Tisagenlecleucel

Patients with active, uncontrolled infection should not start tisagenlecleucel treatment until the infection is resolved. Prior to tisagenlecleucel infusion, infection prophylaxis should follow standard guidelines based on the degree of preceding immunosuppression.

Serious infections, including life-threatening or fatal infections, occurred frequently in patients after tisagenlecleucel infusion. Patients should be monitored for signs and symptoms of infection and treated appropriately. As appropriate, prophylactic antibiotics should be administered and surveillance testing should be employed prior to and during treatment with tisagenlecleucel. Infections are known to complicate the course and management of concurrent cytokine release syndrome.

Febrile neutropenia was frequently observed in patients after tisagenlecleucel infusion and may be concurrent with cytokine release syndrome. In the event of febrile neutropenia, infection should be evaluated and managed appropriately with broad-spectrum antibiotics, fluids and other supportive care, as medically indicated.

In patients achieving complete remission following tisagenlecleucel, resulting low immunoglobulin levels can increase the risk for infections. Attention to signs and symptoms of infection should be implemented according to age and standard specific guidelines.

The safety of immunisation with live viral vaccines during or following tisagenlecleucel treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel treatment, and until immune recovery following treatment with tisagenlecleucel.

Hypogammaglobulinaemia and agammaglobulinaemia can occur in patients with a complete remission after tisagenlecleucel infusion. Immunoglobulin levels should be monitored after treatment with tisagenlecleucel. In patients with low immunoglobulin levels pre-emptive measures such as infection precautions, antibiotic prophylaxis and immunoglobulin replacement should be taken according to age and standard guidelines.

Tumour lysis syndrome (TLS), which may be severe, has occasionally been observed.

To minimise risk of TLS, patients with elevated uric acid or high tumour burden should receive allopurinol, or an alternative prophylaxis, prior to tisagenlecleucel infusion. Signs and symptoms of TLS should be monitored and events managed according to standard guidelines.

HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with medicinal products directed against B cells.

Cytokine release syndrome, including fatal or life-threatening events, has been frequently observed after tisagenlecleucel infusion. In almost all cases, development of cytokine release syndrome occurred between 1 to 10 days (median onset 3 days) after tisagenlecleucel infusion. The median time to resolution of cytokine release syndrome was 7 days.

Symptoms of cytokine release syndrome may include high fever, rigors, myalgia, arthralgia, nausea, vomiting, diarrhoea, diaphoresis, rash, anorexia, fatigue, headache, hypotension, encephalopathy, dyspnoea, tachypnoea, and hypoxia. Additional organ system adverse reactions, including transient cardiac insufficiency and arrhythmia, renal insufficiency, elevated aspartate aminotransferase (AST), elevated alanine aminotransferase (ALT) and elevated bilirubin have been observed. In some cases, disseminated intravascular coagulation (DIC), with low fibrinogen levels, capillary leak syndrome (CLS), and haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) have been reported in the setting of cytokine release syndrome. Patients should be closely monitored for signs or symptoms of these events, including fever.

Risk factors for severe cytokine release syndrome in paediatric and young adult B-cell ALL patients are: high pre-infusion tumour burden, uncontrolled or accelerating tumour burden following lymphodepleting chemotherapy, active infection and early onset of fever or cytokine release syndrome following tisagenlecleucel infusion. Risk factors for developing severe cytokine release syndrome in adult DLBCL patients are not known.

In all indications, appropriate prophylactic and therapeutic treatment for infections should be provided, and complete resolution of any existing infections should be ensured. Infections may also occur during cytokine release syndrome and may increase the risk of a fatal event.

Management of cytokine release syndrome associated with tisagenlecleucel

Cytokine release syndrome is managed solely based on clinical presentation and according to the cytokine release syndrome management algorithm provided in the table below. Anti-IL-6 based therapy such as tocilizumab has been administered for moderate or severe cytokine release syndrome associated with tisagenlecleucel and a minimum of four doses of tocilizumab must be on site and available for administration prior to tisagenlecleucel infusion. Corticosteroids may be administered in cases of life-threatening emergencies. Tisagenlecleucel continues to expand and persist following administration of tocilizumab and corticosteroids. Patients with medically significant cardiac dysfunction should be managed by standards of critical care and measures such as echocardiography should be considered. Tumour necrosis factor (TNF) antagonists are not recommended for management of tisagenlecleucel-associated cytokine release syndrome.

