4.1. Therapeutic indications

Breyanzi is indicated for the treatment of adult patients with diffuse large B-cell lymphoma (DLBCL), high grade B‑cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL) and follicular lymphoma grade 3B (FL3B), who relapsed within 12 months from completion of, or are refractory to, first-line chemoimmunotherapy.

Breyanzi is indicated for the treatment of adult patients with relapsed or refractory DLBCL, PMBCL and FL3B, after two or more lines of systemic therapy.

Breyanzi is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.

Breyanzi is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy including a Bruton's tyrosine kinase (BTK) inhibitor.

4.2. Posology and method of administration

Breyanzi must be administered in a qualified treatment centre.

Treatment should be initiated under the direction of and supervised by a healthcare professional experienced in the treatment of haematological malignancies and trained for administration and management of patients treated with Breyanzi.

At least 1 dose of tocilizumab for use in the event of cytokine release syndrome (CRS) and emergency equipment must be available per patient prior to infusion of Breyanzi. The treatment centre must 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 MHRA Central Alerting System, suitable alternative measures to treat CRS instead of tocilizumab must be available prior to infusion.

Posology

Breyanzi is intended for autologous use (see section 4.4).

Treatment consists of a single dose for infusion containing a dispersion for infusion of CAR-positive viable T-cells in one or more vials.

The target dose is 100 × 106 CAR-positive viable Tcells (consisting of a target 1:1 ratio of CD4+ and CD8+ cell components) within a range of 44‑120 × 106 CAR-positive viable T-cells. See the accompanying release for infusion certificate (RfIC) for additional information pertaining to dose.

The availability of Breyanzi must be confirmed before starting lymphodepleting chemotherapy regimen.

Patients should be clinically re-assessed prior to administration of lymphodepleting chemotherapy and Breyanzi to ensure no reasons to delay therapy (see section 4.4).

Pre-treatment (lymphodepleting chemotherapy)

Lymphodepleting chemotherapy consisting of cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day, administered intravenously for three days. See the prescribing information for fludarabine and cyclophosphamide for information on dose adjustment in renal impairment.

Breyanzi is to be administered 2 to 7 days after completion of lymphodepleting chemotherapy.

If there is a delay of more than 2 weeks between completing lymphodepleting chemotherapy and the infusion of Breyanzi, then the patient should be re-treated with lymphodepleting chemotherapy prior to receiving the infusion (see section 4.4).

Pre-medication

It is recommended that premedication with paracetamol and diphenhydramine (25‑50 mg, intravenously or orally) or another H1-antihistamine, be administered 30 to 60 minutes before the infusion of Breyanzi to reduce the possibility of an infusion reaction.

Prophylactic use of systemic corticosteroids should be avoided, as the use may interfere with the activity of Breyanzi (see section 4.4).

Monitoring after infusion

• Patients should be monitored 2-3 times during the first week following infusion, for signs and symptoms of potential CRS, neurologic events and other toxicities. Physicians should consider hospitalisation at the first signs or symptoms of CRS and/or neurologic events.

• 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 should be instructed to remain within proximity of a qualified treatment centre for at least 2 weeks following infusion.

Special populations

Patients with human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection

There is no clinical experience in patients with active HIV, HBV or HCV infection.

Screening for HIV, active HBV and active HCV must be performed before collection of cells for manufacturing. Leukapheresis material from patients with active HIV or active HCV infection will not be accepted for manufacturing (see section 4.4).

Renal impairment

There is no clinical experience in patients with severe renal impairment (creatinine clearance ≤ 30 mL/min).

Elderly

No dose adjustment is required in patients over 65 years of age.

Paediatric population

The safety and efficacy of Breyanzi in children and adolescents below 18 years of age have not yet been established.

Method of administration

Breyanzi is for intravenous use only.

Preparation of Breyanzi

Before thawing the vials, it must be confirmed that the patient's identity matches the unique patient identifiers on the shipper, external carton and the release for infusion certificate (RfIC). The total number of vials to be administered must also be confirmed with the patient-specific label information on the release for infusion certificate (RfIC) (see section 4.4). The company must be contacted immediately if there are any discrepancies between the labels and the patient identifiers.

Administration

• Do NOT use a leukodepleting filter.

