Usual Adult Dose for Lymphoma

PRETREATMENT:

• Administer the lymphodepleting chemotherapy regimen before infusion of this drug: fludarabine 30 mg/m2/day 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 this drug 2 to 7 days after completion of lymphodepleting chemotherapy.
• Delay the infusion of this drug if the patient has unresolved serious adverse events from preceding chemotherapies, active uncontrolled infection, or active graft-versus-host disease (GVHD).

PREMEDICATION:

• Premedicate the patient with acetaminophen (650 mg orally) and diphenhydramine (25 to 50 mg IV or orally), or another H1-antihistamine, 30 to 60 minutes prior to therapy with this drug.
• Avoid prophylactic use of systemic corticosteroids, as they may interfere with the activity of this drug.

A single dose of this drug contains 50 to 110 x 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 1 to 4 single-dose vials. Each mL contains 1.5 x 10(6) to 70 x 10(6) CAR-positive viable T cells (3).See the respective Certificate of Release for Infusion (RFI Certificate) for each component, for the actual cell counts and volumes to be infused.

ADMINISTRATION:

• When this drug 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.

STEPS:
1) Use IV 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 IV at an infusion rate of approximately 0.5 mL/min, 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 through 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.

Comments:

• Consult the manufacturer product information for preparation and administration.

Use: For the treatment of adult patients with relapsed or refractory large B-cell lymphoma after 2 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 (this drug is not indicated for the treatment of patients with primary central nervous system [CNS] lymphoma)

Renal Dose Adjustments

Data not available
See the prescribing information for fludarabine and cyclophosphamide for information on dose adjustment in renal impairment.

Liver Dose Adjustments

Data not available

Dose Adjustments

CRS GRADING AND MANAGEMENT GUIDANCE:
GRADE 1 (fever):

• Tocilizumab: 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.
• Corticosteroids (if corticosteroids are initiated, continue corticosteroids for at least 3 doses or until complete resolution of symptoms, and consider corticosteroid taper}: 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):

• Tocilizumab: 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 IV fluids or increasing supplemental oxygen. Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses. If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (10 to 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 total.
• Corticosteroids (if corticosteroids are initiated, continue corticosteroids for at least 3 doses or until complete resolution of symptoms, and consider corticosteroid taper}: If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (10 to 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. If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (10 to 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 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: If no improvement within 24 hours or rapid progression of CRS, repeat tocilizumab and escalate dose and frequency of dexamethasone (10 to 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 total.
• Corticosteroids (if corticosteroids are initiated, continue corticosteroids for at least 3 doses or until complete resolution of symptoms, and consider corticosteroid taper}: Administer dexamethasone 20 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 to 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 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: 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 total.
• Corticosteroids (if corticosteroids are initiated, continue corticosteroids for at least 3 doses or until complete resolution of symptoms, and consider corticosteroid taper}: 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 total.

NEUROLOGIC TOXICITY:

• Monitor patients for neurologic toxicities.
• 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 below.
• If concurrent CRS is suspected during neurologic toxicity, administer corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades, tocilizumab, and antiseizure medication according to the neurologic toxicity outlined below:
• 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 to 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 g to 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 g to 2 g, repeat every 24 hours if needed; taper as clinically indicated), and cyclophosphamide 1.5 g/m2.

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for Breyanzi. It includes elements to assure safe use, and implementation system. For additional information: http://www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNINGS:
CYTOKINE RELEASE SYNDROME (CRS):

• CRS, including fatal or life-threatening reactions, occurred in patients receiving this drug.

Recommendations:

• Do not administer this drug to patients with active infection or inflammatory disorders.
• Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids.

NEUROLOGICAL TOXICITIES:

• Neurological toxicities, which may be severe or life-threatening, can occur following treatment with this drug, including concurrently with CRS.

Recommendations:

• Monitor for neurological events.
• Provide supportive care and/or corticosteroids as needed.
• This drug is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.

CONTRAINDICATIONS:

• None

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• This drug is shipped directly to the cell-associated lab or 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 this drug 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.
• Administer this drug in a certified healthcare facility.
• This drug is for autologous use only.
• Do NOT use a leukodepleting filter.
• Administer a lymphodepleting regimen of fludarabine and cyclophosphamide before infusion of this drug.
• Verify the patient's identity prior to infusion.
• Premedicate with acetaminophen and an H1 antihistamine.
• Confirm availability of tocilizumab prior to infusion.
• Confirm the infusion time in advance and adjust the start time of thaw of this drug so that it will be available for infusion when the patient is ready.
• Following administration of the CD8 or CD4 component, flush the tubing with normal saline, using enough volume to clear the tubing and the length of the IV catheter.
• This drug 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.

Storage requirements:

• This drug 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).
• This drug is shipped directly to the cell lab or 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.
• Thaw prior to infusion.

IV compatibility:

• Normal saline

Monitoring:

• Administer this drug 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.