4.1. Therapeutic indications

Aucatzyl is indicated for the treatment of adult patients (≥ 18 years) with relapsed or refractory B cell precursor acute lymphoblastic leukaemia (see section 5.1).

4.2. Posology and method of administration

Aucatzyl must be administered in a qualified treatment centre by a physician with experience in the treatment of haematological malignancies and trained for administration and management of patients treated with Aucatzyl.

Refer to the UK Public Assessment Report on the Medicines and Healthcare products Regulatory Agency (MHRA) website for details of leukapheresis, lymphodepletion and bridging therapies used in the clinical trials for Aucatzyl.

Posology

Aucatzyl is intended for autologous use (see section 4.4).

The target dose of Aucatzyl is 410 × 106 CD19 CAR-positive viable T cells supplied in three or more infusion bags.

See the Release for Infusion Certificate and Dose Schedule Planner for the actual cell counts and volumes to be infused and to guide the appropriate dosage regimen (see section 6.6).

Bone marrow assessment

A bone marrow assessment must be available from a biopsy and/or aspirate sample obtained within 7 days prior to the commencement of the lymphodepleting chemotherapy.

The bone marrow assessment is used to determine the Aucatzyl dosage regimen.

The treatment regimen consists of a split dose to be administered on Day 1 and Day 10 (± 2 days).

Low Tumour Burden Regimen (where lymphoblasts make up ≤ 20% of all nucleated cells in a bone marrow biopsy obtained within 7 days prior to lymphodepletion):

• Day 1: 100 × 106 cells administered via bag infusion

• Day 10 (± 2 days): 10 × 106 cells administered via syringe and 300 × 106 cells administered via bag infusion

High Tumour Burden Regimen (where lymphoblasts make up > 20% of all nucleated cells in a bone marrow biopsy obtained within 7 days prior to lymphodepletion):

• Day 1: 10 × 106 cells administered via syringe

• Day 10 (± 2days): 100 × 106 cells administered via bag infusion and 300 × 106 cells administered via bag infusion

If bone marrow assessment results are inconclusive:

• Repeat the biopsy or aspirate, and note that a repeat biopsy or aspirate must only be taken prior to lymphodepleting chemotherapy.

• If results remain inconclusive, proceed with High Tumour Burden Regimen (i.e. administration of the 10 × 106 dose on Day 1) per the Aucatzyl Dose Schedule Planner.

Pretreatment conditioning (lymphodepleting chemotherapy)

Confirm availability of Aucatzyl prior to starting lymphodepleting chemotherapy.

Refer to the UK Public Assessment Report on the MHRA website for details of the lymphodepletion therapy used in the FELIX clinical trial for Aucatzyl.

Premedication

• To minimise the risk of an infusion reaction, premedicate with paracetamol (1,000 mg orally) approximately 30 minutes prior to Aucatzyl infusion.

• Avoid prophylactic use of systemic corticosteroids because this may interfere with the activity of Aucatzyl.

Special populations

Elderly

No dose adjustment is required in patients over 65 years of age. Twenty percent of patients treated with Aucatzyl in the safety set (25/127) were 65 years of age and over. Overall, differences in safety and efficacy were not observed between elderly and younger adult patients, see section 5.2.

Renal and hepatic impairment

There is no clinical experience in patients with renal or hepatic impairment. Patients with a history of renal or hepatic impairment are likely to be more vulnerable to the consequences of the adverse reactions described below and require special attention, and consideration on a case-by-case basis.

Paediatric Population

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

Method of administration

Aucatzyl is for autologous and intravenous use only.

For instructions on preparation, administration, measures to take in case of accidental exposure and disposal of Aucatzyl see section 6.6. Strictly follow Administration Instructions to minimise dosing errors.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Contraindications of the lymphodepleting chemotherapy must be considered.

4.4. Special warnings and precautions for use

Refer to the UK Public Assessment Report on the MHRA website for details of leukapheresis, lymphodepletion and bridging therapies used in the FELIX clinical trial for Aucatzyl.