• Ensure tocilizumab or suitable alternatives, in the exceptional case where tocilizumab is not available due to a shortage that is listed in the MHRA Central Alerting System, 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 supplied on the respective release for infusion certificate (RfIC).

• Once Breyanzi components have 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.

For detailed instructions on preparation, administration, measures to take in case of accidental exposure and disposal of Breyanzi, see section 6.6.

4.3. Contraindications

Hypersensitivity to any of the excipients listed in section 6.1.

Contraindications of the lymphodepleting chemotherapy must be considered.

4.4. Special warnings and precautions for use

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).

In case of delayed Breyanzi infusion, see section 4.2.

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 (see section 5.1).

Prior treatment with an anti-CD19 therapy

There is limited clinical experience with Breyanzi in patients exposed to prior CD19-directed therapy (see section 5.1). 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 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 (see section 4.8).

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 (see section 4.8).

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 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 (see section 5.2).

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.

Table 1. CRS grading and management guidance

CRS gradea

Tocilizumab

Corticosteroidsb

Grade 1

Fever

If 72 hours or more after infusion, treat symptomatically.

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.

Grade 2

Symptoms require and respond to moderate intervention.

Fever, oxygen requirement less than 40% fraction of inspired oxygen (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).

If 72 hours or more after infusion, consider dexamethasone 10 mg IV every 12‑24 hours.

If less than 72 hours after infusion, administer 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, maximise 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.

Fever, 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, escalate tocilizumab and corticosteroid use as per Grade 2.

Grade 4

Life-threatening symptoms.

Requirements for ventilator support or continuous veno‑venous haemodialysis (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 as per Grade 2.

a Lee et al 2014.

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

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 (see section 4.8).

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.

Table 2. Neurologic toxicity (NT) including ICANS grading and management guidance

Neurologic toxicity grade including presenting symptomsa

Corticosteroids and anti-seizure medication

Grade 1 *

Mild or asymptomatic.

or

ICE score 7-9b

or

Depressed level of consciousnessc: awakens spontaneously.

Start non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.

If 72 hours or more after infusion, observe.

If less than 72 hours after infusion, dexamethasone 10 mg IV every 12 to 24 hours for 2-3 days.

Grade 2 *

Moderate.

or

ICE score 3-6b

or

Depressed level of consciousnessc: awakens to voice.

Start non-sedating, anti-seizure 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 corticosteroid 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 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 *

Severe or medically significant but not immediately life-threatening; hospitalisation or prolongation; disabling.

or

ICE score 0-2b

if ICE score is 0, but the patient is arousable (e.g., awake with global aphasia) and able to perform assessment.

or

Depressed level of consciousnessc: awakens only to tactile stimulus,

or seizuresc, either:

• any clinical seizure, focal or generalised, that resolves rapidly, or

• non-convulsive seizures on EEG that resolve with intervention,

or raised ICPc: focal/local oedema on neuroimaging.

Start non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.

Dexamethasone 10 to 20 mg IV every 8 to 12 hours. Corticosteroids 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 oedema 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 *

Life-threatening.

or

ICE scoreb 0

or

Depressed level of consciousnessc, either:

• patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or

• stupor or coma,

or seizuresc, either:

• life-threatening prolonged seizure (> 5 min), or

• repetitive clinical or electrical seizures without return to baseline in between,

or motor findingsc:

• deep focal motor weakness such as hemiparesis or paraparesis,

or, raised ICP/cerebral oedemac, with signs/symptoms such as:

• diffuse cerebral oedema on neuroimaging, or

• decerebrate or decorticate posturing, or

• cranial nerve VI palsy, or

• papilledema, or

• Cushing's triad.

Start non-sedating, anti-seizure 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 oedema 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.

EEG=Electroencephalogram; ICE=Immune effector cell-associated encephalopathy; ICP=Intracranial pressure.

* Grading per NCI CTCAE or ASTCT/ICANS

a Management is determined by the most severe event, not attributable to any other cause.

b If patient is arousable and able to perform ICE Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (name 3 objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., “show me 2 fingers” or “close your eyes and stick out your tongue” = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points.

c Attributable to no other cause.

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 (see section 4.8). 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 (see section 4.8) 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 (see section 5.1).

