KYMRIAH Dispersion for infusion Ref.[8681] Active ingredients: Tisagenlecleucel

Reasons to delay treatment

Due to the risks associated with Kymriah treatment, infusion should be delayed if a patient has any of the following conditions:

• Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions or hypotension) from preceding chemotherapies.
• Active uncontrolled infection.
• Active graft-versus-host disease (GVHD).
• Significant clinical worsening of leukaemia burden or lymphoma following lymphodepleting chemotherapy.

Blood, organ, tissue and cell donation

Patients treated with Kymriah should not donate blood, organs, tissues and cells for transplantation.

Active central nervous system (CNS) leukaemia or lymphoma

There is limited experience of use of Kymriah in patients with active CNS leukaemia and active CNS lymphoma. Therefore the risk/benefit of Kymriah has not been established in these populations.

Cytokine release syndrome

Cytokine release syndrome, including fatal or life-threatening events, has been frequently observed after Kymriah infusion (see section 4.8). In almost all cases, development of cytokine release syndrome occurred between 1 to 10 days (median onset 3 days) after Kymriah 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 Kymriah 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 Kymriah

Cytokine release syndrome is managed solely based on clinical presentation and according to the cytokine release syndrome management algorithm provided in Table 1. Anti-IL-6 based therapy such as tocilizumab has been administered for moderate or severe cytokine release syndrome associated with Kymriah and a minimum of four doses of tocilizumab must be on site and available for administration prior to Kymriah 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 Kymriah-associated cytokine release syndrome.

Table 1. Cytokine release syndrome management algorithm:

Neurological adverse reactions

Neurological events, in particular encephalopathy, confusional state or delirium, occur frequently with Kymriah and can be severe or life-threatening (see section 4.8). Other manifestations included seizures, aphasia and speech disorder. The majority of neurological events occurred within 8 weeks following Kymriah infusion and were transient. The median time to onset of neurological events was 7 days in B-cell ALL and DLBCL. The median time to resolution was 7 days for B-cell ALL and 12 days for DLBCL. Neurological events can be concurrent with cytokine release syndrome, following resolution of cytokine release syndrome or in the absence of cytokine release syndrome.

Patients should be monitored for neurological events. In case of neurological events, patients should be diagnostically worked up and managed depending on the underlying pathophysiology and in accordance with local standard of care.

Infections and febrile neutropenia

Patients with active, uncontrolled infection should not start Kymriah treatment until the infection is resolved. Prior to Kymriah 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 Kymriah infusion (see section 4.8). 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 Kymriah. Infections are known to complicate the course and management of concurrent cytokine release syndrome.

Febrile neutropenia was frequently observed in patients after Kymriah infusion (see section 4.8) 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 Kymriah, 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.

Prolonged cytopenias

Patients may continue to exhibit cytopenias for several weeks following Kymriah infusion and should be managed according to standard guidelines. The majority of patients who had cytopenias at day 28 following Kymriah treatment resolved to Grade 2 or below within three months after treatment. Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly granulocyte macrophage-colony stimulating factor (GM-CSF), have the potential to worsen cytokine release syndrome symptoms and are not recommended during the first 3 weeks after Kymriah infusion or until cytokine release syndrome has resolved.

Secondary malignancies

Patients treated with Kymriah may develop secondary malignancies or recurrence of their cancer. They should be monitored life-long for secondary malignancies. In the event that a secondary malignancy occurs, the company should be contacted to obtain instructions on patient samples to collect for testing.

Hypogammaglobulinaemia

Hypogammaglobulinaemia and agammaglobulinaemia can occur in patients with a complete remission after Kymriah infusion. Immunoglobulin levels should be monitored after treatment with Kymriah. 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.

Live vaccines

The safety of immunisation with live viral vaccines during or following Kymriah 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 Kymriah treatment, and until immune recovery following treatment with Kymriah (see section 4.5).

Tumour lysis syndrome (TLS)

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 Kymriah infusion. Signs and symptoms of TLS should be monitored and events managed according to standard guidelines.

Concomitant disease

Patients with a history of active CNS disorder or inadequate renal, hepatic, pulmonary or cardiac function were excluded from the studies. These patient are likely to be more vulnerable to the consequences of the adverse reactions described below and require special attention.

Prior bone marrow transplant

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

HBV reactivation

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.

There is currently no experience with manufacturing Kymriah for patients testing positive for HBV, HCV and HIV.

Screening for HBV, HCV and HIV must be performed in accordance with clinical guidelines before collection of cells for manufacturing.

Prior treatment with anti-CD19 therapy

There is limited experience with Kymriah in patients exposed to prior CD19-directed therapy. Kymriah is not recommended if the patient has relapsed with CD19-negative leukaemia after prior anti-CD19 therapy.

Interference with serological testing

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

Sodium and potassium content

This medicinal product contains 24.3 to 121.5 mg sodium per dose, equivalent to 1 to 6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially “potassium-free”.

Content of dextran 40 and dimethyl sulfoxide (DMSO)

This medicinal product contains 10 mg dextran 40 and 82.5 mg dimethyl sulfoxide (DMSO) per mL. Each of these excipients are known to possibly cause anaphylactic reaction following parenteral administration. Patients not previously exposed to dextran and DMSO should be observed closely during the first minutes of the infusion period.

No pharmacokinetic or pharmacodynamic drug interaction studies with tisagenlecleucel have been performed. The co-administration of agents known to inhibit T-cell function has not been formally studied. Administration of low-dose steroids as per the cytokine release syndrome treatment algorithm does not impact the expansion and persistence of CAR-T cells. The co-administration of agents known to stimulate T-cell function has not been investigated and the effects are unknown.

Live vaccines

The safety of immunisation with live viral vaccines during or following Kymriah 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 Kymriah treatment, and until immune recovery following treatment with Kymriah.

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 Kymriah.

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 Kymriah.

Pregnancy

There are no data from the use of Kymriah in pregnant women. No animal studies have been conducted with Kymriah to assess whether it can cause foetal harm when administered to a pregnant woman (see section 5.3). It is not known whether Kymriah has the potential to be transferred to the foetus via the placenta and could cause foetal toxicity, including B-cell lymphocytopenia. Kymriah 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 Kymriah therapy should be discussed with the treating physician. Pregnant women who have received Kymriah may have hypogammaglobulinaemia. Assessment of immunoglobulin levels is indicated in newborns of mothers treated with Kymriah.

Breast-feeding

It is unknown whether Kymriah 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 Kymriah, breast-feeding should be discussed with the treating physician.

Fertility

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

Kymriah 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 Kymriah 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 Kymriah 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%).

Tabulated 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 (Table 2) 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.

Table 2. 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 Kymriah 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.

For clinical management of cytokine release syndrome, see section 4.4 and Table 1.

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. See section 4.4 for the management of febrile neutropenia before and after Kymriah infusion.

In B-cell ALL patients severe infections (Grade 3 and higher), which can be life-threatening or fatal, occurred in 44% of patients after Kymriah infusion. The overall incidence (all grades) was 65% (unspecified 49%, viral 32%, bacterial 24% and fungal 15%) (see section 4.4). 43% of the patients experienced an infection of any type within 8 weeks after Kymriah 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%) (see section 4.4). 34% of the patients experienced an infection of any type within 8 weeks.

Prolonged cytopenias

Cytopenias are very common with Kymriah 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 Kymriah 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 Kymriah infusion.

Hypogammaglobulinaemia

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

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

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 Kymriah.

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.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.