Traceability

The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability the name of the product, the batch number and the name of the treated patient must be kept for a period of 30 years after the expiry date of the product.

Autologous use

Aucatzyl is intended solely for autologous use and must not, under any circumstances, be administered to other patients. Aucatzyl must not be administered if the information on the product labels and Release for Infusion Certificate do not match the patient's identity.

Monitoring

• Patients must be monitored daily for 14 days after the first infusion for signs and symptoms of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome and other toxicities.

• Frequency of monitoring after the first 14 days may be carried out at the physician's discretion and continued for at least 4 weeks after the first infusion.

• Patients must be instructed to remain within proximity of the qualified treatment centre for at least 4 weeks following the first infusion.

Reasons to delay treatment

Delay Aucatzyl treatment if there are unresolved serious adverse reactions from preceding chemotherapies, if the patient is experiencing severe intercurrent infection, or has active graft-versus-host disease. If the patient requires supplementary oxygen, Aucatzyl should only be infused, if considered appropriate, based on the treating physician's benefit / risk assessment.

Reasons to delay the second split dose

Dosage delays or discontinuation may be required after the first split dose to manage adverse reactions.

Patients with Grade 2 cytokine release syndrome and / or Grade 1 immune effector cell-associated neurotoxicity syndrome following the first split dose may receive the second dose on Day 10 (± 2 days) up to Day 21 only if cytokine release syndrome has resolved to Grade 1 or less and immune effector cell-associated neurotoxicity syndrome has completely resolved.

For patients with Grade ≥ 3 (i) severe infection at the time of infusion of Aucatzyl or (ii) requirement for supplementary oxygen or (iii) other clinically relevant adverse reactions following the first split dose: consider postponing Aucatzyl up to Day 21 to allow the situation to resolve.

In addition, the second split dose is not to be administered if ≥ Grade 3 cytokine release syndrome, ≥ Grade 2 immune effector cell-associated neurotoxicity syndrome and / or ≥ Grade 3 pulmonary or cardiac toxicities are observed following the first split dose.

Grading is based on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Cytokine release syndrome

Refer to local institutional / national guidelines for advice on monitoring and management of cytokine release syndrome.

Evaluation for haemophagocytic lymphohistiocytosis / macrophage activation syndrome is to be considered in patients with severe or unresponsive cytokine release syndrome. Treatment should be administered per institutional standards.

Availability of tocilizumab

Treatment centres must have 24-hour immediate access to tocilizumab and emergency equipment must be available prior to infusion. In the exceptional case where tocilizumab is not available owing to a shortage, then alternatives to tocilizumab to treat cytokine release syndrome must be available prior to infusion. Shortages of tocilizumab may be checked for in the MHRA Central Alerting System.

Immune Effector Cell-associated Neurotoxicity Syndrome

Patients should be monitored for signs and symptoms of immune effector cell-associated neurotoxicity syndrome.

Refer to local institutional / national guidelines for advice on monitoring and management of immune effector cell-associated neurotoxicity syndrome.

Prolonged Cytopenias

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Aucatzyl infusion and should be managed according to institutional guidelines.

Patient blood counts must be monitored after Aucatzyl infusion.

Severe infections

Aucatzyl should not be administered to patients with clinically significant active systemic infections. Severe infections, including life-threatening or fatal infections, occurred in patients after receiving Aucatzyl (see section 4.8).

Grade 3 or higher febrile neutropenia was observed in patients after Aucatzyl infusion (see section 4.8) and may be concurrent with cytokine release syndrome.

Patients with human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection

There is no clinical experience in patients with a positive test for HIV, active HBV, or active HCV infection. Screening for HBV, HCV, HIV and other infectious agents must be performed in accordance with clinical guidelines before collection of cells for manufacturing.

Leukapheresis material from patients with active HIV, active HBV, or active HCV infection will not be accepted for manufacturing.

Viral reactivation

Viral reactivation, e.g., HBV reactivation, can occur in patients treated with medicinal products directed against B cells and could result in fulminant hepatitis, hepatic failure, and death.

