Adverse reactions : תופעות לוואי

4.8   Undesirable effects
Summary of the safety profile

The safety data described in this section reflect the exposure to Abecma in the KarMMa, CRB-401 and KarMMa-3 studies in which 409 patients with relapsed and refractory multiple myeloma received Abecma. In KarMMa (N = 128) and CRB-401 (N = 56), the median duration of follow-up (from Abecma infusion to data cutoff date) was 20.8 months. In KarMMa-3 (N = 225), the median duration of follow-up was 29.3 months.

The most common adverse reactions (≥ 20%) included CRS (84.6%), neutropenia (80.0%), anaemia (63.6%), thrombocytopenia (55.0%), infections - pathogen unspecified (43.8%), hypophosphataemia (33.3%), diarrhoea (33.0%), leukopenia (32.8%), hypokalaemia (32.0%), fatigue (29.8%), nausea (28.1%), lymphopenia (26.9%), pyrexia (24.7%), infections - viral (23.2%), headache (22.5%), hypocalcaemia (22.0%), hypomagnesaemia (21.3%), and arthralgia (20.0%); other common adverse events occurring at lower frequency and considered clinically important included hypotension (18.6%), upper respiratory tract infection (15.6%), hypogammaglobulinemia (13.7%), febrile neutropenia (11.2%), pneumonia (11.0%), tremor (5.6%), somnolence (5.6%), encephalopathy (3.4%), syncope (3.2%) and aphasia (2.9%).

Serious adverse reactions occurred in 57.2% of patients. The most common serious adverse reactions (≥ 5%) included CRS (10.3%) and pneumonia (7.1%); other serious adverse events occurring at lower frequency and considered clinically important include febrile neutropenia (4.2%), pyrexia (3.7%), neutropenia (2.7%), sepsis (2.7%), confusional state (2.4%), haemophagocytic lymphohistiocytosis (1.7%), thrombocytopenia (1.5%), encephalopathy (1.5%), dyspnoea (1.5%), seizure (1.0%), mental status changes (1.0%), hypoxia (0.7%) and disseminated intravascular coagulation (0.5%).

The most common Grade 3 or 4 adverse reactions (≥ 5%) were neutropenia (77.3%), anaemia (50.9%), thrombocytopenia (42.5%), leukopenia (31.5%), lymphopenia (25.9%), hypophosphataemia (19.8%), infections - pathogen unspecified (15.2%), febrile neutropenia (10.5%), infections - viral (7.6%), pneumonia (6.8%), hypertension (6.6%), hypocalcaemia (5.6%) and infections - bacterial (5.4%).

Grade 3 or 4 adverse reactions were more often observed within the initial 8 weeks post-infusion (93.2%) compared to after 8 weeks post-infusion (58.1%). The most frequently reported Grade 3 or 4 adverse reactions reported within the first 8 weeks after infusion were neutropenia (75.8%),
anaemia (47.4%), thrombocytopenia (38.6%), leukopenia (30.3%) lymphopenia (23.5%) and hypophosphataemia (18.3%).



Tabulated list of adverse reactions

Table 3 summarises the adverse reactions observed in the clinical studies of 409 patients treated with Abecma within the allowed dose range of 150 to 540 x 106 CAR-positive T cells (see Table 6 in section 5.1 for the corresponding dose range of CAR-positive viable T cells in KarMMa) and from post-marketing reports. Adverse 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), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3.        Adverse reactions observed in patients treated with Abecma 
System organ class                     Adverse reaction                  All grades frequency Infections and               Infections – bacterial                     Very common infestationsa                Infections – viral                         Very common Infections – pathogen unspecified          Very common
Infections – fungal                        Common
Neoplasms benign,            Secondary malignancy of T-cell origin      Rare malignant and unspecified
(including cysts and polyps)
Blood and lymphatic       Neutropenia                                   Very common system disorders          Leukopenia                                    Very common Thrombocytopenia                              Very common
Febrile neutropenia                           Very common
Lymphopenia                                   Very common
Anaemia                                       Very common
Disseminated intravascular coagulation        Common
Immune system disorders Cytokine release syndrome                       Very common Hypogammaglobulinaemia                        Very common
Haemophagocytic lymphohistiocytosis*          Common
Metabolism and nutrition     Hypophosphataemia                          Very common disorders                    Hypokalaemia                               Very common Hyponatraemia                              Very common
Hypocalcaemia                              Very common
Hypoalbuminaemia                           Very common
Decreased appetite                         Very common
Hypomagnesaemia                            Very common
Psychiatric disorders        Insomnia                                   Very common Deliriumb                                  Common



