Table 3.
Overview of statistically significant RORs (HLT level, organized by SOC) and notoriety based on package insert and RMPs
| Disproportionalities in RG3 | Notoriety from package insert | Important potential risks from RMP | |||||||
|---|---|---|---|---|---|---|---|---|---|
| HLTs | Axi-cel | Tisa-cel | PTsa (N) | Axi-cel | PTsa (N) | Tisa-cel | |||
| N | ROR (95% CI) | N | ROR (95% CI) | ||||||
| Blood and lymphatic system disorders | |||||||||
| Neutropenias | 119 | 1.7 (1.4–2) | 65 | 2 (1.5–2.6) | Neutropenia (64) | Yes | Neutropenia (38) | Yes | |
| Febrile neutropenia (56) | Yes | Febrile neutropenia (28) | Yes | ||||||
| Marrow depression and hypoplastic anemias | 110 | 2.6 (2.1–3.2) | 94 | 5.2 (4.2–6.5) | Pancytopenia (62) | Yes | Cytopenia (69) | Yes | |
| Cytopenia (31) | Yes | Pancytopenia (20) | Yes | ||||||
| Coagulopathies | 17 | 2.6 (1.6–4.3) | 27 | 9.9 (6.6–14.8) | Disseminated intravascular coagulation (12) | Linked | Coagulopathy (16) | Yes | |
| Coagulopathy (4) | Yes | Disseminated intravascular coagulation (12) | Yes | ||||||
| Coagulation factor deficiencies | – | – | 5 | 36.5 (13.3–99.9) | Hypofibrinogenaemia (5) | No | |||
| Thrombocytopenias | – | – | 39 | 2.9 (2.1–4.1) | Thrombocytopenia (38) | Yes | |||
| Heparin-induced thrombocytopenia (1) | No | ||||||||
| Lymphatic system disorders NEC | – | – | 10 | 2.4 (1.2–4.5) | Lymphadenopathy (6) | No | |||
| Abdominal lymphadenopathy (2) | No | ||||||||
| Spleen disorders | – | – | 6 | 4 (1.7–9.1) | Splenic hemorrhage (2) | No | |||
| Splenomegaly (2) | No | ||||||||
| Cardiac disorders | |||||||||
| Rate and rhythm disorders NEC | 94 | 6.4 (5.1–8) | 28 | 3.7 (2.5–5.5) | Tachycardia (82) | Yes | Tachycardia (26) | Yes | |
| Bradycardia (11) | No | Bradycardia (4) | No | ||||||
| Supraventricular arrhythmias | 53 | 2.6 (1.9–3.4) | – | – | Atrial fibrillation (37) | Yes | |||
| Sinus tachycardia (11) | Yes | ||||||||
| Ventricular arrhythmias and cardiac arrest | 38 | 3.9 (2.7–5.4) | 12 | 2.5 (1.4–4.5) | Cardiac arrest (19) | Yes | Cardiac arrest (7) | No | |
| Ventricular tachycardia (9) | Yes | Ventricular tachycardia (2) | No | ||||||
| Pulseless electrical activity (2) | No | ||||||||
| Heart failures NEC | 31 | 1.6 (1.1–2.3) | – | – | Cardiorenal syndrome (24) | Linked | |||
| Cardiac failure (4) | Yes | ||||||||
| Cardiomyopathies | 10 | 2.3 (1.2–4.4) | – | – | Cardiomyopathy (6) | No | |||
| Stress cardiomyopathy (4) | No | ||||||||
| Pericardial disorders NEC | – | – | 5# | 2.7 (1.1–6.7) | Pericardial effusion (5) | No | |||
| Congenital disorders | |||||||||
| Congenital disorder NEC | – | – | 4# | 5.9 (2.1–16.1) | Aplasia (4) | No | |||
| Eye disorders | |||||||||
| Pupil disorders | – | – | 5 | 15.3 (6–39.1) | Pupils unequal (2) | Linked | |||
| Pupil fixed (2) | Linked | ||||||||
| Gastrointestinal disorders | |||||||||
| Gastrointestinal ulcers and perforation, site unspecified | 5# | 2.9 (1.2–7.3) | – | – | Gastrointestinal perforation (4) | No | |||
