Safety Profile

Traceability

The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability, the name of the product, the batch number and the name of the treated patient must be kept for a period of 30 years after expiry date of the product.

Autologous use

Breyanzi is intended solely for autologous use and must not, under any circumstances, be administered to other patients. Breyanzi must not be administered if the information on the product labels and release for infusion certificate (RfIC) do not match the patient’s identity.

Reasons to delay treatment

Due to the risks associated with Breyanzi treatment, infusion should be delayed if a patient has any of the following conditions:

• Unresolved serious adverse events (especially pulmonary events, cardiac events, or hypotension), including those after preceding chemotherapies.
• Active uncontrolled infections, or inflammatory disorders.
• Active graft-versus-host disease (GVHD).

Blood, organ, tissue and cell donation

Patients treated with Breyanzi must not donate blood, organs, tissues and cells for transplantation.

Central nervous system (CNS) lymphoma

There is no experience of use of Breyanzi in patients with primary CNS lymphoma. There is limited clinical experience of use of Breyanzi for secondary CNS lymphoma.

Prior treatment with an anti-CD19 therapy

There is limited clinical experience with Breyanzi in patients exposed to prior CD19-directed therapy. There are limited clinical data available on CD19-negative patients treated with Breyanzi. Patients with CD19-negative status by immunohistochemistry may still express CD19. The potential risks and benefits associated with treatment of CD19-negative patients with Breyanzi should be considered.

Cytokine release syndrome (CRS)

CRS including fatal or life-threatening reactions can occur following Breyanzi infusion. For patients who received one prior line of therapy for large B-cell lymphoma (LBCL), the median time to onset was 4 days (range: 1 to 63 days, with the upper limit due to CRS onset, without fever, reported in one patient). For patients who received two or more prior lines of therapy for LBCL, the median time to onset was 4 days (range: 1 to 14 days). For patients who received Breyanzi for FL, the median time to onset was 6 days (range: 1 to 17 days). For patients who received Breyanzi for MCL, the median time to onset was 4 days (range: 1 to 10 days). Less than half of all patients treated with Breyanzi experienced some degree of CRS.

In clinical studies, high tumour burden prior to Breyanzi infusion was associated with a higher incidence of CRS.

Tocilizumab and/or a corticosteroid were used to manage CRS after infusion of Breyanzi.

Monitoring and management of CRS
CRS should be identified based on clinical presentation. Patients should be evaluated for and treated for other causes of fever, hypoxia, and hypotension.

At least one dose of tocilizumab must be available per patient on site prior to infusion of Breyanzi. The treatment centre should have access to an additional dose of tocilizumab within 8 hours of each previous dose. In the exceptional case where tocilizumab is not available due to a shortage that is listed in the Medicines and Healthcare products Regulatory Agency (MHRA) Central Alerting System, the treatment centre must have access to suitable alternative measures instead of tocilizumab to treat CRS. Patients should be monitored 2-3 times during the first week following Breyanzi infusion at the qualified treatment centre for signs and symptoms of CRS. Frequency of monitoring after the first week should be carried out at the physician’s discretion and should be continued for at least 2 weeks after infusion. Patients and caregivers should be informed about the potential late onset of CRS and instructed to seek immediate medical attention if patients experience any signs or symptoms of CRS.

At the first sign of CRS, treatment with supportive care, tocilizumab or tocilizumab and corticosteroids should be instituted as indicated in Table 1. Breyanzi continues to expand following administration of tocilizumab and corticosteroids.

Patients who experience CRS should be closely monitored for cardiac and organ functioning until resolution of symptoms. For severe or life-threatening CRS, intensive care unit level monitoring and supportive therapy should be considered.

Evaluation for haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) should be considered in patients with severe or unresponsive CRS. Treatment of HLH/MAS should be administered per institutional guidelines.

If concurrent neurologic toxicity is suspected during CRS, administer:

• Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades in Tables 1 and 2
• Tocilizumab according to the CRS grade in Table 1
• Anti-seizure medication according to the neurologic toxicity grade in Table 2.

Neurologic adverse reactions

Neurologic toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS), which may be fatal or life-threatening, occurred following treatment with Breyanzi, including concurrently with CRS, after CRS resolution, or in the absence of CRS. For patients who received one prior line of therapy for LBCL, the median time to onset of the first event was 8 days (range: 1 to 63 days), for patients who received two or more prior lines of therapy for LBCL, the median time to onset of the first event was 9 days (range: 1 to 66 days), for patients who received Breyanzi for FL, the median time to onset of the first event was 8 days (range: 4 to 16 days) , and for patients who received Breyanzi for MCL, the median time to onset of the first event was 8 days (range: 1 to 25 days). The most common neurologic symptoms included encephalopathy, tremor, aphasia, delirium, dizziness and headache.

Monitoring and management of neurologic toxicities
Patients should be monitored 2-3 times during the first week following infusion, at the qualified treatment centre for signs and symptoms of neurologic toxicities. Frequency of monitoring after the first week should be carried out at the physician’s discretion and should be continued for at least 2 weeks after infusion. Patients and caregivers should be informed about the potential late onset of neurologic toxicities and instructed to seek immediate medical attention if patients experience any signs or symptoms of neurologic toxicities.