System organ class                            Adverse reaction                           All grades frequency Nervous system disorders          Encephalopathyc                                      Very common Headache*                                            Very common
Dizzinessd                                           Very common
Aphasiae                                             Common
Ataxiaf                                              Common
Motor dysfunctiong                                   Common
Tremor                                               Common
Seizure                                              Common
Hemiparesis                                          Uncommon
Immune effector cell-associated                      Uncommon neurotoxicity syndrome**
Cardiac disorders                 Tachycardia*                                         Very common Atrial fibrillation*                                 Common
Vascular disorders                Hypertension                                         Very common Hypotension*h                                        Very common
Respiratory, thoracic, and        Dyspnoea                                             Very common mediastinal disorders             Cough                                                Very common Pulmonary oedema                                     Common
Hypoxia*                                             Common
Gastrointestinal disorders        Vomiting                                             Very common Diarrhoea                                            Very common
Nausea                                               Very common
Constipation                                         Very common
Gastrointestinal haemorrhagei                        Common
Musculoskeletal and               Arthralgia                                           Very common connective tissue                 Myalgia                                              Common disorders
General disorders and             Pyrexia*                                             Very common administration site               Fatigue*j                                            Very common conditions                        Oedemak                                              Very common Chills*                                              Very common
Asthenia                                             Common

Investigations                    Alanine aminotransferase increased                   Very common Aspartate aminotransferase increased                 Very common
Blood alkaline phosphatase increased                 Common
C-reactive protein increased*                        Common
* Event that has been reported as a manifestation of CRS.
** Event was not systematically collected in clinical trials.
a Infections and infestations system organ class adverse events are grouped by pathogen type and selected clinical syndromes.
b Delirium includes delirium, disorientation, agitation, hallucination, restlessness.
c Encephalopathy includes amnesia, bradyphrenia, cognitive disorder, confusional state, depressed level of consciousness,  disturbance in attention, dyscalculia, dysgraphia, encephalopathy, incoherent, lethargy, memory impairment, mental impairment, mental status changes, metabolic encephalopathy, neurotoxicity, somnolence, stupor.
d Dizziness includes dizziness, presyncope, syncope, vertigo.
e Aphasia includes aphasia, dysarthria, slow speech, and speech disorder.
f Ataxia includes ataxia, dysmetria, gait disturbance.
g Motor dysfunction includes motor dysfunction, muscular spasms, muscular weakness, parkinsonism.
h Hypotension includes hypotension, orthostatic hypotension.



i Gastrointestinal haemorrhage includes gastrointestinal haemorrhage, gingival bleeding, haematochezia, haemorrhoidal haemorrhage, melaena, mouth haemorrhage.
j Fatigue includes fatigue, malaise.
k Oedema includes oedema, oedema peripheral, face oedema, generalised oedema, peripheral swelling.


Description of selected adverse reactions

Cytokine release syndrome
In the pooled studies (KarMMa, CRB-401 and KarMMa-3), CRS occurred in 84.6% of patients receiving Abecma. Grade 3 or higher CRS (Lee et al, 2014) occurred in 5.1% of patients, with fatal (Grade 5) CRS reported in 0.7% of patients. The median time-to-onset, any grade, was 1 day (range: 1 to 17) and the median duration of CRS was 4 days (range: 1 to 63).

The most common manifestations of CRS (≥ 10%) included pyrexia (82.6%), hypotension (29.1%), tachycardia (24.7%), chills (18.8%), hypoxia (15.9%), headache (11.2%) and increased C-reactive protein (10.5%). Grade 3 or higher events that may be observed in association with CRS included atrial fibrillation, capillary leak syndrome, hypotension, hypoxia and HLH/MAS.

Of the 409 patients, 59.7% of patients received tocilizumab; 37.2% received a single dose while 22.5% received more than 1-dose of tocilizumab for treatment of CRS. Overall, 22.7% of patients received at least 1 dose of corticosteroids for treatment of CRS. Of the 92 patients in KarMMa and CRB-401 who received the target dose of 450 x 106 CAR-positive T cells, 54.3% of patients received tocilizumab and 22.8% received at least 1 dose of corticosteroids for treatment of CRS. Of the 225 patients in KarMMa-3 who received Abecma infusion, 71.6% of patients received tocilizumab and 28.4% received at least 1 dose of corticosteroids for the treatment of CRS. See section 4.4 for monitoring and management guidance.