Cytokine release syndrome management algorithm:

It is not recommended that patients receive tisagenlecleucel within 4 months of undergoing an allogeneic stem cell transplant (SCT) because of the potential risk of tisagenlecleucel worsening GVHD. Leukapheresis for tisagenlecleucel manufacturing should be performed at least 12 weeks after allogeneic SCT.

There are no data from the use of tisagenlecleucel in pregnant women. No animal studies have been conducted with tisagenlecleucel to assess whether it can cause foetal harm when administered to a pregnant woman. It is not known whether tisagenlecleucel has the potential to be transferred to the foetus via the placenta and could cause foetal toxicity, including B-cell lymphocytopenia. tisagenlecleucel is not recommended during pregnancy and in women of childbearing potential not using contraception.

Pregnant women should be advised on the potential risks to the foetus. Pregnancy after tisagenlecleucel therapy should be discussed with the treating physician. Pregnant women who have received tisagenlecleucel may have hypogammaglobulinaemia. Assessment of immunoglobulin levels is indicated in newborns of mothers treated with tisagenlecleucel.

It is unknown whether tisagenlecleucel cells are excreted in human milk. A risk to the breast-fed infant cannot be excluded. Women who are breast-feeding should be advised of the potential risk to the breast-fed infant.

Following administration of tisagenlecleucel, breast-feeding should be discussed with the treating physician.

Women of childbearing potential/Contraception in males and females

Pregnancy status for females of child-bearing age should be verified prior to starting treatment with tisagenlecleucel.

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

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

Fertility

There are no data on the effect of tisagenlecleucel on fertility. Effects of tisagenlecleucel on male and female fertility have not been evaluated in animal studies.

Tisagenlecleucel has major influence on the ability to drive and use machines.

Due to the potential for neurological events, including altered mental status or seizures, patients receiving tisagenlecleucel are at risk for altered or decreased consciousness or coordination in the 8 weeks following infusion.

Summary of the safety profile

B-cell ALL

The most common non-haematological adverse reactions were cytokine release syndrome (77%), infections (65%), hypogammaglobulinaemia (47%), pyrexia (40%) and decreased appetite (39%).

Grade 3 and 4 adverse reactions were reported in 88% of patients. The most common Grade 3 and 4 non-haematological adverse reaction was cytokine release syndrome (47%).

The most common Grade 3 and 4 haematological laboratory abnormalities were white blood cells decreased (99%), neutrophils decreased (95%), lymphocytes decreased (95%), platelets decreased (77%) and haemoglobin decreased (53%).

Grade 3 and 4 adverse reactions were more often observed within the initial 8 weeks post-infusion (83% of patients) compared to after 8 weeks post-infusion (46% of patients).

DLBCL

The adverse reactions described in this section were identified in 111 patients infused with tisagenlecleucel in one global multicentre international study, i.e. the ongoing pivotal clinical study CCTL019C2201.

The most common non-haematological adverse reactions were cytokine release syndrome (58%), infections (54%), pyrexia (35%), diarrhoea (32%), nausea (29%), hypotension (26%) and fatigue (26%).

Grade 3 and 4 adverse reactions were reported in 89% of patients. The most common Grade 3 and 4 non-haematological adverse reactions were infections (32%) and cytokine release syndrome (22%).

The most common (>25%) Grade 3 and 4 haematological laboratory abnormalities were lymphocyte count decreased (95%), neutrophil count decreased (81%), white blood cell count decreased (77%), haemoglobin decreased (59%) and platelet count decreased (55%).

Grade 3 and 4 adverse reactions were more often observed within the initial 8 weeks post-infusion (85%) compared to after 8 weeks post-infusion (49%).

List of adverse drug reactions

The adverse reactions described in this section were identified in 75 and 111 patients in the ongoing multicentre pivotal clinical studies (CCTL019B2202 and CCTL019C2201). Adverse drug reactions from these clinical studies are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first, using the following convention: 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.

Adverse drug reactions observed in clinical studies:

Studies B2202 (N=75) + C2201 (N=111):

Infections and infestations^a

Very common: Infections – pathogen unspecified, Viral infections, Bacterial infections, Fungal infections

Blood and lymphatic system disorders

Very common: Febrile neutropenia, Leukopenia, Lymphopenia, Anaemia, Thrombocytopenia

Common: Disseminated intravascular coagulation, Coagulopathy, Histiocytosis haematophagic, Pancytopenia

Immune system disorders

Very common: Cytokine release syndrome, Hypogammaglobulinaemia^b

Common: Graft-versus-host disease

Metabolism and nutrition disorders

Very common: Decreased appetite, Hypokalaemia, Hypophosphataemia, Hypocalcaemia, Hypomagnesaemia, Hypoalbuminaemia, Hyperuricaemia, Hyperglycaemia