If neurologic toxicity is suspected, it is to be managed according to the recommendations in Table 2. Other causes of neurologic symptoms should be ruled out, including vascular events. Intensive care supportive therapy should be provided for severe or life-threatening neurologic toxicities.

If concurrent CRS is suspected during the neurologic toxicity administer:

• Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades in Tables 1 and 2
• Tocilizumab according to the CRS grade in Table 1
• Antiseizure medication according to the neurologic toxicity grade in Table 2.

Infections and febrile neutropenia

Breyanzi should not be administered to patients with a clinically significant active infection or inflammatory disorder. Severe infections including life-threatening or fatal infections, have occurred in patients after receiving this medicinal product. Patients should be monitored for signs and symptoms of infection before and after administration and treated appropriately. Prophylactic anti-microbials should be administered according to standard institutional guidelines.

Febrile neutropenia has been observed in patients after treatment with Breyanzi and may be concurrent with CRS. In the event of febrile neutropenia, infection should be evaluated and managed with broad-spectrum antibiotics, fluids and other supportive care as medically indicated.

Patients treated with Breyanzi may be at an increased risk of severe/fatal COVID-19 infections. Patients should be counselled on the importance of prevention measures.

Viral reactivation

Viral reactivation, (e.g., HBV, human herpesvirus 6 [HHV-6] and John Cunningham [JC] virus) may occur in immunosuppressed patients.

Viral reactivation manifestations may complicate and delay the diagnosis and appropriate treatment of CAR T-cell-related adverse events. Appropriate diagnostic evaluations should be performed to help differentiate these manifestations from CAR T-cell-related adverse events.

HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with medicinal products directed against B-cells. For patients with a prior history of HBV, prophylactic antiviral suppressive therapy is recommended to prevent HBV reactivation during and after Breyanzi therapy. 

Reactivation of JC virus, leading to progressive multifocal leukoencephalopathy (PML), has been reported in patients treated with Breyanzi who have also received prior treatment with other immunosuppressive medicinal products. Cases with fatal outcome have been reported.

Serological testing

Screening for HBV, HCV, and HIV should be performed before collection of cells for manufacturing. 

Prolonged cytopenias 

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Breyanzi. Blood counts should be monitored prior to and after Breyanzi administration. Prolonged cytopenias should be managed according to clinical guidelines.

Hypogammaglobulinaemia

B-cell aplasia leading to hypogammaglobulinaemia can occur in patients receiving treatment with Breyanzi. Hypogammaglobulinaemia has been very commonly observed in patients treated with Breyanzi. Immunoglobulin levels should be monitored after treatment and managed per clinical guidelines including infection precautions, antibiotic prophylaxis and/or immunoglobulin replacement.

Secondary malignancies including of T-cell origin 

Patients treated with Breyanzi may develop secondary malignancies. T-cell malignancies have been reported following treatment of haematological malignancies with a BCMA- or CD19-directed CAR T-cell therapy, including Breyanzi. T-cell malignancies, including CAR-positive malignancies, have been reported within weeks and up to several years following administration of a CD19- or BCMA-, directed CAR T-cell therapy. There have been fatal outcomes. Patients should be monitored life-long for secondary malignancies. In the event that a secondary malignancy of T-cell origin occurs, the company should be contacted to obtain instructions on the collection of tumour samples for testing.

Tumour lysis syndrome (TLS)

TLS may occur in patients treated with CAR T therapies. To minimise the risk of TLS, patients with elevated uric acid or high tumour burden should receive allopurinol, or an alternative prophylaxis, prior to Breyanzi infusion. Signs and symptoms of TLS should be monitored and managed in accordance with clinical guidelines.

Hypersensitivity reactions

Allergic reactions may occur with the infusion of Breyanzi. Serious hypersensitivity reactions including anaphylaxis, may be due to dimethyl sulfoxide.

Transmission of an infectious agent

Although Breyanzi is tested for sterility and mycoplasma, a risk of transmission of infectious agents exists. Healthcare professionals administering Breyanzi must, therefore, monitor patients for signs and symptoms of infections after treatment and treat appropriately, if needed. 

Interference with virological testing
Due to limited and short spans of identical genetic information between the lentiviral vector used to create Breyanzi and HIV, some HIV nucleic acid tests (NAT) may give a false positive result.

Prior stem cell transplantation (GVHD)

It is not recommended that patients who underwent an allogeneic stem cell transplant and suffer from active acute or chronic GVHD receive treatment because of the potential risk of Breyanzi worsening GVHD. 

Long-term follow-up

Patients are expected to be enrolled in a registry and will be followed in the registry in order to better understand the long-term safety and efficacy of Breyanzi.

Excipients

This medicinal product contains 12.5 mg sodium per vial, equivalent to 0.6% of the WHO recommended maximum daily intake of 2 g sodium for an adult. 

This medicinal product contains 0.2 mmol (or 6.5 mg) potassium per vial. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.