| Diverticular perforation (1) | No | ||||||||
| Gastrointestinal vascular occlusion and infarction | 4# | 4.9 (1.7–13.7) | – | – | Intestinal ischemia (4) | No | |||
| Peritoneal and retroperitoneal hemorrhages | 3# | 6.6 (1.9–22) | – | – | Hemoperitoneum (1) | No | |||
| Retroperitoneal hematoma (1) | No | ||||||||
| Retroperitoneal hemorrhage (1) | No | ||||||||
| Abdominal findings abnormal | – | – | 3# | 6.3 (1.9–20.3) | Abdominal mass (3) | No | |||
| Hepatobiliary disorders | |||||||||
| Hepatic failure and associated disorders | – | – | 16# | 2.5 (1.1–5.7) | Hepatic failure (16) | No | |||
| Cholestasis and jaundice | – | – | 8 | 2.8 (1.3–5.7) | Hyperbilirubinemia (4) | No | |||
| Cholestasis (2) | No | ||||||||
| Immune system disorders | |||||||||
| Immune and associated conditions NEC | 850 | 92.7 (82.1–104.6) | 333 | 44.8 (38.2–52.7) | Cytokine release syndrome (841) | Yes | Cytokine release syndrome (330) | Yes |
Both CAR-T cells GvHD |
| Hemophagocytic lymphohistiocytosis (22) | Yes | Hemophagocytic lymphohistiocytosis (14) | Yes | ||||||
| Immunodeficiency disorders NEC | 24 | 2.2 (1.4–3.4) | 120 | 35.7 (28.7–44.4) | Hypogammaglobulinemia (20) | Yes | Hypogammaglobulinemia (117) | Yes | |
| Immunodeficiency (3) | Linked | Immunodeficiency (3) | Linked | ||||||
| Infections and infestations | |||||||||
| Sepsis, bacteremia, viremia, and fungemia NEC | 78 | 1.6 (1.3–2.1) | 34 | 1.5 (1.1–2.2) | Sepsis (36) | Linked | Sepsis (17) | Linked | |
| Septic shock (22) | Linked | Bacteremia (8) | Linked | ||||||
| Clostridia infections | 22 | 2.6 (1.7–4) | 10 | 2.5 (1.3–4.7) | Clostridium difficile infection (11) | Linked | Clostridium difficile infection (8) | Linked | |
| Clostridium difficile colitis (9) | Linked | Clostridium difficile colitis (2) | Linked | ||||||
| Staphylococcal infections | 19 | 2.1 (1.3–3.4) | 27 | 7.1 (4.8–10.6) | Staphylococcal infection (12) | Linked | Staphylococcal infection (24) | Linked | |
| Staphylococcal bacteremia (4) | Linked | Staphylococcal bacteremia (3) | Linked | ||||||
| Pseudomonal infections | 12 | 3.7 (2–6.7) | 7 | 4.6 (2.1–9.9) | Pseudomonas infection (5) | Linked | Pseudomonas infection (6) | Linked | |
| Pseudomonal bacteremia (3) | Linked | Pneumonia pseudomonal (1) | Linked | ||||||
| Polyomavirus infections | 10# | 2.1 (1.1–4.1) | 7 | 3.3 (1.5–7) | Progressive multifocal leukoencephalopathy (7) | Linked | Bk virus infection (7) | Linked | |
| Jc virus infection (4) | Linked | ||||||||
| Enterococcal infections | 9 | 2.9 (1.5–5.7) | 16 | 12.2 (7.2–20.6) | Enterococcal infection (5) | Linked | Enterococcal infection (15) | Linked | |
| Urinary tract infection enterococcal (2) | Linked | Enterococcal sepsis (1) | Linked | ||||||
| Escherichia infections | – | – | 6# | 2.6 (1.1–6) | Escherichia infection (3) | Linked | |||
| Escherichia urinary tract infection (2) | Linked | ||||||||
| Klebsiella infections | – | – | 5 | 4.1 (1.6–10) | Klebsiella infection (4) | Linked | |||
