Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
Mantle cell lymphoma
The safety data described in this section reflect exposure to Tecartus in ZUMA-2, a Phase 2 study in which a total of 82 patients with relapsed/refractory MCL received a single dose of CAR-positive viable T cells (2 × 106 or 0.5 × 106 anti-CD19 CAR T cells/kg) based on a recommended dose which was weight-based.

The most significant and frequently occurring adverse reactions were CRS (91%), infections (55%) and encephalopathy (51%).

Serious adverse reactions occurred in 56% of patients. The most common serious adverse reactions included encephalopathy (26%), infections (28%) and cytokine release syndrome (15%).

Grade 3 or higher adverse reactions were reported in 67% of patients. The most common Grade 3 or higher non-haematological adverse reactions included infections (34%) and encephalopathy (24%).
The most common Grade 3 or higher haematological adverse reactions included neutropenia (99%), leukopenia (98%), lymphopenia (96%), thrombocytopenia (65%) and anaemia (56%).

Acute lymphoblastic leukaemia
The safety data described in this section reflect exposure to Tecartus in ZUMA-3, a Phase 1/2 study in which a total of 100 patients with relapsed/refractory B-cell precursor ALL received a single dose of CAR-positive viable T cells (0.5 × 106, 1 × 106, or 2 × 106 anti-CD19 CAR T cells/kg) based on a recommended dose which was weight based.

The most significant and frequently occurring adverse reactions were CRS (91%), encephalopathy (57%), and infections (41%).

Serious adverse reactions occurred in 70% of patients. The most common serious adverse reactions included CRS (25%), infections (22%) and encephalopathy (21%).

Grade 3 or higher adverse reactions were reported in 76% of patients. The most common Grade 3 or higher non-haematological adverse reactions included infections (27%), CRS (25%) and encephalopathy (22%).

Tabulated list of adverse reactions

Adverse reactions described in this section were identified in a total of 182 patients exposed to Tecartus in two multi-centre pivotal clinical studies, ZUMA-2 (n=82) and ZUMA-3 (n=100). These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3      Adverse drug reactions identified with Tecartus

System Organ Class (SOC)             Frequency                Adverse reactions Infections and infestations
Very common              Unspecified pathogen infections
Bacterial infections
Fungal infections
Viral Infections
Blood and lymphatic system disorders
Very common                Leukopeniaa
Neutropeniaa
Lymphopeniaa
Thrombocytopeniaa
Anaemiaa
Febrile neutropenia
Common                   Coagulopathy
Immune system disorders
Very common              Cytokine Release Syndromeb
Hypogammaglobulinaemia
Common                   Hypersensitivity
Haemophagocytic lymphohistiocytosis
Metabolism and nutrition disorders
Very common              Hypophosphataemiaa
Decreased appetite
Hypomagnesaemia
Hyperglycaemiaa
Common                   Hypoalbuminemiaa
Dehydration
Psychiatric disorders
Very common              Delirium
Anxiety
Insomnia
Nervous system disorders
Very common              Encephalopathy
Tremor
Headache
Immune effector cell-associated neurotoxicity syndrome (ICANSb, c)
Aphasia
Dizziness
Neuropathy
Common                   Seizure
Ataxia
Increased intracranial pressure
Cardiac disorders
Very common              Tachycardias
Bradycardias
Common                   Non-ventricular arrhythmias
System Organ Class (SOC)                 Frequency                             Adverse reactions Vascular disorders
Very common                           Hypotension
Hypertension
Haemorrhage
Common                                    Thrombosis
Respiratory, thoracic and mediastinal disorders
Very common                               Cough
Dyspnoea
Pleural effusion
Hypoxia
Common                                Respiratory failure
Pulmonary oedema
Gastrointestinal disorders
Very common                           Nausea
Diarrhoea
Constipation
Abdominal pain
Vomiting
Oral pain
Common                                Dry mouth
Dysphagia
Skin and subcutaneous tissue disorders
Very common                                Rash
Skin disorder
Musculoskeletal and connective tissue disorders
Very common                                Musculoskeletal pain
Motor dysfunction
Renal and urinary disorders
Very common                               Renal insufficiency
Common                                    Urine output decreased
General disorders and administration site conditions
Very common                               Oedema
Fatigue
Pyrexia
Pain
Chills
Common                                Infusion related reaction
Eye Disorders
Common                                Visual impairment
Investigations
Very common                           Alanine aminotransferase increaseda Blood uric acid increaseda
Aspartate aminotransferase increaseda
Hypocalcaemiaa
Hyponatraemiaa
Direct bilirubin increaseda
Hypokalaemiaa
Common                                Bilirubin increaseda
Only cytopenias that resulted in (i) new or worsening clinical sequelae or (ii) that required therapy or (iii) adjustment in current therapy are included in Table 3.
a Frequency based on Grade 3 or higher laboratory parameter.
b See section Description of selected adverse reactions.
c The frequency of ICANS has been estimated from events reported in the post-marketing setting. ZUMA-2 data cutoff: 24 
July 2021; ZUMA-3 data cutoff: 23 July 2021


