Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Bristol-Myers Squibb Pharma EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
Hypersensitivity to any of the excipients listed in section 6.1.
Contraindications of the lymphodepleting chemotherapy must be considered.
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.
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.
Due to the risks associated with Breyanzi treatment, infusion should be delayed if a patient has any of the following conditions:
In case of delayed Breyanzi infusion, see section 4.2.
Patients treated with Breyanzi must not donate blood, organs, tissues and cells for transplantation.
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).
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.
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). 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).
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 European Medicines Agency shortage catalogue, 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 4 weeks after infusion. Patients should be counselled to seek immediate medical attention should signs or symptoms of CRS occur at any time, and treated promptly.
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:
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 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) and 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). The most common neurologic symptoms included encephalopathy, tremor, aphasia, delirium, dizziness and headache (see section 4.8).
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 a least 4 weeks after infusion. Patients should be counselled to seek immediate medical attention should signs and symptoms of neurologic toxicity occur at any time, and treated promptly.
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:
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; hospitalization 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.
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, (e.g., HBV, human herpesvirus 6 [HHV-6]) 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).
Screening for HBV, HCV, and HIV should be performed before collection of cells for manufacturing. (see section 4.2).
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.
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.
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.
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.
Allergic reactions may occur with the infusion of Breyanzi. Serious hypersensitivity reactions including anaphylaxis, may be due to dimethyl sulfoxide.
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.
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.
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.
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.
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.
No interaction studies have been performed in humans.
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.
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.
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.
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.
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.
There are no data on the effect of lisocabtagene maraleucel on fertility.
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 8 weeks after Breyanzi infusion.
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%).
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%).
The frequencies of adverse reactions are based on pooled data from 6 studies (TRANSCEND 017001, TRANSCEND WORLD [JCAR017-BCM-001, cohort 1, 2, 3 and 7], PLATFORM [JCAR017-BCM-002], OUTREACH 017007, TRANSFORM [BCM-003], and PILOT 017006), in 561 adult patients and from post-marketing reports within the dose range of 44-120 × 106 CAR-positive viable T cells with R/R LBCL, defined as DLBCL, HGBCL, PMBCL and FL3B, 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), 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 Bacterial infectious disorders |
| Common | 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 Hypofibrinogenaemia | |
| Uncommon | Pancytopenia | |
| Immune system disorders | Very common | Cytokine release syndrome Hypogammaglobulinaemia |
| 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 Cerebrovascular disorder^m Seizuren | |
| Uncommon | Facial paralysis Brain oedema | |
| Not known | Immune effector cell-associated neurotoxicity syndrome* | |
| Cardiac disorders | Very common | Tachycardia |
| Common | Arrhythmia° | |
| Uncommon | Cardiomyopathy | |
| Vascular disorders | Very common | Hypotension |
| Common | Hypertension Thrombosisp | |
| Respiratory, thoracic and mediastinal disorders | Very common | Cough Dyspnoeaq |
| Common | Pleural effusion Hypoxia | |
| Uncommon | Pulmonary oedema | |
| Gastrointestinal disorders | Very common | Nausea Diarrhoea Constipation Abdominal pain Vomiting |
| Common | Gastrointestinal haemorrhager | |
| Skin and subcutaneous tissue disorders | Common | Rash |
| Renal and urinary disorders | Common | Acute kidney injurys |
| General disorders and administration site conditions | Very common | Fatigue Pyrexia Oedemat |
| 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, migraine with aura, 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
h Peripheral neuropathy includes demyelinating polyneuropathy, hyperaesthesia, hypoaesthesia, hyporeflexia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensory neuropathy, sensory loss
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 thrombosis, haemorrhage intracranial, transient ischaemic attack
n Seizure includes seizure, status epilepticus
° Arrhythmia includes arrhythmia, atrial fibrillation, atrioventricular block complete, atrioventricular block second degree, supraventricular tachycardia, ventricular tachycardia
p Thrombosis includes deep vein thrombosis, embolism, embolism venous, pulmonary embolism, thrombosis, vena cava thrombosis, venous thrombosis, venous thrombosis limb
q Dyspnoea includes acute respiratory failure, dyspnoea, dyspnoea exertional, respiratory failure.
r Gastrointestinal haemorrhage includes gastric haemorrhage, gastric ulcer haemorrhage, gastrointestinal haemorrhage, haematochezia, lower gastrointestinal haemorrhage, melaena, rectal haemorrhage, upper gastrointestinal haemorrhage
s Acute kidney injury includes acute kidney injury, blood creatinine increased, glomerular filtration rate decreased, renal failure, renal impairment, renal injury
t Oedema includes generalised oedema, localised oedema, oedema, oedema genital, oedema peripheral, peripheral swelling, scrotal oedema, swelling.
For patients who received one prior line of therapy for LBCL, CRS occurred in 45% of patients, 1% of whom experienced Grade 3 CRS (no fatal events). 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 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. There were no fatal events. 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 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. See section 4.4 for monitoring and management guidance.
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 (no fatal events). The median time to onset of the first event was 8 days (range: 1 to 63 days); 97% of all neurologic toxicities occurred within the first 8 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 (no fatal events). The median time to onset of the first event was 9 days (range: 1 to 66 days); 99% of all neurologic toxicities occurred within the first 8 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. 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 has been observed in 7% of patients after receiving Breyanzi who received one prior line of therapy for LBCL and 9% of patients after receiving Breyanzi who received two or more prior lines of therapy.
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.
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 1% 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.
No 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. See section 4.4 for monitoring and management guidance.
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 Day 35 laboratory findings of Grade 3-4 thrombocytopenia (n=50) or Grade 3-4 neutropenia (n=26) 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 31 days (4, 309); neutropenia 31 days (17, 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%). See section 4.4 for monitoring and management guidance.
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 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. See section 4.4 for monitoring and management guidance.
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% (1/169) of patients, and treatment-induced ATAs were detected in 4% (7/168) 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 16% (48/304) of patients. The relationships between ATA status and efficacy, safety or pharmacokinetics were not conclusive due to the limited number of patients with ATAs.
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 national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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