Hypogammaglobulinaemia

Hypogammaglobulinaemia is caused by B cell aplasia and has been seen as a consequence of depletion of normal B cells by CAR T cell therapy. Hypogammaglobulinaemia can occur in patients treated with Aucatzyl (see section 4.8).

Hypogammaglobulinaemia predisposes patients to become more susceptible to infections. Immunoglobulin levels should be monitored after treatment with Aucatzyl and managed per institutional guidelines including infection precautions, antibiotics or antiviral prophylaxis and immunoglobulin replacement.

Prior stem cell transplantation (graft versus host disease)

It is recommended that patients do not receive Aucatzyl within 3 months of undergoing an allogeneic stem cell transplantation because of the potential risk of Aucatzyl worsening graft versus host disease. There must be a gap of 3 months after allogeneic stem cell transplantation before leukapheresis is carried out to obtain material to manufacture Aucatzyl.

Stem cell transplantation after CAR T cell therapy

The role of allogeneic stem cell transplant following CAR T cell therapy is unclear. Note: a chemotherapy-based preparative regimen associated with a subsequent stem cell transplant procedure will neutralise the effect of CAR T cells.

Secondary malignancies including of T cell origin

Patients treated with Aucatzyl may develop secondary malignancies. T cell malignancies have been reported following treatment of haematological malignancies with a BCMA- or CD19-directed CAR T cell therapy. T cell malignancies, including CAR-positive malignancies, have been reported within weeks and up to several years following administration of a CD19- or BCMA-directed CAR T cell therapy. There have been fatal outcomes. Patients should be monitored life-long for signs of secondary malignancies. In the event that a secondary malignancy occurs, the company should be contacted to obtain instructions on the collection of patient samples for testing.

Tumour lysis syndrome

Tumour lysis syndrome, which may be severe, has occasionally been observed in the FELIX trial and with other CAR T cell products. To minimise the risk of tumour lysis syndrome, patients with high tumour burden should receive tumour lysis syndrome prophylaxis as per standard guidelines prior to Aucatzyl infusion. Signs and symptoms of tumour lysis syndrome after Aucatzyl infusions must be monitored, and events managed according to standard guidelines.

Hypersensitivity reactions

Serious hypersensitivity reactions, including anaphylaxis, may occur due to dimethyl sulfoxide in Aucatzyl.

Transmission of an infectious agent

Although Aucatzyl is tested for Sterility and Mycoplasma, a risk of transmission of infectious agents exists. Healthcare professionals administering Aucatzyl must, therefore, monitor patients for signs and symptoms of infection after treatment and treat appropriately, if needed.

Interference with virological testing

Due to limited and short spans of identical genetic information between the lentiviral vector used to create Aucatzyl and HIV, some HIV nucleic acid tests may give a false positive result.

Blood, organ, tissue and cell donation

Patients treated with Aucatzyl must not donate blood, organs, tissues and cells for transplantation.

Patient Card

The Patient Card must be given to the patient after treatment.

Sodium Content

This medicinal product contains 1131 mg sodium per target dose, equivalent to 57% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Potassium Content

This medicinal product contains 39 mg potassium per target dose, equivalent to 1% of the WHO recommended maximum daily intake of 3.51 g potassium for an adult.

Long-term follow-up

Patients are expected to be enrolled in a long-term follow-up scheme in order to better understand the long-term effects of Aucatzyl.

Paediatric population

There is not any clinical experience of Aucatzyl in paediatric patients. No specific guidance for use in this patient population exists.

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

No interaction studies have been performed.

Some patients required tocilizumab and/or corticosteroids for the management of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (see section 4.4).

Prophylactic use of systemic corticosteroids may interfere with the activity of Aucatzyl. Prophylactic use of systemic corticosteroids is therefore not recommended before infusion (see section 4.2).

Patients with high tumour burden (≥ 20%) had a greater frequency of cytokine release syndrome, which was managed by the use of tocilizumab and/or corticosteroids. Patients with a higher tumour burden showed a more robust CAR T cell expansion which is known to increase the likelihood of occurrence of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Administration of tocilizumab or corticosteroids for the treatment of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome did not affect the rate or extent of expansion and persistency.