| Pneumonia Klebsiella (1) | Linked | ||||||||
| Viral infections NEC | – | – | 17 | 2.6 (1.6–4.2) | Viral upper respiratory tract infection (7) | Linked | |||
| Viral sinusitis (5) | Linked | ||||||||
| Rhinoviral infections | – | – | 21 | 71.8 (41.5–124.1) | Rhinovirus infection (21) | Linked | |||
| Adenoviral infections | – | – | 5 | 12.4 (4.9–31.3) | Adenovirus infection (5) | Linked | |||
| Coronavirus infections | – | – | 6# | 2.8 (1.2–6.3) | Coronavirus infection (5) | Linked | |||
| COVID-19 (1) | Linked | ||||||||
| Respiratory syncytial viral infections | – | – | 5 | 7.6 (3–19) | Respiratory syncytial virus infection (11) | Linked | |||
| Fungal infections NEC | – | – | 22 | 3.8 (2.5–6) | Fungal infection (10) | Yes | |||
| Mucormycosis (5) | Linked | ||||||||
| Candida infections | – | – | 11 | 2.5 (1.4–4.6) | Candida infection (11) | Linked | |||
| Systemic candida (1) | Linked | ||||||||
| Aspergillus infections | – | – | 10 | 4.9 (2.5–9.2) | Aspergillus infection (5) | Linked | |||
| Bronchopulmonary aspergillosis (5) | Linked | ||||||||
| Metabolism and nutrition disorders | |||||||||
| Sodium imbalance | 15 | 2.7 (1.6–4.6) | – | – | Hyponatremia (11) | Yes | |||
| Hypernatremia (4) | No | ||||||||
| Electrolyte imbalance NEC | – | – | 8 | 3 (1.5–6.2) | Tumor lysis syndrome (8) | Yes |
Axi-cel Tumor lisis syndrome |
||
| Metabolic acidoses (excluding diabetic acidoses) | – | – | 12 | 8.2 (4.5–14.9) | Lactic acidosis (9) | No | |||
| Metabolic acidosis (3) | No | ||||||||
| Mixed acid-base disorders | – | – | 6 | 25 (10.3–60.7) | Acidosis (6) | No | |||
| Neoplasms benign, malignant, and unspecified (including cysts and polyps) | |||||||||
| Neoplasms malignant site unspecified NEC | – | – | 186 | 18.7 (15.6–22.3) | Malignant neoplasm progression (170) | No | |||
| Second primary malignancy (15) | No |
Both CAR-T cells Secondary malignancies |
|||||||
| Nervous system disorders | |||||||||
| Nervous system disorders NEC | 528 | 76.3 (66.6–87.3) | 122 | 17.4 (14.1–21.3) | Neurotoxicity (516) | Yes | Neurotoxicity (112) | Yes | |
| Nervous system disorder (13) | Yes | Nervous system disorder (9) | Yes | ||||||
| Encephalopathies toxic and metabolic | 147 | 60.2 (47.5–76.3) | 25 | 11.2 (7.4–17.1) | Immune effector cell-associated neurotoxicity syndrome (139) | Linked | Immune effector cell-associated neurotoxicity syndrome (23) | Linked | |
| Toxic encephalopathy (5) | Linked | Toxic encephalopathy (2) | Linked | ||||||
| Encephalopathies NEC | 137 | 23.4 (19–28.7) | 28 | 7.4 (5–11) | Encephalopathy (134) | Yes | Encephalopathy (22) | Yes | |
| Hypoxic-ischemic encephalopathy (2) | Linked | Leukoencephalopathy (5) | No | ||||||
| Cortical dysfunction NEC | 116 | 31 (24.6–39.1) | 26 | 10.2 (6.8–15.4) | Aphasia (103) | Yes | Aphasia (22) | Yes | |
| Dysgraphia (19) | Linked | Dysgraphia (5) | No | ||||||
| Disturbances in consciousness NEC | 93 | 2.5 (2–3.1) | 44 | 2.5 (1.8–3.5) | Somnolence (70) | Yes | Depressed level of consciousness (28) | Yes | |
