4.1. Therapeutic indications

Lunsumio as monotherapy is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.

4.2. Posology and method of administration

Lunsumio must only be administered under the supervision of a healthcare professional qualified in the use of anti-cancer therapies, in a setting with appropriate medical support to manage severe reactions such as cytokine release syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) (see below and section 4.4).

Posology

Prophylaxis and premedication

Lunsumio should be administered to well-hydrated patients.

Table 1 provides details on recommended premedication for CRS and infusion related reactions.

Table 1 Premedication to be administered to patients prior to Lunsumio infusion

Patients requiring premedication

Premedication

Administration

Cycles 1 and 2: all patients

Cycles 3 and beyond: patients who experienced any grade CRS with previous dose

Intravenous corticosteroids: dexamethasone 20 mg or methylprednisolone 80 mg

Complete at least 1 hour prior to Lunsumio infusion

Anti-histamine: 50‑100 mg diphenhydramine hydrochloride or equivalent oral or intravenous anti-histamine

At least 30 minutes prior to Lunsumio infusion

Anti-pyretic: 500‑1000 mg paracetamol

The recommended dose of Lunsumio for each 21 day‑cycle is detailed in Table 2.

Table 2 Dose of Lunsumio for patients with relapsed or refractory follicular lymphoma

Day of treatment

Dose of Lunsumio

Rate of infusion

Cycle 1

Day 1

1 mg

Infusions of Lunsumio in Cycle 1 should be administered over a minimum of 4 hours.

Day 8

2 mg

Day 15

60 mg

Cycle 2

Day 1

60 mg

If the infusions were well-tolerated in Cycle 1, subsequent infusions of Lunsumio may be administered over 2 hours.

Cycles 3 and beyond

Day 1

30 mg

Duration of treatment

Lunsumio should be administered for 8 cycles, unless a patient experiences unacceptable toxicity or disease progression.

For patients who achieve a complete response, no further treatment beyond 8 cycles is required. For patients who achieve a partial response or have stable disease in response to treatment with Lunsumio after 8 cycles, an additional 9 cycles of treatment (17 cycles total) should be administered, unless a patient experiences unacceptable toxicity or disease progression.

Delayed or missed dose

If any dose in cycle 1 is delayed for > 7 days, the previous tolerated dose should be repeated prior to resuming the planned treatment schedule.

If a dose interruption occurs between Cycles 1 and 2 that results in a treatment-free interval of ≥ 6 weeks, Lunsumio should be administered at 1 mg on Day 1, 2 mg on Day 8, then resume the planned Cycle 2 treatment of 60 mg on Day 15.

If a dose interruption occurs that results in a treatment-free interval of ≥ 6 weeks between any Cycles in Cycle 3 onwards, Lunsumio should be administered at 1 mg on Day 1, 2 mg on Day 8, then resume the planned treatment schedule of 30 mg on Day 15.

Dose modification

Patients who experience grade 3 or 4 reactions (e.g. serious infection, tumour flare, tumour lysis syndrome) should have treatment temporarily withheld until symptoms are resolved (see section 4.4).

Cytokine Release Syndrome

CRS should be identified based on clinical presentation (see section 4.4). Patients should be evaluated and treated for, other causes of fever, hypoxia, and hypotension, such as infections/sepsis. Infusion related reactions (IRR) may be clinically indistinguishable from manifestations of CRS. If CRS or IRR is suspected, patients should be managed according to the recommendations in Table 3.

Table 3 CRS grading1 and management

CRS grade

CRS management2

Next scheduled infusion of Lunsumio

Grade 1

Fever ≥ 38°C

If CRS occurs during infusion:

• The infusion should be interrupted and symptoms treated

• The infusion should be re‑started at the same rate once the symptoms resolve

• If symptoms recur with re‑administration, the current infusion should be discontinued

If CRS occurs post-infusion:

• The symptoms should be treated

If CRS lasts > 48 hours after symptomatic management:

• Dexamethasone3 and/or tocilizumab4,5 should be considered

The symptoms should be resolved for at least 72 hours prior to next infusion

The patient should be monitored more frequently

Grade 2

Fever ≥ 38°C and/or hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen6 by nasal cannula or blow-by

If CRS occurs during infusion:

• The infusion should be interrupted and symptoms treated

• The infusion should be re-started at 50% the rate once the symptoms resolve

• If symptoms recur with re-administration, the current infusion should be discontinued