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. (see section 4.2).

Prolonged cytopenias

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Breyanzi (see section 4.8). 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 (see section 4.8). 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.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed in humans.

Monoclonal antibodies directed against the epidermal growth factor receptor (anti-EGFR mabs)

Long-term persistence of CAR T-cells may be affected by the subsequent use of anti-EGFR mabs however, there is limited information available on the clinical use of anti-EGFR mabs in patients treated with Breyanzi.

Live vaccines

The safety of immunisation with live viral vaccines during or following treatment with Breyanzi has not been studied. As a precautionary measure, vaccination with live 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.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Pregnancy status for women of child-bearing potential should be verified using a pregnancy test prior to starting treatment with Breyanzi.

See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.

There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with Breyanzi.

Pregnancy

There are no data from the use of lisocabtagene maraleucel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted to assess whether it can cause foetal harm when administered to a pregnant woman (see section 5.3).

It is not known if lisocabtagene maraleucel has the potential to be transferred to the foetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause foetal toxicity, including B-cell lymphocytopenia. Therefore, Breyanzi is not recommended for women who are pregnant, or for women of childbearing potential not using contraception. Pregnant women should be advised on the potential risks to the foetus. Pregnancy after Breyanzi therapy should be discussed with the treating physician.

Assessment of immunoglobulin levels and B-cells in newborns of mothers treated with should be considered.

Breast-feeding

It is unknown whether lisocabtagene maraleucel is excreted in human milk or transferred to the breast-feeding child. Women who are breast-feeding should be advised of the potential risk to the breast-fed child.

Fertility

There are no data on the effect of lisocabtagene maraleucel on fertility.

4.7. Effects on ability to drive and use machines

Breyanzi may have major influence on the ability to drive and use machines.

Due to the potential for neurologic events, including altered mental status or seizures with Breyanzi, patients receiving Breyanzi should refrain from driving or operating heavy or potentially dangerous machines for at least 4 weeks after Breyanzi infusion, or longer at the physician's discretion.

4.8. Undesirable effects

Summary of the safety profile

LBCL

Patients who received one prior line of therapy for LBCL

The adverse reactions described in this section were characterised in 177 patients infused with Breyanzi from 3 pooled studies TRANSFORM [BCM-003], PILOT [017006], and TRANSCEND WORLD [JCAR017-BCM-001, Cohort 2].

The most common adverse reactions of any grade were neutropenia (71%), anaemia (45%), CRS (45%) and thrombocytopenia (43%).

The most common serious adverse reactions were CRS (12%), neutropenia (3%), bacterial infectious disorders (3%), infection with an unspecified pathogen (3%), thrombocytopenia (2%), febrile neutropenia (2%), pyrexia (2%), aphasia (2%), headache (2%), confusional state (2%), pulmonary embolism (2%), anaemia (1%), upper gastrointestinal haemorrhage (1%) and tremor (1%).

The most common Grade 3 or higher adverse reactions included neutropenia (68%), thrombocytopenia (33%), anaemia (31%), lymphopenia (17%), leukopenia (17%), febrile neutropenia (5%) and bacterial infections (5%).

Patients who received two or more prior lines of therapy for LBCL

The adverse reactions described in this section were characterised in 384 patients infused with Breyanzi from 4 pooled studies (TRANSCEND [017001], TRANSCEND WORLD [JCAR017-BCM-001, Cohort 1, 3 and 7], PLATFORM [JCAR017-BCM-002] and OUTREACH [017007].

The most common adverse reactions of any grade were neutropenia (68%), anaemia (45%), CRS (38%), fatigue (37%) and thrombocytopenia (36%).

The most common serious adverse reactions were CRS (18%), infection with an unspecified pathogen (6%), pyrexia (4%), encephalopathy (4%), febrile neutropenia (4%), neutropenia (3%), thrombocytopenia (3%), aphasia (3%), bacterial infectious disorders (3%), tremor (3%), confusional state (3%), anaemia (2%) and hypotension (2%).

The most common Grade 3 or higher adverse reactions included neutropenia (64%), anaemia (34%), thrombocytopenia (29%), leukopenia (25%), lymphopenia (9%), infection with an unspecified pathogen (8%) and febrile neutropenia (8%).