Live vaccines

The safety of immunisation with live viral vaccines during or following treatment with Aucatzyl has not been studied. As a precautionary measure, vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of lymphodepletion chemotherapy, during Aucatzyl treatment, and until immune recovery following treatment. Refer to local institutional / national guidance for advice on live vaccines.

Bridging Therapies

Blinatumomab was not permitted as a bridging therapy in the FELIX clinical study, and there is no clinical experience with use of this product as a bridging therapy before Aucatzyl treatment.

Herbal remedies with immunomodulatory properties

There are no formal interaction studies with herbal remedies and Aucatzyl; general precautions are recommended due to their potential immunomodulatory effects.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in males and females

The pregnancy status of women of childbearing potential must be verified before starting Aucatzyl treatment.

See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.

There is insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with Aucatzyl.

For females who are not postmenopausal (< 24 months of amenorrhea) or who are not surgically sterile (absence of ovaries and/or uterus), two methods of contraception, comprising of one highly effective method of contraception together with a barrier method, must be used during the treatment period and for at least 12 months after the last dose of Aucatzyl. They must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during treatment and for 12 months after receiving the last dose of Aucatzyl.

Pregnancy

There are limited data available with the use of Aucatzyl in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with Aucatzyl to assess whether it can cause foetal harm when administered to a pregnant woman (see section 5.3).

It is not known if Aucatzyl has the potential to be transferred to the foetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause foetal toxicity, including B cell lymphocytopenia. Therefore, Aucatzyl is not recommended for women who are pregnant, or for women of childbearing potential not using contraception. Pregnant women must be advised on the potential risks to the foetus.

Pregnancy after Aucatzyl therapy must be discussed with the treating physician.

Assessment of immunoglobulin levels and B cells in newborn infants of mothers treated with Aucatzyl must be considered.

Breast-feeding

It is unknown whether Aucatzyl cells are excreted in human milk or transferred to the breast-feeding child. Breast-feeding women must be advised of the potential risk to the breast-fed child.

Fertility

There are very limited data on the effect of Aucatzyl on fertility. Effects on male and female fertility have not been evaluated in animal studies.

4.7. Effects on ability to drive and use machines

Aucatzyl may have a major influence on the ability to drive and use machines.

Because of the potential for neurological events, including altered mental status or seizures, patients must refrain from driving or operating heavy or potentially dangerous machines until at least 8 weeks after infusion or until resolution of the neurological event as confirmed by the treating physician.

4.8. Undesirable effects

Summary of the safety profile

The safety of Aucatzyl was evaluated in one open-label, single-arm study (study FELIX) in which 127 adult patients with relapsed or refractory B cell acute lymphoblastic leukaemia received a median dose of 410 × 106 viable CAR T cells (range: 10 to 480 × 106 viable CAR T cells).

Exposure to Aucatzyl was preceded by unstimulated leukapheresis followed by lymphodepletion with fludarabine and cyclophosphamide (safety profiles for these procedures were generally consistent with those expected with leukapheresis and lymphodepletion). Bridging therapy was permitted.

The median (minimum, maximum) duration of follow-up after being administered Aucatzyl is 21.5 (8.6, 41.4) months.

The most common adverse reaction of any grade included cytokine release syndrome (69%), infections-pathogen unspecified (45%) and musculoskeletal pain (31%).

The most common non-laboratory Grade 3 or higher adverse reactions were infections-pathogen unspecified (32%), febrile neutropenia (24%) and bacterial infectious disorders (11%).

The most common serious adverse reactions of any grade included infections-pathogen unspecified (28%), febrile neutropenia (13%) and immune effector cell-associated neurotoxicity syndrome (9%).

Patients undergo leukapheresis, bridging therapy and lymphodepletion therapy prior to administration of Aucatzyl. Refer to local / national guidance documents for information on adverse events that may occur in association with the leukapheresis procedure. Refer to the relevant summaries of product characteristics for information on adverse events that may arise subsequent to exposure to medicinal products used in the bridging and lymphodepletion therapies.