| Syncope (10) | Yes | Somnolence (15) | Yes | ||||||
| Depressed level of consciousness (10) | Yes | ||||||||
| Lethargy (10) | Linked | ||||||||
| Tremor (excluding congenital) | 74 | 6.9 (5.3–8.8) | 26 | 4.8 (3.2–7.2) | Tremor (72) | Yes | Tremor (26) | Yes | |
| Intention tremor (2) | Linked | ||||||||
| Seizures and seizure disorders NEC | 43 | 3.9 (2.8–5.3) | 15 | 2.8 (1.6–4.7) | Seizure (29) | Yes | Seizure (10) | Yes | |
| Status epilepticus (9) | Linked | Status epilepticus (5) | Yes | ||||||
| Memory loss (excluding dementia) | 40 | 3.1 (2.2–4.3) | – | – | Memory impairment (34) | Yes | |||
| Amnesia (6) | Linked | ||||||||
| Speech and language abnormalities | 26 | 3.9 (2.6–5.8) | – | – | Dysarthria (12) | Linked | |||
| Speech disorder (11) | Yes | ||||||||
| Mental impairment (excluding dementia and memory loss) | 18 | 2.8 (1.7–4.6) | – | – | Cognitive disorder (11) | Yes | |||
| Disturbance in attention (6) | Yes | ||||||||
| Increased intracranial pressure disorders | 11 | 4.7 (2.5–8.8) | 8 | 7.4 (3.6–15.2) | Brain oedema (10) | Linked | Brain edema (6) | Linked | |
| Intracranial pressure increased (1) | Linked | Intracranial pressure increased (2) | Linked | ||||||
| Encephalitis NEC | 3# | 7.5 (2.2–25.4) | – | – | Noninfective encephalitis (3) | No | |||
| Autonomic nervous system disorders | 3# | 9.3 (2.7–32) | – | – | Autonomic neuropathy (2) | No | |||
| Orthostatic intolerance (1) | No | ||||||||
| Generalized tonic-clonic seizures | – | – | 5 | 10.4 (4.1–26.1) | Generalized tonic-clonic seizure (5) | Linked | |||
| Central nervous system hemorrhages and cerebrovascular accidents | – | – | 17# | 1.6 (1–2.6) | Cerebrovascular accident (4) | Linked | |||
| Cerebral infarction (3) | Linked | ||||||||
| Embolic stroke (3) | Linked | ||||||||
| Paralysis and paresis (excluding cranial nerve) | – | – | 11 | 3.6 (1.9–6.6) | Hemiparesis (9) | No | |||
| Paraparesis (7) | No | ||||||||
| Myelitis (including infective) | – | – | 4 | 25.9 (8.7–76.7) | Noninfectious myelitis (2) | No | |||
| Myelitis transverse (2) | No | ||||||||
| Acute polyneuropathies | – | – | 3# | 7.2 (2.2–23.4) | Guillain–Barré syndrome (3) | No | |||
| Psychiatric disorders | |||||||||
| Confusion and disorientation | 136 | 9.2 (7.6–11.1) | 35 | 4.4 (3.1–6.2) | Confusional state (123) | Yes | Confusional state (30) | Yes | |
| Disorientation (39) | Yes | Disorientation (9) | Linked | ||||||
| Mental disorders NEC | 29 | 6.8 (4.6–10) | 16 | 7.8 (4.6–13) | Mental status changes (27) | Yes | Mental status changes (15) | Yes | |
| Mental disorder (2) | Linked | Mental disorder (1) | Linked | ||||||
| Deliria | 16 | 4.4 (2.6–7.4) | 11 | 6.5 (3.5–12.1) | Delirium (16) | Yes | Delirium (9) | Yes | |
| Intensive care unit delirium (1) | Linked | Intensive care unit delirium (2) | Linked | ||||||
| Thinking disturbances | 13 | 11 (6–20) | – | – | Bradyphrenia (10) | Linked | |||
