Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of safety profile
The adverse reactions (ARs) described in this section were identified from the pivotal clinical trial GO29781 in patients treated at the recommended dose (n=218). Patients had follicular lymphoma (41.3%), diffuse large B-cell lymphoma/transformed follicular lymphoma (40.4%) mantle cell lymphoma (11.5%), Richter’s transformation (6.4%), and other histologies (0.5%). The median number of cycles of Lunsumio received was 8 (range 1 -17), 37% of patients received 8 cycles, and 15% received more than 8 cycles up to 17 cycles.

The most common adverse reactions (≥ 20%) observed were cytokine release syndrome, neutropenia, pyrexia, hypophosphatemia and headache. The most common serious adverse reactions (≥ 2%) observed included cytokine release syndrome (CRS) (21% by ASTCT grading system), pyrexia (5%), and pneumonia (3%). Nine of 218 patients (4.1%) discontinued Lunsumio due to an adverse event.
CRS was the only adverse reaction that led to discontinuation in more than one patient (2 patients [0.9%]).

Tabulated list of adverse reactions

The adverse reactions are listed below by MedDRA system organ class (SOC) and categories of frequency. Frequency categories 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 the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 4 Adverse reactions occurring in patients treated with Lunsumio 
System organ class / preferred term or
All grades                   Grade 3 – 4 adverse reaction

Infections and infestations
Upper respiratory tract infection                       Common                        Common 
Urinary tract infection                                 Common                        Common 
Pneumonia                                               Common                        Common 
Neoplasms benign, malignant and unspecified (including cysts and polyps) 
Tumour flare                                            Common                        Common 
Blood and lymphatic system disorders

Neutropenia1                                          Very common                  Very common 
Anaemia                                               Very common                     Common 
Thrombocytopenia2                                     Very common                     Common 
Febrile neutropenia                                     Common                        Common 
Haemophagocytic lymphohistiocytosis5                   Uncommon                     Uncommon 

System organ class / preferred term or
All grades                 Grade 3 – 4 adverse reaction

Immune system disorders

Cytokine release syndrome3                         Very common                   Common 
Metabolism and nutrition disorders

Hypophosphataemia                                  Very common                Very common 
Hypokalaemia                                       Very common                   Common 
Hypomagnesaemia                                    Very common                   Very rare 
Tumour lysis syndrome                               Uncommon                    Uncommon 
Nervous system disorders

Headache                                           Very common                  Uncommon 
Immune effector cell-associated
Common                      Very rare neurotoxicity syndrome4,5

Gastrointestinal disorders
Diarrhoea                                          Very common                   Very rare 
Skin and subcutaneous tissue disorders

Rash                                               Very common                  Uncommon 
Pruritus                                           Very common                   Very rare 
Dry skin                                           Very common                   Very rare 
General disorders and administration site conditions

Pyrexia                                            Very common                   Common 
Chills                                             Very common                  Uncommon 
Investigations

Alanine aminotransferase, increased                Very common                   Common 
Aspartate aminotransferase, increased                Common                      Common 1
Neutropenia includes neutropenia and neutrophil count decreased
2
Thrombocytopenia includes thrombocytopenia and platelet count decreased 3
By American Society for Transplant and Cellular Therapy
4
Consistent with the medical concept of ICANS according to American Society for Transplant and Cellular Therapy and includes confusional state, ICANS, lethargy, encephalopathy, depressed level of consciousness, and memory impairment
5
The frequency calculation is based on additional clinical studies



Description of selected adverse reactions

Cytokine release syndrome (CRS)
CRS (ASTCT grading system) of any grade occurred in 39% (86/218) of patients, with grade 2 occurring in 14%, grade 3 occurring in 2.3%, and grade 4 occurring in 0.5% of patients treated with Lunsumio. The one patient with the grade 4 event was a patient with FL in the leukemic phase who also experienced concurrent TLS.

CRS of any grade occurred in 15% of patients after the Cycle 1, Day 1 dose; 5% after the Cycle 1, Day 8 dose; 33% after the Cycle 1, Day 15 dose, 5% occurred in patients after the Cycle 2 and 1% in Cycles 3 and beyond. The median time to CRS onset from the start of administration in Cycle 1 Day 1 was 5 hours (range: 1-73 hours), Cycle 1 Day 8 was 28 hours (range: 5-81 hours), Cycle 1 Day 15 was 25 hours (range: 0.1-391 hours), and Cycle 2 Day 1 was 46 hours (range: 12-82 hours). CRS resolved in all patients, and the median duration of CRS events was 3 days (range 1-29 days).

Of the 86 patients that experienced CRS, the most common signs and symptoms of CRS included pyrexia (98%), chills (36%), hypotension (35%), tachycardia (24%), hypoxia (22%) and headache (16%).

Tocilizumab and/or corticosteroids were used to manage a CRS event in 16% of patients: 6% received tocilizumab alone, 6% received corticosteroids alone, and 4% received both tocilizumab and corticosteroids. Among the 10% of patients who received tocilizumab (with or without a corticosteroid), 86% received only one dose of tocilizumab, with no more than two doses of tocilizumab administered for a single CRS event. In patients experiencing Grade 2 CRS, 48% of patients were treated with symptomatic management without corticosteroids or tocilizumab, 18% received tocilizumab alone, 21% received corticosteroids alone, and 12% received both corticosteroids and tocilizumab. Patients with grade 3 or grade 4 CRS received tocilizumab, corticosteroids, vasopressors and/or oxygen supplementation. Three percent of patients experienced hypotension and/or hypoxia without fever following Lunsumio administration; 2% of patients received tocilizumab and/or corticosteroids in the absence of fever.

Hospitalizations due to CRS occurred in 21% of patients and the median duration of hospitalization was 5 days (range 0-30 days).

Neutropenia

Neutropenia of any grade occurred in 28% of patients, including 24% Grade 3-4 events. The median time to onset of first neutropenia/neutrophil count decreased events was 48 days (range: 1-280 days), with median duration of 8 days (range: 1-314 days). Of the 60 patients who had neutropenia/neutrophil count decreased events 68% received treatment G-CSF to treat the events.

Serious infections

Serious infections of any grade occurred in 17% of patients. 1.8% of patients experienced serious infections concurrently with grade 3-4 neutropenia. The median time to onset of first serious infection was 50 days (range: 1-561 days), with median duration of 12 days (range: 2-174 days). Grade 5 events occurred in 0.9% of patients, which included pneumonia and sepsis.

Immune Effector Cell-Associated Neurotoxicity Syndrome

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) occurred in 2.1% (20/949) of patients, 19 patients had Grade 1-2 events and 1 patient had Grade 3 event. The majority of events occurred during the first cycle of treatment. The majority of cases resolved. The median time to onset from initial dose was 17 days (range: 1 to 48 days). The median duration was 3 days (range: 1-20 days).


Tumour flare
Tumour flare (including pleural effusion and tumour inflammation) occurred in 4% of patients, which included 1.8% grade 2 and 2.3% grade 3 events. The median time to onset was 13 days (range 5-84 days), and median duration was 10 days (range 1-77 days).

Tumour Lysis Syndrome (TLS)

TLS occurred in 0.9% of patients, concurrent with CRS. One patient with follicular lymphoma was in the leukemic phase who experienced Grade 4 TLS. TLS onset was on days 2 and 24, and resolved within 4 and 6 days, respectively.

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/