FL

The adverse reactions described in this section were characterised in 130 patients infused with Breyanzi from study TRANSCEND‑FL (FOL-001).

The most common adverse reactions of any grade were neutropenia (68%), CRS (58%), anaemia (40%), headache (29%), thrombocytopenia (29%) and constipation (21%).

The most common serious adverse reactions were CRS (9%), aphasia (4%), febrile neutropenia (3%), pyrexia (2%) and tremor (2%).

The most common Grade 3 or higher adverse reactions included neutropenia (61%), leukopenia (12%), lymphopenia (12%), thrombocytopenia (12%) and anaemia (10%).

MCL

The adverse reactions described in this section were characterised in 88 patients infused with Breyanzi from study TRANSCEND‑MCL Cohort [017001].

The most common adverse reactions of any grade were CRS (61%), neutropenia (59%), anaemia (44%), fatigue (35%), thrombocytopenia (30%), and headache (23%).

The most common serious adverse reactions were CRS (24%), confusional state (6%), pyrexia (3%), mental status changes (2%), encephalopathy (2%), upper respiratory tract infection (2%), and pleural effusion (2%).

The most common Grade 3 or higher adverse reactions included neutropenia (56%), anaemia (38%), thrombocytopenia (25%), hypophosphataemia (9%), and leukopenia (7%).

Tabulated list of adverse reactions

The frequencies of adverse reactions are based on pooled data from 7 studies (TRANSCEND [017001], including LBCL and MCL Cohorts, TRANSCEND WORLD [JCAR017-BCM-001, cohort 1, 2, 3 and 7], PLATFORM [JCAR017-BCM-002], OUTREACH [017007], TRANSFORM [BCM-003], PILOT [017006] and TRANSCEND‑FL (JCAR017-FOL-001), in 779 adult patients and from post-marketing reports who received a dose of lisocabtagene maraleucel. The adverse reaction frequencies from clinical studies are based on all-cause adverse event frequencies, where a proportion of the events for an adverse reaction may have other causes.

Adverse reactions reported are presented below. These reactions are presented by MedDRA system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), and uncommon (≥ 1/1,000 to < 1/100) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3: Adverse drug reactions identified with Breyanzi

System Organ Class (SOC)

Frequency

Adverse reaction

Infections and infestationsa

Very common

Infections - pathogen unspecified

Common

Bacterial infectious disorders

Viral infectious disorders

Fungal infectious disorders

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Uncommon

Secondary malignancy of T-cell origin

Blood and lymphatic system disorders

Very common

Neutropenia

Anaemia

Thrombocytopenia

Leukopenia

Lymphopenia

Common

Febrile neutropenia

HypofibrinogenaemiaW

Uncommon

Pancytopenia

Immune system disorders

Very common

Cytokine release syndrome

Common

HypogammaglobulinaemiaV

Uncommon

Haemophagocytic lymphohistiocytosis

Metabolism and nutrition disorders

Common

Hypophosphataemia

Uncommon

Tumour lysis syndrome

Psychiatric disorders

Very common

Insomnia

Common

Deliriumb

Anxiety

Nervous system disorders

Very common

Headachec

Encephalopathyd

Dizzinesse

Tremorf

Common

Aphasiag

Peripheral neuropathyh

Visual disturbancei

Ataxiaj

Taste disorderk

Cerebellar syndromel

Uncommon

Cerebrovascular disorderm

Seizuren

Paresiso

Brain oedema

Not Known

Immune effector cell-associated neurotoxicity syndrome*

Cardiac disorders

Very common

Tachycardia

Common

Arrhythmiap

Uncommon

Cardiomyopathy

Vascular disorders

Very common

Hypotension

Common

Hypertension

Thrombosisq

Respiratory, thoracic and mediastinal disorders

Very common

Cough

Common

Dyspnoear

Pleural effusion

Hypoxia

Uncommon

Pulmonary oedema

Gastrointestinal disorders

Very common

Nausea

Diarrhoea

Constipation

Abdominal pain

Vomiting

Common

Gastrointestinal haemorrhages

Skin and subcutaneous tissue disorders

Very common

Rash

Renal and urinary disorders

Common

Acute kidney injuryt

General disorders and administration site conditions

Very common

Fatigue

Pyrexia

Oedemau

Common

Chills

Injury, poisoning and procedural complications

Common

Infusion related reaction

* Event was not systematically collected in clinical trials.

