Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most common adverse reactions (≥ 20%) were cytokine release syndrome, neutropenia, anaemia, thrombocytopenia, and rash.

The most common serious adverse reactions reported in ≥ 2% of patients were cytokine release syndrome (22.1%), sepsis (4.1%), COVID-19 (3.4%), tumour flare (3.4%), COVID-19 pneumonia (2.8%), febrile neutropenia (2.1%), neutropenia (2.1%), and pleural effusion (2.1%).

Permanent discontinuation of Columvi due to an adverse reaction occurred in 5.5% of patients. The most common adverse reactions leading to permanent discontinuation of Columvi were COVID-19 (1.4%) and neutropenia (1.4%).


Tabulated list of adverse reactions

Adverse reactions occurring in relapsed or refractory DLBCL patients treated with Columvi monotherapy (n=145) in study NP30179 are listed in Table 5. Patients received a median of 5 cycles of Columvi treatment (range: 1 to 13 cycles).

The adverse reactions are listed by MedDRA system organ class and categories of frequency. The following categories of frequency have been used: 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).
Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 5. Adverse reactions reported in patients with relapsed or refractory DLBCL treated with Columvi monotherapy


System organ class Adverse reaction                        All grades              Grade 34 
Viral infections1                  Very common               Common*
Bacterial infections2                Common                  Common
Upper respiratory tract
Common                 Very rare** infections3
Infections and        Sepsis4                               Common                 Common* infestations          Lower respiratory tract
Common                 Very rare** infections5
Pneumonia                             Common                 Uncommon Urinary tract infection6              Common                 Uncommon Fungal infections7                    Common                 Very rare** Neoplasms benign,
malignant and
Tumour flare                         Very common                Common unspecified (incl cysts and polyps)
Neutropenia                          Very common             Very Common Blood and           Anaemia                              Very common               Common lymphatic system Thrombocytopenia                        Very common               Common disorders           Lymphopenia                            Common                  Common Febrile neutropenia8                   Common                  Common Immune system
Cytokine release syndrome9           Very common                Common disorders
Hypophosphataemia                    Very common                Common Hypomagnesaemia                      Very common               Very rare** Metabolism and      Hypocalcaemia                        Very common               Very rare** nutrition disorders Hypokalaemia                         Very common               Uncommon Hyponatraemia                          Common                   Common Tumour lysis syndrome                  Common                   Common Psychiatric
Confusional state                       Common                 Very rare** disorders
Headache                             Very common               Very rare** Nervous system      Somnolence                             Common                  Uncommon disorders           Tremor                                 Common                  Very rare** Myelitis10                            Uncommon                 Uncommon 

System organ class Adverse reaction                                   All grades                   Grade 34 
Constipation                              Very common                   Very rare** Diarrhoea                                 Very common                   Very rare** Gastrointestinal          Nausea                                    Very common                   Very rare** disorders                 Gastrointestinal
Common                       Common haemorrhage11
Vomiting                                     Common                     Very rare** Skin and subcutaneous       Rash12                                           Very common                     Common tissue disorders
General disorders and administration Pyrexia                                          Very common                   Very rare** site conditions
Alanine aminotransferase
Common                       Common increased
Aspartate aminotransferase
Common                       Common increased
Blood alkaline phosphatase
Investigations                                                         Common                       Common increased
Gamma-glutamyltransferase
Common                       Common increased
Blood bilirubin increased                           Common                     Uncommon Hepatic enzyme increased                            Common                      Common * Grade 5 reactions reported. See serious infections in Description of selected adverse reactions.
** No Grade 3-4 events were reported.
1 Includes COVID-19, COVID-19 pneumonia, herpes zoster, influenza, and ophthalmic herpes zoster.
2 Includes vascular device infection, bacterial infection, Campylobacter infection, biliary tract infection
 bacterial, urinary tract infection bacterial, Clostridium difficile infection, Escherichia infection, and peritonitis.
3 Includes upper respiratory tract infection, sinusitis, nasopharyngitis, chronic sinusitis, and rhinitis.
4
Includes sepsis and septic shock.
5 Includes lower respiratory tract infection and bronchitis.
6 Includes urinary tract infection and Escherichia urinary tract infection.
7 Includes oesophageal candidiasis and oral candidiasis.
8 Includes febrile neutropenia and neutropenic infection.
9 Based on ASTCT consensus grading (Lee 2019).
10 Myelitis occurred concurrently with CRS.
11
Includes gastrointestinal haemorrhage, large intestinal haemorrhage, and gastric haemorrhage.
12 Includes rash, rash pruritic, rash maculo-papular, dermatitis, dermatitis acneiform, dermatitis exfoliative,  erythema, palmar erythema, pruritis, and rash erythematous.

Description of selected adverse reactions
Neurologic Toxicity
Among 145 patients who received Columvi, the most frequent neurologic toxicities of any grade were headache (10%), peripheral neuropathy (8%), dizziness or vertigo (7%), and mental status changes (4.8%, including confusional state, cognitive disorder, disorientation, somnolence, and delirium).
Grade 3 or higher neurologic adverse reactions occurred in 2.1% of patients and included somnolence, delirium, and myelitis. Cases of ICANS of any grade occurred in 4.8% of patients.
Cytokine release syndrome
In study NP30179, any grade CRS (by ASTCT criteria) occurred in 67.6% of patients, with Grade 1 CRS being reported in 50.3% of patients, Grade 2 CRS in 13.1% patients, Grade 3 CRS in 2.8% of patients and Grade 4 CRS in 1.4% of patients. CRS occurred more than once in 32.4% (47/145) of patients; 36/47 patients experienced multiple Grade 1 CRS events only. There were no fatal cases of CRS. CRS resolved in all patients except one. One patient discontinued treatment due to CRS.