If CRS occurs post-infusion:

• The symptoms should be treated

If no improvement occurs after symptomatic management:

• Dexamethasone3 and/or tocilizumab4,5 should be considered

The symptoms should be resolved for at least 72 hours prior to next infusion

Premedication should be maximized as appropriate7

Consideration should be given to administration of the next infusion 50% rate, with more frequent monitoring of the patient

Grade 3

Fever ≥ 38°C and/or hypotension requiring a vasopressor (with or without vasopressin) and/or hypoxia requiring high flow oxygen8 by nasal cannula, face mask, non-rebreather mask, or Venturi mask

If CRS occurs during infusion:

• The current infusion should be discontinued

• The symptoms should be treated

• Dexamethasone3 and tocilizumab4, 5 should be administered

If CRS occurs post-infusion:

• The symptoms should be treated

• Dexamethasone3 and tocilizumab4, 5 should be administered

If CRS is refractory to dexamethasone and tocilizumab:

• Alternative immunosuppressants9 and methylprednisolone 1 000 mg/day intravenously should be administered until clinical improvement

The symptoms should be resolved for at least 72 hours prior to next infusion

Patients should be hospitalized for the next infusion

Premedication should be maximized as appropriate7

The next infusion should be administered at a 50% rate

Grade 4

Fever ≥ 38°C and/or hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring oxygen by positive pressure (e.g., CPAP, BiPAP, intubation and mechanical ventilation)

If CRS occurs during or post-infusion:

• Treatment with Lunsumio should be permanently discontinued

• The symptoms should be treated

• Dexamethasone3 and tocilizumab4, 5 should be administered

If CRS is refractory to dexamethasone and tocilizumab:

• Alternative immunosuppressants9 and methylprednisolone 1 000 mg/day intravenously should be administered until clinical improvement

1 ASTCT = American Society for Transplant and Cellular Therapy. Premedication may mask fever, therefore if clinical presentation is consistent with CRS, please follow these management guidelines.

2 If CRS is refractory to management, consider other causes including hemophagocytic

lymphohistiocytosis

3 Dexamethasone should be administered at 10 mg intravenously every 6 hours (or equivalent) until clinical improvement

4 In study GO29781, tocilizumab was administered intravenously at a dose of 8 mg/kg (not to exceed 800 mg per infusion), as needed for CRS management

5 If no clinical improvement in the signs and symptoms of CRS occurs after the first dose, a second dose of intravenous tocilizumab 8 mg/kg may be administered at least 8 hours apart (maximum 2 doses per CRS event). Within each time period of 6 weeks of Lunsumio treatment, the total amount of tocilizumab doses should not exceed 3 doses

6 Low-flow oxygen is defined as oxygen delivered at < 6 L/minute.

7 Refer to Table 1 for additional information

8 High-flow oxygen is defined as oxygen delivered at ≥ 6 L/minute

9 Riegler L et al. (2019)

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) grading and management

ICANS should be identified based on clinical presentation (see Section 4.4). Rule out other causes of neurologic symptoms. If ICANS is suspected, it should be managed according to the recommendations in Table 4.

Table 4 Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

Gradea

Actions

Grade 1

ICEb 7-9 or depressed level of consciousness but awakens spontaneously

Withhold Lunsumio and monitor neurologic toxicity symptoms until ICANS resolves.c,d

Provide supportive therapy and consider neurologic consultation and evaluation.

Consider a single dose of dexamethasone 10mg, if not taking other corticosteroids.

Consider non-sedating, anti-seizure medicinal products (e.g., levetiracetam) for seizure prophylaxis.

Grade 2

ICEb 3-6 or depressed level of consciousness but awakens to voice

Withhold Lunsumio and monitor neurologic toxicity symptoms until ICANS resolves.c,d

Provide supportive therapy and consider neurologic consultation and evaluation.

Treat with dexamethasone 10 mg intravenously every 6 hours, if not taking other corticosteroids, until improvement to Grade 1, then taper.

Consider non-sedating, anti-seizure medicinal products (e.g., levetiracetam) for seizure prophylaxis.

Grade 3

ICEb 0-2 or depressed level of consciousness but awakens to tactile stimulus or any clinical seizure that resolves rapidly or focal/local oedema on neuroimaging

Withhold Lunsumio and monitor neurologic toxicity symptoms until ICANS resolves.d,e

Provide supportive therapy, which may include intensive care, and consider neurologic consultation and evaluation.