a Infections and infestations are grouped per MedDRA high level group term

b Delirium includes agitation, delirium, delusion, disorientation, hallucination, hallucination visual, irritability, restlessness

c Headache includes headache, migraine, ophthalmic migraine, sinus headache

d Encephalopathy includes amnesia, cognitive disorder, confusional state, depersonalisation/ derealisation disorder, depressed level of consciousness, disturbance in attention, encephalopathy, flat affect, lethargy, leukoencephalopathy, loss of consciousness, memory impairment, mental impairment, mental status changes, paranoia, somnolence, stupor

e Dizziness includes dizziness, dizziness postural, presyncope, syncope

f Tremor includes essential tremor, intention tremor, resting tremor, tremor

g Aphasia includes aphasia, disorganised speech, dysarthria, dysphonia, slow speech, speech disorder

h Peripheral neuropathy includes, demyelinating polyneuropathy, hyperaesthesia, hypoaesthesia, hyporeflexia, loss of proprioception, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensory neuropathy, sensory loss, carpal tunnel syndrome

i Visual disturbance includes blindness, blindness unilateral, gaze palsy, mydriasis, nystagmus, vision blurred, visual field defect, visual impairment

j Ataxia includes ataxia, gait disturbance

k Taste disorder includes dysgeusia, taste disorder

l Cerebellar syndrome includes balance disorder, dysdiadochokinesis, dyskinesia, dysmetria, hand-eye coordination impaired

m Cerebrovascular disorder includes cerebral infarction, cerebral venous sinus thrombosis, embolic cerebral infarction, haemorrhage intracranial, transient ischaemic attack

n Seizure includes seizure, status epilepticus

o Paresis includes facial paralysis, facial paresis, vocal cord paralysis

p Arrhythmia includes arrhythmia, atrial fibrillation, atrioventricular block complete, atrioventricular block second degree,, supraventricular tachycardia, extrasystoles, ventricular extrasystoles, ventricular tachycardia

q Thrombosis includes deep vein thrombosis, embolism, pulmonary embolism, thrombosis, vena cava thrombosis, venous thrombosis, venous thrombosis limb

r Dyspnoea includes acute respiratory failure, dyspnoea, dyspnoea exertional, respiratory failure.

s Gastrointestinal haemorrhage includes gastric haemorrhage, gastric ulcer haemorrhage, gastrointestinal haemorrhage, haematochezia, lower gastrointestinal haemorrhage, melaena, rectal haemorrhage, upper gastrointestinal haemorrhage

t Acute kidney injury includes acute kidney injury, blood creatinine increased, glomerular filtration rate decreased, renal failure, renal impairment, renal injury

u Oedema includes face oedema, generalised oedema, localised oedema, oedema, oedema genital, oedema peripheral, peripheral swelling, scrotal oedema, swelling, swelling face.

v Hypogammaglobulinemia includes blood immunoglobulin A decreased, blood immunoglobulin G decreased, blood immunoglobulin M decreased, hypogammaglobulinaemia, immunoglobulins decreased.

w Hypofibrinogenaemia includes blood fibrinogen decreased, hypofibrinogenaemia

Description of selected adverse reactions

Cytokine release syndrome

For patients who received one prior line of therapy for LBCL, CRS occurred in 45% of patients, 1% of whom experienced Grade 3 CRS. 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) and the median duration of CRS was 4 days (range: 1 to 16 days).

The most common manifestations of CRS included pyrexia (44%), hypotension (12%), chills (5%), hypoxia (5%), tachycardia (4%), headache (3%) and fatigue (2%).

In LBCL clinical studies, 42 of 177 (24%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of Breyanzi. Eighteen (10%) patients received tocilizumab only, 24 (14%) patients received tocilizumab and a corticosteroid and no patients received corticosteroids only.

For patients who received two or more prior lines of therapy for LBCL, CRS occurred in 38% of patients, 2% of whom experienced Grade 3 or 4 (severe or life‑threatening) CRS. Among patients who died after receiving Breyanzi, 4 had ongoing CRS events at the time of death. The median time to onset was 4 days (range: 1 to 14 days) and the median duration was 5 days (range: 1 to 17 days).