Tabulated list of adverse reactions

Table 1 summarises the adverse reactions in a total of 127 patients exposed to Aucatzyl in the Phase Ib and Phase II FELIX study. These 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse drug reactions identified with Aucatzyl

System Organ Class (SOC)

Frequency

Adverse Reaction

Infections and infestations

Very Common

Infections – pathogen unspecified

Bacterial infectious disorders COVID-19

Viral infectious disorders excluding COVID-19

Fungal infectious disorders

Blood and lymphatic system disorders

Very Common

Neutropeniaa

Leukopeniaa

Lymphopeniaa

Thrombocytopeniaa

Anaemiaa

Febrile neutropenia

Coagulopathy

Immune system disorders

Very Common

Cytokine release syndrome

Common

Hypogammaglobulinaemia

Haemophagocytic lymphohistiocytosis

Metabolism and nutrition disorders

Very Common

Decreased appetite

Psychiatric disorders

Common

Delirium

Nervous system disorders

Very Common

Headache

Immune effector cell-associated neurotoxicity syndrome

Encephalopathy

Dizziness

Common

Tremor

Cardiac disorders

Very Common

Tachycardia

Common

Arrhythmia

Cardiac Failure

Palpitations

Vascular disorders

Very Common

Hypotension

Haemorrhage

Respiratory, thoracic and mediastinal disorders

Very Common

Cough

Gastrointestinal disorders

Very Common

Nausea

Diarrhoea

Vomiting

Abdominal Pain

Constipation

Common

Stomatitis

Skin and subcutaneous tissue disorders

Very Common

Rash

Musculoskeletal and connective tissue disorders

Very Common

Musculoskeletal pain

General disorders and administration site conditions

Very Common

Pyrexia

Pain

Fatigue

Oedema

Common

Chills

Investigations

Very Common

Alanine aminotransferase increaseda

Weight decreased

Hyperferritinaemia

Aspartate aminotransferase increaseda

Injury, poisoning and procedural complications

Common

Infusion related reaction

a Frequency based on Grade 3 or higher laboratory parameter.

Description of selected adverse reactions

Cytokine Release Syndrome

Cytokine release syndrome was reported in 69% (87/127) of patients, including Grade 3 cytokine release syndrome in 2% (3/127) of patients. There were no reported Grade 4 or 5 events. The median time to onset of cytokine release syndrome of any grade was 8 days (range: 1 to 23 days) with a median duration 5 days (range: 1 to 21 days). The most common manifestations of cytokine release syndrome among patients who experienced cytokine release syndrome included fever (69%), hypotension (25%) and hypoxia (13%).

Sixty-four percent (56/87) of patients experienced cytokine release syndrome after the first, but prior to the second infusion of Aucatzyl. In the study, 80% (70/87) of patients who experienced cytokine release syndrome had a high tumour burden at the time of lymphodepleting treatment (≥ 5% lymphoblasts in the bone marrow), with 39 % (34/87) of patients presenting with > 75% lymphoblast in their bone marrow. The primary treatment for cytokine release syndrome was tocilizumab (76%; 66/87), with patients also receiving corticosteroids (23%; 20/87) and other anti-cytokine therapies (14%; 12/87).

Haemophagocytic Lymphohistiocytosis / Macrophage Activation Syndrome

Haemophagocytic lymphohistiocytosis / macrophage activation syndrome, including severe and life-threatening reactions may occur following treatment with Aucatzyl. Haemophagocytic lymphohistiocytosis / macrophage activation syndrome was reported in 2% (2/127) of patients and included Grade 3 and Grade 4 events with a time of onset at Day 22 and Day 41, respectively. One patient experienced a concurrent immune effector cell-associated neurotoxicity syndrome event after Aucatzyl infusion.

Immune Effector Cell-Associated Neurotoxicity Syndrome

Immune effector cell-associated neurotoxicity syndrome, which may be severe, life-threatening or fatal, occurred in 23% (29/127) of patients, including Grade ≥ 3 in 7% (9/127) of patients following treatment with Aucatzyl.