Neurologic adverse reactions including ICANS
In the pooled studies, of the 409 patients, independent of investigator attribution of neurotoxicity, the most frequent neurologic or psychiatric adverse reactions (≥ 5%) included headache (22.5%), dizziness (12.5%), confusional state (11.0%), insomnia (10.3%), anxiety (5.9%), tremor (5.6%), and somnolence (5.6%). Other neurological adverse reactions occurring at a lower frequency and considered clinically important included encephalopathy (3.4%) and aphasia (2.9%).

Neurotoxicity identified by the investigators, which was the primary method of assessing CAR T cell-associated neurotoxicity in the KarMMa and KarMMa-3 studies, occurred in 57 (16.1%) of the 353 patients receiving Abecma, including Grade 3 or 4 in 3.1% of patients (with no Grade 5 events).
The median time to onset of the first event was 3 days (range: 1 to 317; one patient developed encephalopathy at Day 317 as a result of worsening pneumonia and Clostridium difficile colitis).
The median duration was 3 days (range: 1 to 252; one patient developed neurotoxicity [highest Grade 3] 43 days after ide-cel infusion which resolved after 252 days). Overall, 7.1% of patients received at least 1 dose of corticosteroid for treatment of CAR T cell-associated neurotoxicity.

In KarMMa, across the target dose levels, 7.8% of patients received at least 1 dose of corticosteroid for treatment of CAR T cell-associated neurotoxicity, while at the target dose of 450 x 106 CAR- positive T cells, 14.8% of patients received at least 1 dose of corticosteroids.

In KarMMa-3, across all patients who received Abecma infusion at the target dose range, 6.7% of patients received at least 1 dose of corticosteroid for treatment of CAR T cell-associated neurotoxicity.

Of the 353 patients in the KarMMa and KarMMa-3 studies, the most common manifestations of investigator identified neurotoxicity (≥ 2%) included confusional state (8.5%), encephalopathy (3.4%), somnolence (2.8%), aphasia (2.5%), tremor (2.3%), disturbance in attention (2.0%) and dysgraphia (2.0%). See section 4.4 for monitoring and management guidance.


Febrile neutropenia and infections
In the pooled studies, infections occurred in 62.8% of patients. Grade 3 or 4 infections occurred in 23.2% of patients. Grade 3 or 4 infections with an unspecified pathogen occurred in 15.2%, viral infections in 7.6%, bacterial infections in 4.6% and fungal infections in 1.2% of patients. Fatal infections of unspecified pathogen were reported in 2.0 % of patients, 0.7% of patients had fatal fungal or viral infection and 0.2% of patients had fatal bacterial infection. See section 4.4 for monitoring and management guidance.

Febrile neutropenia (Grade 3 or 4) was observed in 10.8% of patients after Abecma infusion. Febrile neutropenia may be concurrent with CRS. See section 4.4 for monitoring and management guidance.

Prolonged cytopenia
Patients may exhibit prolonged cytopenias following lymphodepleting chemotherapy and Abecma infusion. In the pooled studies, 38.2% of the 395 patients who had Grade 3 or 4 neutropenia and 71.3% of the 230 patients who had Grade 3 or 4 thrombocytopenia during the first month following Abecma infusion had not resolved by last assessment during the first month. Among the 151 patients with neutropenia not resolved by month 1, 88.7% recovered from Grade 3 or 4 neutropenia with a median time to recovery from Abecma infusion of 1.9 months. Of the 164 patients with thrombocytopenia not resolved by month 1, 79.9% recovered from Grade 3 or 4 thrombocytopenia with the median time to recovery of 2.0 months. See section 4.4 for monitoring and management guidance.

Hypogammaglobulinaemia
Hypogammaglobulinaemia was reported in 13.7% of patients treated with Abecma in the pooled studies with a median time to onset of 90 days (range 1 to 326). See section 4.4 for monitoring and management guidance.

Immunogenicity

Abecma has the potential to induce anti-CAR antibodies. In clinical studies, humoral immunogenicity of Abecma was measured by determination of anti-CAR antibody in serum pre- and post- administration. In the pooled studies of KarMMa, CRB-401 and KarMMa-3, 3.2% of patients tested positive for pre-infusion anti-CAR antibodies and post-infusion anti-CAR antibodies were detected in 56.2% of the patients. There is no evidence that the presence of pre-existing or post-infusion anti- CAR antibodies impact the cellular expansion, safety or effectiveness of Abecma.

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/