The most common manifestations of CRS included pyrexia (38%), hypotension (18%), tachycardia (13%), chills (9%), and hypoxia (8%).

In LBCL clinical studies, 74 of 384 (19%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of Breyanzi. Thirty-seven (10%) patients received tocilizumab only, 29 (8%) received tocilizumab and a corticosteroid and 8 (2%) received corticosteroids only.

For patients who received Breyanzi for FL, CRS occurred in 58% of patients, 0.8% of whom experienced Grade 3 CRS. The median time to onset was 6 days (range: 1 to 17 days) and the median duration of CRS was 3 days (range: 1 to 10 days).

The most common manifestations of CRS included pyrexia (57%), hypotension (14%), chills (4%) hypoxia (2%) and tachycardia (0.8%).

In the FL clinical study, 33 of 130 (25%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of Breyanzi. Eighteen (14%) patients received tocilizumab only, 15 (12%) received tocilizumab and a corticosteroid and no patients received corticosteroids only. See section 4.4 for monitoring and management guidance.

For patients who received Breyanzi for MCL, CRS occurred in 61% of patients, 1% of whom experienced Grade 3 or 4 CRS. The median time to onset was 4 days (range: 1 to 10 days) and the median duration of CRS was 4 days (range: 1 to 14 days).

The most common manifestations of CRS included pyrexia (60%), hypotension (22%), hypoxia (11%) tachycardia (10%), chills (8%), headache (8%), nausea (3%), and dyspnoea (2%).

In the TRANSCEND-MCL Cohort, 24 of 88 (27%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of Breyanzi. 15 (17%) patients received tocilizumab only, 8 (9%) received tocilizumab and a corticosteroid and 1 (1%) patient received corticosteroids only.

See section 4.4 for monitoring and management guidance.

Neurologic adverse reactions

For patients who received one prior line of therapy for LBCL, CAR T-cell-associated neurologic toxicities, assessed by the investigator, occurred in 18% of patients receiving Breyanzi, including Grade 3 in 5% of patients. The median time to onset of the first event was 8 days (range: 1 to 63 days); 84% of all neurologic toxicities occurred within 2 weeks following Breyanzi infusion. The median duration of neurologic toxicities was 6 days (range: 1 to 89 days).

The most common neurologic toxicities included encephalopathy (10%), tremor (8%), aphasia (5%), dizziness (2%), and headache (1%).

For patients who received two or more prior lines of therapy for LBCL, CAR T-cell-associated neurologic toxicities assessed by the investigator occurred in 26% of patients receiving Breyanzi, including Grade 3 or 4 in 10% of patients. The median time to onset of the first event was 9 days (range: 1 to 66 days); 83% of all neurologic toxicities occurred within 2 weeks following Breyanzi infusion. The median duration of neurologic toxicities was 10 days (range: 1 to 84 days).

The most common neurologic toxicities included encephalopathy (18%), tremor (9%), aphasia (8%), delirium (7%), headache (4%), ataxia (3%) and dizziness (3%). Seizures (2%) and cerebral oedema (0.3%) have also occurred in patients treated with Breyanzi.

For patients who received Breyanzi for FL, CAR T-cell-associated neurologic toxicities, assessed by the investigator, occurred in 16% of patients receiving Breyanzi, including Grade 3 in 3% of patients. The median time to onset of the first event was 8 days (range: 4 to 16 days); 95% of all neurologic toxicities occurred within 2 weeks following Breyanzi infusion. The median duration of neurologic toxicities was 3 days (range: 1 to 17 days).

The most common neurologic toxicities included tremor (8%), aphasia (8%), encephalopathy (5%), delirium (4%) and headache (2%). See section 4.4 for monitoring and management guidance of neurologic toxicities.

For patients who received Breyanzi for MCL, CAR T‑cell-associated neurologic toxicities, assessed by the investigator, occurred in 31% of patients receiving Breyanzi, including Grade 3 or 4 in 9% of patients. The median time to onset of the first event was 8 days (range: 1 to 25 days); 100% of all neurologic toxicities occurred within the first 8 weeks following Breyanzi infusion. The median duration of neurologic toxicities was 5 days (range: 1 to 45 days).