Common: Fluid overload, Hypermagnesaemia, Hyponatraemia, Hyperphosphataemia, Tumour lysis syndrome

Psychiatric disorders

Very common: Delirium^c, Anxiety, Sleep disorder^d

Nervous system disorders

Very common: Headache^e, Encephalopathy^f, Dizziness

Common: Tremor, Peripheral neuropathy^g, Speech disorders^h, Seizureⁱ, Cerebral haemorrhage^**, Neuralgia, Ischaemic cerebral infarction

Cardiac disorders

Very common: Tachycardia^j

Common: Cardiac failure^k, Arrhythmia^l, Cardiac arrest

Vascular disorders

Very common: Hypotension, Hypertension

Common: Capillary leak syndrome, Flushing

Respiratory, thoracic and mediastinal disorders

Very common: Cough^m, Hypoxia, Dyspnoeaⁿ, Pulmonary oedema, Pleural effusion, Tachypnoea

Common: Epistaxis, Lung infiltration

Gastrointestinal disorders

Very common: Diarrhoea, Nausea, Vomiting, Constipation, Abdominal pain^o

Common: Dry mouth, Mouth haemorrhage, Stomatitis, Abdominal distension, Ascites, Abdominal compartment syndrome, Hepatobiliary, disorders, Hyperbilirubinaemia

Skin and subcutaneous tissue disorders

Very common: Rash^p

Common: Pruritus, Erythema, Night sweats, Petechiae, Hyperhidrosis

Musculoskeletal and connective tissue disorders

Very common: Back pain, Myalgia, Arthralgia

Renal and urinary disorders

Very common: Acute kidney injury^q

General disorders and administration site conditions

Very common: Pyrexia, Fatigue, Oedema^r, Pain^s, Chills

Common: Asthenia, Influenza-like illness, Multiple organ dysfunction syndrome

Investigations

Very common: Haemoglobin decreased, Lymphocyte count decreased, White blood cell count decreased, Neutrophil count decreased, Platelet count decreased^*, Aspartate aminotransferase increased, Alanine aminotransferase increased, Blood bilirubin increased, International normalised ratio increased, Weight decreased

Common: Activated partial thromboplastin time prolonged, Blood fibrinogen decreased, Serum ferritin increased, Blood alkaline phosphatase increased, Fibrin D dimer increased, Prothrombin time prolonged

^a Infections and infestations presented reflect high-level group terms.
^b Hypogammaglobulinaemia includes immunoglobulins decreased, blood immunoglobulin A decreased, blood immunoglobulin G decreased, blood immunoglobulin M decreased, immunodeficiency common variable and hypogammaglobulinaemia.
^c Delirium includes agitation, delirium, hallucination, hallucination visual, irritability and restlessness.
^d Sleep disorder includes sleep disorder, insomnia and nightmare.
^e Headache includes headache and migraine.
^f Encephalopathy includes depressed level of consciousness, mental status changes, automatism, cognitive disorder, confusional state, disturbance in attention, encephalopathy, posterior reversible encephalopathy syndrome, somnolence, lethargy, memory impairment, metabolic encephalopathy and thinking abnormal.
^g Peripheral neuropathy includes paraesthesia, peripheral sensory neuropathy, neuropathy peripheral, hyperaesthesia and hypoaesthesia.
^h Speech disorders includes speech disorders, dysarthria and aphasia.
ⁱ Seizure includes seizure, generalised tonic-clonic seizures and status epilepticus.
^j Tachycardia includes sinus tachycardia and tachycardia.
^k Cardiac failure includes cardiac failure, left ventricular dysfunction, cardiac failure congestive and right ventricular dysfunction.
^l Arrhythmia includes atrial fibrillation and supraventricular tachycardia.
^m Cough includes cough, productive cough and upper-airway cough syndrome.
ⁿ Dyspnoea includes dyspnoea, dyspnoea exertional, respiratory distress and respiratory failure.
^o Abdominal pain includes abdominal pain, abdominal pain upper and abdominal discomfort.
^p Rash includes rash, rash maculo-papular, rash papular and rash pruritic.
^q Acute kidney injury includes acute kidney injury, anuria, azotaemia, blood creatinine increased, renal failure, renal tubular dysfunction and renal tubular necrosis.
^r Oedema includes oedema peripheral, generalised oedema, localised oedema and face oedema.
^s Pain includes pain and pain in extremity.
* Frequency is based on laboratory values. Patients are counted only for the worst grade observed post baseline.
** With reported sequelae of secondary cerebral oedema.