In patients with CRS, the most common manifestations of CRS included pyrexia (99.0%), tachycardia (25.5%), hypotension (23.5%), chills (14.3%) and hypoxia (12.2%). Grade 3 or higher events associated with CRS included hypotension (3.1%), hypoxia (3.1%), pyrexia (2.0%) and tachycardia (2.0%).

CRS of any grade occurred in 54.5% of patients following the first 2.5 mg dose of Columvi at Cycle 1 Day 8 with median time to onset (from start of infusion) of 12.6 hours (range: 5.2 to 50.8 hours) and median duration of 31.8 hours (range: 0.5 to 316.7 hours); in 33.3% of patients following the 10 mg dose at Cycle 1 Day 15 with median time to onset of 26.8 hours (range: 6.7 to 125.0 hours) and median duration of 16.5 hours (range: 0.3 to 109.2 hours); and in 26.8% of patients following the 30 mg dose at Cycle 2 with median time to onset of 28.2 hours (range: 15.0 to 44.2 hours) and median duration of 18.9 hours (range: 1.0 to 180.5 hours). CRS was reported in 0.9% of patients at Cycle 3 and in 2% of patients beyond Cycle 3.

Grade  2 CRS occurred in 12.4% of patients following the first Columvi dose (2.5 mg) with median time to onset of 9.7 hours (range: 5.2 to 19.1 hours) and median duration of 50.4 hours (range: 6.5 to 316.7 hours). Following Columvi 10 mg dose at Cycle 1 Day 15, the incidence of Grade  2 CRS decreased to 5.2% of patients with median time to onset of 26.2 hours (range: 6.7 to 144.2 hours) and median duration of 30.9 hours (range: 3.7 to 227.2 hours). Grade  2 CRS following Columvi 30 mg dose at Cycle 2 Day 1 occurred in one patient (0.8%) with time to onset of 15.0 hours and duration of 44.8 hours. No Grade  2 CRS was reported beyond Cycle 2.

In 145 patients, 7 (4.8%) patients experienced elevated liver function tests (AST and ALT > 3  ULN and/or total bilirubin > 2  ULN) reported concurrently with CRS (n=6) or with disease progression (n=1).

Among the 25 patients who experienced Grade  2 CRS after Columvi, 22 (88.0%) received tocilizumab, 15 (60.0%) received corticosteroids and 14 (56.0%) received both tocilizumab and corticosteroids. Ten patients (40.0%) received oxygen. All 6 patients (24.0%) with Grade 3 or 4 CRS received a single vasopressor.

Hospitalisations due to patients experiencing CRS following Columvi administration occurred in 22.1% of patients and the reported median duration of hospitalisation was 4 days (range: 2 to 15 days).

Serious infections
In study NP30179, serious infections were reported in 15.9% of patients. The most frequent serious infections reported in ≥ 2% of patients were sepsis (4.1%), COVID-19 (3.4%), and COVID-19 pneumonia (2.8%). Infection-related deaths were reported in 4.8% of patients (due to sepsis, COVID-19 pneumonia and COVID-19). Four patients (2.8%) experienced serious infections concurrently with Grade 3 or 4 neutropenia.

Neutropenia
Neutropenia (including neutrophil count decreased) was reported in 40.0% of patients and severe neutropenia (Grade 3 or 4) was reported in 29.0% of patients. The median time to onset of the first neutropenia event was 29 days (range: 1 to 203 days). Prolonged neutropenia (lasting longer than 30 days) occurred in 11.7% of patients. The majority of patients with neutropenia (79.3%) were treated with G-CSF. Febrile neutropenia was reported in 3.4% of patients.


Tumour flare
Tumour flare was reported in 11.7% of patients, including Grade 2 tumour flare in 4.8% of patients and Grade 3 tumour flare in 2.8% of patients. Tumour flare was reported involving lymph nodes in the head and neck presenting with pain and involving lymph nodes in the thorax with symptoms of breathlessness due to development of pleural effusion. Most tumour flare events (16/17) occurred during Cycle 1, and no tumour flare events were reported beyond Cycle 2. The median time to onset of tumour flare of any grade was 2 days (range: 1 to 16 days), and the median duration was 3.5 days (range: 1 to 35 days).

Among the 11 patients who experienced Grade ≥ 2 tumour flare, 2 (18.2%) patients received analgesics, 6 (54.5%) patients received corticosteroids and analgesics including morphine derivatives, 1 ( 9.1%) patient received corticosteroids and anti-emetics, and 2 (18.2%) patients did not require treatment. All tumour flare events resolved except in one patient with a Grade ≥ 2 event. No patients discontinued treatment due to tumour flare.

Tumour lysis syndrome
TLS was reported in 2 patients (1.4%) and was Grade 3 in severity in both cases. The median time to onset of TLS onset was 2 days, and the median duration was 4 days (range: 3 to 5 days).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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 sideeffects.health.gov.il/