The most common neurologic toxicities included encephalopathy (26%), tremor (7%), delirium (6%), aphasia (6%), headache (5%), and dizziness (3%). Seizures (1%) have occurred in patients treated with Breyanzi.

See section 4.4 for monitoring and management guidance of neurologic toxicities.

There have been reports of fatal events of ICANS in the post-marketing setting.

Febrile neutropenia and infections

Febrile neutropenia has been observed in 7% and 9% of patients who received Breyanzi for LBCL after one prior line of therapy and two or more prior lines of therapy respectivelyin 5% of patients who received Breyanzi for FL and in 6% of patients after receiving Breyanzi for MCL.

For patients who received one prior line of therapy for LBCL, infections (all grades) occurred in 25% of patients. Grade 3 or higher infections occurred in 10% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 3% of patients, bacterial infections occurred in 5%, and viral and fungal infections occurred in 2% and none of patients, respectively.

For patients who received two or more prior lines of therapy for LBCL, infections (all grades) occurred in 38% of patients. Grade 3 or higher infections occurred in 12% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 8% of patients, bacterial infections occurred in 4% of patients, viral and fungal infections occurred in 1% of patients.

For patients who received Breyanzi for FL, infections (all grades) occurred in 20% of patients. Grade 3 occurred in 5% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 4% of patients, bacterial infections occurred in 2% of patients, viral and fungal infections occurred in 1% and none of patients, respectively.

For patients who received Breyanzi for MCL, infections (all grades) occurred in 35% of patients. Grade 3 or higher occurred in 15% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 6% of patients, bacterial infections occurred in 5% of patients, viral and fungal infections occurred in 5% and 1% of patients, respectively.

Opportunistic infections (all grades) have been observed in 2% of the 177 patients treated with Breyanzi who received one prior line of therapy for LBCL, with Grade 3 or higher opportunistic infections having occurred in 0.6% of patients. Opportunistic infections (all grades) have been observed in 3% of the 384 patients treated with Breyanzi who received two or more prior lines of therapy for LBCL, with Grade 3 or higher opportunistic infections having occurred in 1% of patients. Opportunistic infections (all grades) have been observed in 0.8% of the 130 patients treated with Breyanzi who received Breyanzi for FL, with no Grade 3 or higher opportunistic infections observed. Opportunistic infections (all grades) have been observed in 1% of the 88 patients who received Breyanzi for MCL, all of which were Grade 3 or higher.

Two fatal infections were reported from the 177 patients treated with Breyanzi who received one prior line of therapy for LBCL. Four fatal infections were reported from the 384 patients treated with Breyanzi who received two or more prior lines of therapy for LBCL among pooled LBCL studies. Of these, 1 was reported as a fatal opportunistic infection. No fatal infections were reported in the 130 patients treated with Breyanzi for FL. Two fatal infections were reported in the 88 patients treated with Breyanzi for MCL.

See section 4.4 for monitoring and management guidance.

Prolonged cytopenias

For patients who received one prior line of therapy for LBCL, Grade 3 or higher cytopenias present at Day 35 following Breyanzi administration, occurred in 35% of patients, and included thrombocytopenia (28%), neutropenia (26%), and anaemia (9%).

Of the 177 total patients treated in TRANSFORM, PILOT, and TRANSCEND WORLD (Cohort 2) who had respectively Day 35 and Day 29 laboratory findings of Grade 3-4 thrombocytopenia (n = 50) or Grade 3- 4 neutropenia (n = 46) or Grade 3-4 anaemia (n = 15), for whom follow-up laboratory cytopenia results were available, the median time (min, max) to resolution (cytopenia recovering to Grade 2 or less) was as follows in days: thrombocytopenia 32 days (4, 309); neutropenia 32 days (8, 339); and anaemia 22 days (4, 64).

For patients who received two or more prior lines of therapy for LBCL, Grade 3 or higher cytopenias present at Day 29 following Breyanzi administration, occurred in 38% of patients, and included thrombocytopenia (31%), neutropenia (21%) and anaemia (7%).

