion in peripheral blood occurred 10 days after infusion. Median Cmax and AUC0-28d were 81,390 copies/µg and 657,799 day*copies/µg, respectively. BREYANZI was present in peripheral blood for an estimated median of 18.0 months (range: 0.6 to 42.1 months).

Patients receiving medications for CRS and/or neurologic toxicities

In general, patients with higher CAR-T cell expansion tended to have higher rates of CRS and neurologic toxicities. Some patients required tocilizumab and/or corticosteroids for the management of CRS or neurologic toxicities [see Dosage and Administration (2.3)]. BREYANZI continued to expand and persist in patients who received tocilizumab and/or corticosteroids treatment. In Study 3 - LBCL Cohort, patients treated with tocilizumab (N=49) had a 3.6-fold and 3.7-fold higher median Cmax and AUC0-28d of BREYANZI, respectively, compared to patients who did not receive tocilizumab (N=189). Similarly, patients who received corticosteroids (N=50) had a 3.8-fold and 3.7-fold higher median Cmax and AUC0-28d of BREYANZI, respectively, compared to patients who did not receive corticosteroids (N=188).

Immunogenicity

The observed incidence of anti-product antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-product antibodies in the studies described below with the incidence of antiproduct antibodies in other studies, including those of BREYANZI or of other similar products.

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) in Study 3 – LBCL Cohort, 1% (1/89) in Study 1, 0% (0/51) in Study 2, 2% (2/86) in Study 4, 2% (2/102) in Study 5 - FL Cohort, 13% (11/87) in Study 3 – MCL Cohort, and 0% (0/66) in Study 5 – MZL Cohort of patients. Treatment-induced or treatment-boosted anti-product antibodies were detected in 11% (27/257) in Study 3 – LBCL Cohort, 1% (1/89) in Study 1, 2% (1/49) in Study 2, 7% (6/84) in Study 4, 18% (18/100) in Study 5 – FL Cohort, 18% (15/85) in Study 3 – MCL Cohort, and 20% (13/66) in Study 5 – MZL Cohort of patients. Due to the small number of patients who had antiproduct antibodies, the relationship between anti-product antibody status and efficacy, safety, or pharmacokinetics was not conclusive.

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 a prescription medicine used to treat five types of non-Hodgkin lymphoma:

• Large B cell lymphoma, when:
  • your first treatment has not worked or your cancer returned within a year of your first treatment
    OR
  • your first treatment has not worked or your cancer returned after the first treatment, and you are not eligible for hematopoietic stem cell transplantation because of medical conditions or age
    OR
  • two or more kinds of treatment have not worked or stopped working.

• Chronic lymphocytic leukemia or small lymphocytic lymphoma when two or more kinds of treatment have not worked or stopped working.
• Follicular lymphoma, when two or more kinds of treatment have not worked or stopped working.
• Mantle cell lymphoma when two or more kinds of treatment have not worked or stopped working, including a prior Bruton tyrosine kinase (BTK) inhibitor medicine.
• Marginal zone lymphoma when two or more kinds of treatment have not worked or stopped working.

BREYANZI is different than other cancer medicines because it is made from your own white blood cells, which have been genetically modified to recognize and attack your lymphoma cells.

Before getting BREYANZI, tell your healthcare provider about all your medical problems, including if you have or have had:

• Neurologic problems (such as seizures, stroke, or memory loss)
• Lung or breathing problems
• Heart problems
• Liver problems
• Kidney problems
• A recent or active infection

Tell your healthcare provider about all the medications you take, including prescription and overthe-counter medicines, vitamins, and herbal supplements.

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.
  • You will receive infusions of one cell type, immediately followed by the other cell type.
  • 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.
• You should plan to stay close to a healthcare facility for at least 2 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?

• Avoid driving for at least 2 weeks after you get BREYANZI.
• 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
• low blood pressure
• muscle pain

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.

BREYANZI may increase your risk of getting cancers including certain types of blood cancers. Your healthcare provider should monitor you for this.

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. US License No.: 2156.

Celgene Corporation, a Bristol-Myers Squibb Company, Summit, NJ 07901. US License No.: 2252.

Bristol-Myers Squibb Company, Devens, MA 01434. US License No.: 1713.

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.009 12/2025