Breyanzi

Cytokine Release Syndrome (CRS)

• 45% (n=68/150) of patients receiving Breyanzi after 1 line of therapy for LBCL experienced CRS; median time to onset: 4 days; CRS resolved in all patients with a median duration of 4 days.
• 46% (n=122/268) of patients receiving Breyanzi after 2 or more lines of therapy for LBCL experienced CRS; median time to onset: 5 days; CRS resolved in 98% with a median duration of 5 days.
• Most common manifestations: fever, hypotension, tachycardia, chills, hypoxia, headache.
• Potential for serious adverse events associated with CRS including cardiac arrhythmias (eg, atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.
• Ensure that 2 doses of tocilizumab are available prior to infusion.
• Monitor patients daily for 7 days post infusion; monitor for CRS for at least 4 weeks.

CRS Grading and Management Guidance

Grading of CRS based on Lee criteria.

If corticosteroids are initiated, continue corticosteroids for at least 3 doses or until complete resolution of symptoms, and consider corticosteroid taper.

Grade 1

Definition: Fever

Tocilizumab: If <72 hours after infusion, consider tocilizumab 8mg/kg IV over 1 hour (not to exceed 800mg). If ≥72 hours after infusion, treat symptomatically.

Corticosteroids: If <72 hours after infusion, consider dexamethasone 10mg IV every 24 hours. If ≥72 hours after infusion, treat symptomatically.

Grade 2

Definition: Symptoms require and respond to moderate intervention. Oxygen requirement <40% FiO₂, or hypotension responsive to fluids or low dose of 1 vasopressor, or grade 2 organ toxicity.

Tocilizumab: Administer tocilizumab 8mg/kg IV over 1 hour (not to exceed 800mg). 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.

Corticosteroids: If <72 hours after infusion, administer dexamethasone 10mg IV every 12-24 hours. If ≥72 hours after infusion, consider dexamethasone 10mg IV every 12-24 hours.

• If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (10-20mg IV every 6 to 12 hours).
• If no improvement or continued rapid progression, maximize dexamethasone, switch to high-dose methylprednisolone 2mg/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

Definition: Symptoms require and respond to aggressive intervention. Oxygen requirement

≥40% FiO₂, or hypotension requiring high-dose or multiple vasopressors, or grade 3 organ toxicity, or grade 4 transaminitis.

Tocilizumab: Per grade 2.

Corticosteroids: Administer dexamethasone 10mg IV every 12 hours.

• If no improvement within 24 hours or rapid progression of CRS, repeat tocilizumab and escalate dose and frequency of dexamethasone (10-20mg IV every 6 to 12 hours).
• If no improvement or continued rapid progression, maximize dexamethasone, switch to high-dose methylprednisolone 2mg/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

Definition: Life-threatening symptoms. Requirements for ventilator support or continuous veno-venous hemodialysis or grade 4 organ toxicity (excluding transaminitis).

Tocilizumab: Per grade 2.

Corticosteroids: Administer dexamethasone 20mg 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 2mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses tocilizumab in 24 hours, or 4 doses in total.

Neurologic Toxicities

• 27% (n=41/150) of patients receiving Breyanzi after 1 line of therapy for LBCL experienced CAR T cell-associated neurologic toxicities; median time to onset was 8 days; median duration of neurologic toxicity was 6 days.
• 35% (n=95/268) of patients receiving Breyanzi after 2 or more lines of therapy for LBCL experienced CAR T cell-associated neurologic toxicities; median time to onset was 8 days; median duration of neurologic toxicity was 12 days.
• Neurologic toxicities resolved in 85% of patients.
• Of patients developing neurotoxicity, 77% (n=105/136) also developed CRS.
• Most common neurologic toxicities: encephalopathy, tremor, aphasia, headache, dizziness, delirium.
• Monitor patients daily for 7 days post infusion; monitor for neurologic toxicities for at least 4 weeks.

Neurologic Toxicity Grading and Management Guidance

Grading neurologic toxicities based on NCI CTCAE criteria.

Grade 1

• Start non-sedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis.
• If ≥72 hours after infusion, observe.
• If <72 hours after infusion, consider dexamethasone 10mg IV every 12 to 24 hours for 2 to 3 days.

Grade 2

• Start non-sedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis.
• Dexamethasone 10mg IV every 12 hours for 2-3 days, or longer for persistent symptoms. 
• Consider taper for a total steroid exposure of >3 days.
• If no improvement after 24 hours or worsening of neurologic toxicity increase dose and/or frequency of dexamethasone up to a maximum of 20mg IV every 6 hours.
• If no improvement after another 24 hours, rapidly progressing symptoms, or life-threatening complications arise, give methylprednisolone (2mg/kg loading dose, followed by 2mg/kg divided 4 times a day; taper within 7 days).

Grade 3

• Start nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis.
• Dexamethasone 10-20mg 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 (1-2g, repeat every 24 hours if needed; taper as clinically indicated) and cyclophosphamide 1.5g/m².

Grade 4

• Start nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis.
• Dexamethasone 20mg 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 (1-2g, repeat every 24 hours if needed; taper as clinically indicated), and cyclophosphamide 1.5g/m².

Hypersensitivity Reactions
Allergic reactions may occur with infusion. Serious hypersensitivity reactions may be due to DMSO.

Serious Infections

• Infections of any grade occurred in 36% of patients receiving Breyanzi for LBCL. 
• Febrile neutropenia developed after infusion in 8% of patients.
• Monitor for signs/symptoms of infection; administer prophylactic antimicrobials according to guidelines.
• Avoid Breyanzi administration in patients with clinically significant, active systemic infections.
• Perform screening for HBV, HCV, and HIV before collection of cells for manufacturing. 
• Patients with prior history of HBV: consider concurrent antiviral suppressive therapy to prevent reactivation.

Prolonged Cytopenias

• Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and Breyanzi.
• These included thrombocytopenia, neutropenia, and anemia.
• Monitor CBC prior to and after administration of Breyanzi.

Hypogammaglobulinemia

• B-cell aplasia and hypogammaglobulinemia can occur in patients receiving Breyanzi.
• Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated.

Secondary Malignancies

• Patients treated with Breyanzi may develop secondary malignancies.
• Monitor lifelong for secondary malignancies.
• Contact BMS (888) 805-4555 to report secondary malignancies.

Effects on Driving, Using Machines

• Patients on Breyanzi are at risk for developing altered or decreased consciousness or impaired coordination in the 8 weeks following administration.
• Patients should refrain from driving or engaging in hazardous occupations or activities (eg, operating heavy machinery) for at least 8 weeks.

Immunogenicity

• Breyanzi has the potential to induce anti-product antibodies.
• The relationship between anti-product antibody status and efficacy, safety, or pharmacokinetics has not been established.