| Tangentiality (2) | Linked | ||||||||
| Thinking abnormal (2) | Linked | ||||||||
| Communications disorders | 6 | 24.5 (9.3–64.7) | – | – | Communication disorder (5) | Linked | |||
| Mutism (1) | Linked | ||||||||
| Speech and language usage disturbances | 3# | 26.5 (6.6–106.2) | – | – | Disorganised speech (3) | Linked | |||
| Hallucinations (excluding sleep related) | – | – | 10 | 5.6 (2.9–10.7) | Hallucination (9) | No | |||
| Hallucination, visual (1) | No | ||||||||
| Renal and urinary disorders | |||||||||
| Bladder and urethral symptoms | 30 | 2.1 (1.5–3.1) | – | – | Incontinence (15) | No | |||
| Urinary incontinence (6) | No | ||||||||
| Nephropathies and tubular disorders NEC | – | – | 5# | 3.6 (1.4–8.9) | Nephropathy toxic (5) | Linked | |||
| Renal vascular and iscaemic conditions | – | – | 3# | 4.2 (1.3–13.3) | Renal tubular Necrosis (3) | Linked | |||
| Respiratory, thoracic, and mediastinal disorders | |||||||||
| Conditions associated with abnormal gas exchange | 64 | 9.1 (6.9–11.9) | 58 | 18.7 (14–24.9) | Hypoxia (64) | Yes | Hypoxia (57) | Yes | |
| Hypocapnia (1) | No | ||||||||
| Pneumothorax and pleural effusions NEC | 33 | 2.2 (1.5–3.1) | - | - | Pleural effusion (31) | Yes | |||
| Pneumothorax (2) | No | ||||||||
| Respiratory failures (excluding neonatal) | 27 | 2 (1.3–3) | 21 | 3.4 (2.2–5.4) | Respiratory failure (22) | Yes | Respiratory failure (15) | Yes | |
| Acute respiratory failure (6) | Yes | Acute respiratory failure (6) | Yes | ||||||
| Respiratory alkalosis (1) | Yes | ||||||||
| Lower respiratory tract signs and symptoms | – | – | 6# | 2.5 (1.1–5.7) | Pulmonary haemorrhage (4) | No | |||
| Pleuritic pain (1) | No | ||||||||
| Lung opacity (1) | No | ||||||||
| Vascular disorders | |||||||||
| Vascular hypotensive disorders | 156 | 6.4 (5.3–7.6) | 107 | 9.8 (7.9–12.2) | Hypotension (148) | Yes | Hypotension (107) | Yes | |
| Orthostatic hypotension (8) | Yes | Capillary leak syndrome (4) | Yes | ||||||
| Circulatory collapse and shock | 12 | 2.6 (1.4–4.7) | 8 | 3.8 (1.8–7.8) | Shock (7) | Linked | Shock (3) | Linked | |
| Shock haemorrhagic (2) | Linked | Circulatory collapse (3) | Linked | ||||||
Axi-cel axicabtagene ciloleucel, CI confidence interval, COVID-19 coronavirus disease 2019, GvHD graft vs host disease, HLT High-Level Term, NEC not elsewhere classified, PTs preferred terms, RMPs risk management plans, ROR reporting odds ratios, SOC System Organ Class, Tisa-cel tisagenlecleucel
aTwo PTs more frequent reported
Onco-hematological HLTs were not shown
Linked = event not reported in the package insert as a PT but linked to other listed events (e.g., shock and hypotension, sepsis and infection, disorientation and confusion, dysgraphia and other cortical dysfunctions such as dyscalculia). Other important potential risks reported in RMPs of tisa-cel were: new occurrence or exacerbation of an autoimmune disorder, hematological disorders (including aplastic anemia and bone marrow failure)