Treat with dexamethasone 10 mg intravenously every 6 hours, if not taking other corticosteroids, until improvement to Grade 1, then taper.

Consider non-sedating anti-seizure medication for seizure prophylaxis until resolution of ICANS. Use anti-seizure medication for seizure management as needed.

For recurrent grade 3 ICANS, consider permanently discontinuing Lunsumio.

Grade 4

ICEb is 0 or patient is unarousable or requires vigorous or repetitive tactile stimuli, or life-threatening prolonged seizure (>5 min) or repetitive seizures without return to baseline or deep focal motor weakness or diffuse cerebral oedema on neuroimaging

Permanently discontinue Lunsumio.

Provide supportive therapy, which may include intensive care, and consider neurologic consultation and evaluation.

Treat with dexamethasone 10 mg intravenously every 6 hours, if not taking other corticosteroids, until improvement to Grade 1, then taper.

Alternatively, consider administration of methylprednisolone 1 000 mg per day intravenously for 3 days, if symptoms improve, then manage as above.

Consider non-sedating anti-seizure medication for seizure prophylaxis until resolution of ICANS. Use anti-seizure medication for seizure management as needed.

a American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading criteria.

b If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (name 3 objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., “show me 2 fingers” or “close your eyes and stick out your tongue” = 1 point); Writing (ability to write a standard sentence = 1 point; and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points.

c Consider the type of neurologic toxicity before deciding to withhold Lunsumio.

d See Delayed or missed dose for guidance on restarting Lunsumio after dose delay.

e Evaluate benefit/risk before restarting Lunsumio.

Special populations

Elderly

No dose adjustment of Lunsumio is required in patients ≥ 65 years of age (see section 5.2).

Renal impairment

Lunsumio has not been studied in patients with severe renal impairment. Dose adjustments are not considered necessary in patients with mild to moderate renal impairment based on pharmacokinetics (see section 5.2).

Hepatic impairment

Lunsumio has not been studied in patients with hepatic impairment. Dose adjustments are not considered necessary based on pharmacokinetics (see section 5.2).

Paediatric population

The safety and efficacy of Lunsumio in children below 18 years of age have not yet been established.

Method of administration

Lunsumio is for intravenous use only.

Lunsumio must be diluted using aseptic technique under the supervision of a healthcare professional. It should be administered as an intravenous infusion through a dedicated infusion line. Do not use an in-line filter to administer Lunsumio. Drip chamber filters can be used to administer Lunsumio.

The first cycle of Lunsumio should be administered over a minimum of 4 hours as intravenous infusion. If the infusions are well-tolerated in cycle 1, the subsequent cycles may be administered over a 2‑hours infusion.

Lunsumio must not be administered as intravenous push or bolus.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability

In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded.

Cytokine Release Syndrome (CRS)

CRS, including life-threatening reactions, have occurred in patients receiving Lunsumio (see section 4.8). Signs and symptoms included pyrexia, chills, hypotension, tachycardia, hypoxia, and headache. Infusion related reactions may be clinically indistinguishable from manifestations of CRS. CRS events occurred predominantly in cycle 1 and were mainly associated with Day 1 and Day 15 dose administrations.

Patients should be premedicated with corticosteroids, antipyretics and antihistamines at least through cycle 2. Patients must receive adequate hydration prior to the administration of Lunsumio. Patients should be monitored for signs or symptoms of CRS. Patients should be counselled to seek immediate medical attention should signs or symptoms of CRS occur at any time. Physicians should institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated. (see section 4.2).

Haemophagocytic lymphohistiocytosis (HLH), including fatal cases, has been reported in patients receiving Lunsumio. HLH is a life-threatening syndrome characterized by fever, hepatomegaly and cytopenias. HLH should be considered when the presentation of CRS is atypical or prolonged. Patients should be monitored for clinical signs and symptoms of HLH (see Section 4.2). For suspected HLH, Lunsumio must be interrupted and treatment for HLH initiated.

Serious infections

Serious infections such as pneumonia, bacteraemia, and sepsis or septic shock have occurred in patients receiving Lunsumio, some of which were life-threatening or fatal events (see section 4.8). Febrile neutropenia was observed in patients after receiving Lunsumio infusion.