In clinical studies, 90% (26/29) of patients who experienced immune effector cell-associated neurotoxicity syndrome and all patients who experienced Grade ≥ 3 immune effector cell-associated neurotoxicity syndrome had > 5% lymphoblasts in their bone marrow at the time of lymphodepleting treatment. Among the 9 patients who experienced Grade ≥ 3 immune effector cell-associated neurotoxicity syndrome, 56% (5/9) of patients presented with > 75% lymphoblasts in their bone marrow. Among the 29 patients who experienced immune effector cell-associated neurotoxicity syndrome, 62% (18/29) experienced an onset after the second infusion of Aucatzyl.

The median time to onset for immune effector cell-associated neurotoxicity syndrome events was 12 days (range: 1 to 31 days) with a median duration of 8 days (range: 1 to 53 days). The most common symptoms included (> 2%) confusional state (9.4%) and tremor (4.7%).

Eighty-three percent (24/29) of patients received treatment for immune effector cell-associated neurotoxicity syndrome. All treated patients received high-dose corticosteroids and 50% (12/24) of patients received anti-epileptics prophylactically.

Prolonged Cytopenia

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Aucatzyl infusion.

In patients who were responders to Aucatzyl, Grade ≥ 3 cytopenias at Month 1 following infusion were observed in 69% (68/99) of patients and included neutropenia (59%, 58/99) and thrombocytopenia (49%, 48/99). Grade 3 or higher cytopenias at Month 3 following Aucatzyl infusion was observed in 20% (20/99) of patients and included neutropenia (13%, 13/99) and thrombocytopenia (11%, 11/99).

Severe Infections

Severe, life-threatening and fatal infections occurred in patients after Aucatzyl infusion.

Non-COVID-19 infections of all grades occurred in 71% (90/127) of patients. Grade 3 or higher non-COVID-19 infections were reported in 45% (57/127) of patients.

Grade 3 or higher febrile neutropenia was observed in 24% (30/127) of patients after Aucatzyl infusion and may be concurrent with cytokine release syndrome.

Monitor patients for signs and symptoms of infection before and after Aucatzyl infusion and treat appropriately (see section 4.4). Administer prophylactic antimicrobials according to local guidelines.

Hypogammaglobulinaemia

Hypogammaglobulinaemia was reported in 9% (12/127) of patients treated with Aucatzyl including 2 cases (2%, 2/127) of Grade 3 hypogammaglobulinaemia.

Immunogenicity

The humoral immunogenicity of Aucatzyl was measured using an assay for the detection of anti-drug antibodies against Aucatzyl. In the FELIX study, 8.7% (11/127) of patients tested positive for anti-CD19 CAR antibodies pre-infusion. Treatment induced anti-CD19 CAR antibodies were detected in 1.7% (2/127) of patients. There is no evidence that the presence of pre-existing or post-infusion anti-CD19 CAR antibodies impact the effectiveness, safety, initial expansion and persistency of Aucatzyl.

The cellular immunogenicity of Aucatzyl was measured using an assay for the detection of T cell responses, measured by production of interferon gamma (IFNγ), to the full length anti-CD19 CAR. Only 4% (3/75) of patients tested positive in the cellular immunogenicity readout (IFNγ) post-infusion. There is no evidence that the cellular immunogenicity impacts the kinetics of initial expansion and persistence of Aucatzyl, or the safety or effectiveness of Aucatzyl.

Secondary malignancies

There have been cases of the following adverse effect(s) reported after treatment with other CAR T cell products, which might also occur after treatment with Aucatzyl: secondary malignancy of T cell origin.

Paediatric population

Clinical safety in a paediatric population has not yet been evaluated.

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. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

During clinical studies, occurrences of overdose were observed at the administration of the first dose in 4% (5/127) of patients. All 5 patients had high tumour burden and should have received a 10 × 106 first dose but received a higher dose between 68 and 103 × 106 CAR T cells. Cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome and haemophagocytic lymphohistiocytosis, including severe events, were observed in patients who experienced overdose. In the event of a suspected overdose, any adverse reactions are to be treated in accordance with guidance provided in section 4.4.