Of the 384 total patients treated in TRANSCEND, TRANSCEND WORLD (Cohort 1, 3, and 7), PLATFORM, and OUTREACH who had Day 29 laboratory findings of Grade 3-4 thrombocytopenia (n = 117) or Grade 3- 4 neutropenia (n = 80) or Grade 3-4 anaemia (n = 27), for whom follow-up laboratory cytopenia results were available, the median time (min, max) to resolution (cytopenia recovering to Grade 2 or less) was as follows in days: thrombocytopenia 30 days (2, 329); neutropenia 29 days (3, 337); and anaemia 15 days (3, 78).

For patients who received Breyanzi for FL, Grade 3 or higher cytopenias present at Day 29 following Breyanzi administration, occurred in 22% of patients, and included thrombocytopenia (15%), neutropenia (15%) and anaemia (5%). See section 4.4 for monitoring and management guidance.

Of the 130 total patients treated in TRANSCEND ‑FL who had Day 29 laboratory findings of Grade 3‑4 thrombocytopenia (n = 19) or Grade 3- 4 neutropenia (n = 20) or Grade 3-4 anaemia (n = 6), for whom follow-up laboratory cytopenia results were available, the median time (min, max) to resolution (cytopenia recovering to Grade 2 or less) was as follows in days: thrombocytopenia 36 days (16, 694); neutropenia 30 days (5, 110); and anaemia 36 days (8, 64).

For patients who received Breyanzi for MCL, Grade 3 or higher cytopenias present at Day 29 following Breyanzi administration, occurred in 40% of patients, and included thrombocytopenia (32%), neutropenia (24%) and anaemia (5%).

Of the 88 total patients treated in the TRANSCEND-MCL Cohort who had Day 29 laboratory findings of Grade 3‑4 thrombocytopenia (n = 28) or Grade 3‑4 neutropenia (n = 21) or Grade 3‑4 anaemia (n = 4), for whom follow-up laboratory cytopenia results were available, the median time (min, max) to resolution (cytopenia recovering to Grade 2 or less) was as follows in days: thrombocytopenia 30 days (5, 302); neutropenia 30 days (8, 275); and anaemia 18 days (9, 32).

See section 4.4 for monitoring and management guidance.

Hypogammaglobulinaemia

For patients who received one prior line of therapy for LBCL, adverse events of hypogammaglobulinemia occurred in 7% of patients. For patients who received two or more prior line of therapy for LBCL, adverse events of hypogammaglobulinaemia occurred in 11% of patients. For patients who received Breyanzi for FL, adverse events of hypogammaglobulinaemia occurred in 2% of patients. For patients who received Breyanzi for MCL, adverse events of hypogammaglobulinaemia occurred in 7% of patients. See section 4.4 for monitoring and management guidance.

Immunogenicity

Breyanzi has the potential to induce antibodies against this medicinal product. Humoral immunogenicity of Breyanzi was measured by determination of anti‑CAR antibody pre- and post-administration. In patients who received one prior line of therapy for LBCL (TRANSFORM, PILOT and TRANSCEND WORLD, cohort 2), pre-existing anti-therapeutic antibodies (ATAs) were detected in 0.6% (1/172) of patients, and treatment-induced ATAs were detected in 19% (32/172) of patients. In the pooled studies for patients who received two or more prior lines of therapy for LBCL (TRANSCEND and TRANSCEND WORLD, cohort's 1 and 3), pre-existing ATAs were detected in 9% (29/309) of patients, and treatment-induced or treatment-boosted ATAs were detected in 15% (46/304) of patients. In patients who received Breyanzi for FL (TRANSCEND-FL), pre-existing anti-therapeutic antibodies (ATAs) were detected in 1.6% (2/124) of patients, and treatment-induced or treatment-boosted ATAs were detected in 26.8% (33/123) of patients. In patients who received Breyanzi for MCL (TRANSCEND-MCL Cohort), pre-existing ATAs were detected in 13% (11/88) of patients, and treatment-induced or treatment-boosted ATAs were detected in 20% (17/86) of patients. The relationships between ATA status and efficacy, safety or pharmacokinetics were not conclusive due to the limited number of patients with ATAs at the study level.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No data from clinical studies are available regarding overdose of Breyanzi