Lunsumio should not be administered in the presence of active infections. Caution should be exercised when considering the use of Lunsumio in patients with a history of recurring or chronic infections (e.g., chronic, active Epstein-Barr Virus), with underlying conditions that may predispose to infections or who have had significant prior immunosuppressive treatment. Patients should be administered prophylactic antibacterial, antiviral and/or antifungal medicinal products, as appropriate. Patients should be monitored for signs and symptoms of infection, before and after Lunsumio administration, and treated appropriately. In the event of febrile neutropenia, patients should be evaluated for infection and managed with antibiotics, fluids and other supportive care, according to local guidelines.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

ICANS have occurred in patients receiving Lunsumio, including serious and life threatening reactions. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Manifestations of ICANS reported in clinical trials included confusional state, lethargy, encephalopathy, depressed level of consciousness, and memory impairment. The majority of cases occurred during Cycle 1.

Patients should be monitored for signs and symptoms of ICANS following Lunsumio administration. Patients must be counselled to seek immediate medical attention should signs or symptoms occur at any time (see Patient card below).

Patients should be advised to exercise caution while (or avoid if symptomatic) driving, cycling or using heavy or potentially dangerous machines (see section 4.7).

At the first signs or symptoms of ICANS, manage according to the ICANS guidance provided in Table 4. Treatment with Lunsumio should be withheld or discontinued permanently as recommended.

Tumour flare

Tumour flare has been reported in patients treated with Lunsumio (see section 4.8). Manifestations included new or worsening pleural effusions, localised pain and swelling at the sites of lymphoma lesions and tumour inflammation. Consistent with the mechanism of action of Lunsumio, tumour flare is likely due to the influx of T-cells into tumour sites following Lunsumio administration.

There are no specific risk factors for tumour flare that have been identified, however, there is a heightened risk of compromise and morbidity due to mass effect secondary to tumour flare in patients with bulky tumours located in close proximity to airways and/or a vital organ. Patients treated with Lunsumio should be monitored and evaluated for tumour flare at critical anatomical sites.

Tumour lysis syndrome (TLS)

TLS has been reported in patients receiving Lunsumio (see section 4.8). Patients must have adequate hydration prior to the administration of Lunsumio. Patients should be administered prophylactic anti-hyperuricemic therapy (e.g allopurinol, rasburicase), as appropriate. Patients should be monitored for signs or symptoms of TLS, especially patients with high tumour burden or rapidly proliferative tumours, and patients with reduced renal function. Patients should be monitored for blood chemistries and abnormalities should be managed promptly.

Immunisation

Live and/or live-attenuated vaccines should not be given concurrently with Lunsumio. Studies have not been conducted in patients who recently received live vaccines.

Patient card

The prescriber must discuss the risks of Lunsumio therapy with the patient. The patient should be provided with the patient card and instructed to carry it at all times. The patient card describes the common signs and symptoms of CRS and ICANS, including instructions on when a patient should seek medical attention.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

A transient clinically relevant effect on CYP450 substrates with a narrow therapeutic index (e.g. warfarin, voriconazole, cyclosporine, etc) cannot be excluded, since initiation of Lunsumio treatment causes a transient increase in cytokine levels which may cause inhibition of CYP450 enzymes. On initiation of Lunsumio therapy in patients being treated with CYP450 substrates with a narrow therapeutic index, therapeutic monitoring should be considered. The dose of the concomitant medicinal product should be adjusted as needed.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception

Women of childbearing potential should use effective contraception while receiving Lunsumio and for at least 3 months after the last infusion of Lunsumio.

Pregnancy

There are no data from the use of Lunsumio in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Lunsumio is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether mosunetuzumab/metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Lunsumio therapy.

Fertility

No human data on fertility are available. No impairments were observed in male or female reproductive organs in the 26-week toxicity studies with cynomolgus monkeys at exposures (AUC) similar to exposure (AUC) in patients receiving the recommended dose.

4.7. Effects on ability to drive and use machines

Lunsumio has major influence on the ability to drive and use machines. Due to the potential for ICANS, patients receiving Lunsumio are at risk of depressed level of consciousness (see section 4.4). Due to the potential for ICANS, patients should be advised to exercise caution while (or avoid if symptomatic) driving, cycling or using heavy or potentially dangerous machines.

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 5 Adverse reactions occurring in patients treated with Lunsumio

System organ class / preferred term or adverse reaction

All grades

Grade 3 – 4

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 lymphohistiocytosis

Uncommon

Uncommon

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 neurotoxicity syndrome4,5

Common

Very rare

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

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

4.9. Overdose

In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.