Description of selected adverse drug reactions

Cytokine release syndrome

In the ongoing clinical studies in paediatric and young adult B-cell ALL (N=75), cytokine release syndrome was reported in 77% of patients (47% with Grade 3 or 4). Two deaths occurred within 30 days of tisagenlecleucel infusion: one patient died with cytokine release syndrome and progressive leukaemia and the second patient had resolving cytokine release syndrome with abdominal compartment syndrome, coagulopathy and renal failure when death occurred due to an intracranial haemorrhage.

In the ongoing clinical study in DLBCL (N=111), cytokine release syndrome was reported in 58% of patients, (22% with Grade 3 or 4).

Cytokine release syndrome was graded with the Penn scale as follows: Grade 1: mild reactions, e.g. reactions requiring supportive care; Grade 2: moderate reactions, e.g. reactions requiring intravenous therapies; Grade 3: severe reactions, e.g. reactions requiring low-dose vasopressors or supplemental oxygen; Grade 4: life-threatening reactions, e.g. those requiring high-dose vasopressors or intubation; Grade 5: death.

Febrile neutropenia and infections

Severe febrile neutropenia (Grade 3 or 4) was observed in 36% of paediatric and young adult B-cell ALL patients and 15% of DLBCL patients.

In B-cell ALL patients severe infections (Grade 3 and higher), which can be life-threatening or fatal, occurred in 44% of patients after tisagenlecleucel infusion. The overall incidence (all grades) was 65% (unspecified 49%, viral 32%, bacterial 24% and fungal 15%). 43% of the patients experienced an infection of any type within 8 weeks after tisagenlecleucel infusion.

In DLBCL patients severe infections (Grade 3 and higher), which can be life-threatening or fatal, occurred in 32% of patients. The overall incidence (all grades) was 54% (unspecified 44%, bacterial 10%, fungal 10% and viral 8%). 34% of the patients experienced an infection of any type within 8 weeks.

Prolonged cytopenias

Cytopenias are very common with tisagenlecleucel therapy.

In paediatric and young adult B-cell ALL patients, Grade 3 and 4 cytopenias not resolved by day 28 were reported based on laboratory findings and included leukopenia (55%), neutropenia (53%), lymphopenia (43%), thrombocytopenia (41%) and anaemia (12%).

In adult DLBCL, patients, Grade 3 and 4 cytopenias not resolved by day 28 were reported based on laboratory findings and included thrombocytopenia (41%), lymphopenia (28%), neutropenia (24%), leukopenia (21%) and anaemia (14%).

Neurological adverse reactions

The majority of neurological events occurred within 8 weeks following infusion and were transient.

In paediatric and young adult B-cell ALL patients, manifestations of encephalopathy and/or delirium occurred in 40% of patients (13% were Grade 3 or 4) within 8 weeks after tisagenlecleucel infusion. In DLBCL patients, manifestations of encephalopathy and/or delirium occurred in 21% of patients (12% were Grade 3 or 4) within 8 weeks after tisagenlecleucel infusion.

Hypogammaglobulinaemia

Hypogammaglobulinaemia was reported in 47% of patients treated with tisagenlecleucel for r/r ALL and 14% of patients with r/r DLBCL.

Pregnant women who have received tisagenlecleucel may have hypogammaglobulinaemia. Immunoglobulin levels should be assessed in newborns of mothers treated with tisagenlecleucel.

Immunogenicity

In clinical studies, humoral immunogenicity of tisagenlecleucel was measured by determination of anti-murine CAR19 antibodies (anti-mCAR19) in serum pre- and post-administration. The majority of patients tested positive for pre-dose anti-mCAR19 antibodies in paediatric and young adult ALL (B2202 and B2205J, 84.6%) and adult DLBCL (C2201, 91.4%).

Treatment-induced anti-mCAR19 antibodies were shown in 34.6% of paediatric and young adult ALL and 5% of adult DLBCL patients. Pre-existing and treatment-induced antibodies were not associated with an impact on clinical response nor did they have an impact on the expansion and persistence of tisagenlecleucel. There is no evidence that the presence of pre-existing and treatment-induced anti-mCAR19 antibodies impacts the safety or effectiveness of tisagenlecleucel.

T-cell immunogenicity responses were not observed in paediatric and young adult B-cell ALL and adult r/r DLBCL patients.

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 the national reporting system listed in Appendix V.