Description of selected adverse reactions from ZUMA-2 and ZUMA-3 (n=182) , and from post marketing reporting

Cytokine release syndrome
CRS occurred in 91% of patients. Twenty percent (20%) of patients experienced Grade 3 or higher (severe or life-threatening) CRS. The median time to onset was 3 days (range: 1 to 13 days) and the median duration was 9 days (range: 1 to 63 days). Ninety-seven percent (97%) of patients recovered from CRS.

The most common signs or symptoms associated with CRS among the patients who experienced CRS included pyrexia (94%), hypotension (64%), hypoxia (32%), chills (31%), tachycardia (27%), sinus tachycardia (23%), headache (22%), fatigue (16%), and nausea (13%). Serious adverse reactions that may be associated with CRS included hypotension (22%), pyrexia (15%), hypoxia (9%), tachycardia (3%), dyspnoea (2%) and sinus tachycardia (2%). See section 4.4 for monitoring and management guidance.

Neurologic events and adverse reactions
Neurologic adverse reactions occurred in 69% of patients. Thirty-two percent (32%) of patients experienced Grade 3 or higher (severe or life-threatening) adverse reactions. The median time to onset was 7 days (range: 1 to 262 days). Neurologic events resolved for 113 out of 125 patients (90.4%) with a median duration of 12 days (range: 1 to 708 days). Three patients had ongoing neurologic events at the time of death, including one patient with the reported event of serious encephalopathy and another patient with the reported event of serious confusional state. The remaining unresolved neurologic events were Grade 2. Ninety-three percent of all treated patients experienced the first CRS or neurological event within the first 7 days after Tecartus infusion.

The most common neurologic adverse reactions including ICANS represented tremor (32%), confusional state (27%), encephalopathy (27%), aphasia (21%), and agitation (11%). Serious adverse reactions including encephalopathy (15%), aphasia (6%), confusional state (5%) and serious cases of cerebral oedema which may become fatal have occurred in patients treated with Tecartus. See section 4.4 for monitoring and management guidance.

Febrile neutropenia and infections
Febrile neutropenia was observed in 12% of patients after Tecartus infusion. Infections occurred in 87 of the 182 patients treated with Tecartus in ZUMA-2 and ZUMA-3. Grade 3 or higher (severe, life-threatening or fatal) infections occurred in 30% of patients including unspecified pathogen, bacterial, fungal and viral infections in 23%, 8%, 2% and 4% of patients respectively. See section 4.4 for monitoring and management guidance.

Prolonged cytopenias
Cytopenias are very common following prior lymphodepleting chemotherapy and Tecartus therapy.

Prolonged (present on or beyond Day 30 or with an onset at Day 30 or beyond) Grade 3 or higher cytopenias occurred in 48% of patients and included neutropenia (34%), thrombocytopenia (27%) and anaemia (15%). See section 4.4 for management guidance.

Hypogammaglobulinaemia
Hypogammaglobulinaemia occurred in 12% of patients. Grade 3 or higher hypogammaglobulinemia occurred in 1% of patients. See section 4.4 for management guidance.

Immunogenicity

The immunogenicity of Tecartus has been evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection of binding antibodies against FMC63, the originating antibody of the anti-CD19 CAR. To date, no anti-CD19 CAR T-cell antibody immunogenicity has been observed in MCL patients. Based on an initial screening assay, 17 patients in ZUMA-2 at any time point tested positive for antibodies; however, a confirmatory orthogonal cell-based assay demonstrated that all 17 patients in ZUMA-2 were antibody negative at all time points tested. Based on an initial screening assay, 16 patients in ZUMA-3 tested positive for antibodies at any timepoint. Among patients with evaluable samples for confirmatory testing, two patients were confirmed to be antibody-positive after treatment. One of the two patients had a confirmed positive antibody result at Month 6. The second patient had a confirmed positive antibody result at retreatment Day 28 and Month 3. There is no evidence that the kinetics of initial expansion, CAR T-cell function and persistence of Tecartus, or the safety or effectiveness of Tecartus, were altered in these patients.

Secondary malignancies

There have been cases of the following adverse effect(s) reported after treatment with other CAR T- cell products, which might also occur after treatment with Tecartus: secondary malignancy of T-cell origin.

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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il