Kymriah

/ Novartis

Paediatric and young adult CD19+ B-cell ALL patients
* For patients 50 kg and below: 0.2 to 5 x 106 CAR-positive viable T cells/kg body weight.
* For patients above 50 kg: 0.1 to 2.5 x 108 CAR-positive viable T cells (non-weight based).
Adult DLBCL and FL patients
* 0.6 to 6.0 x 108 CAR-positive viable T cells (non-weight based).
Pre-treatment conditioning (lymphodepleting chemotherapy)
The availability of this medical product must be confirmed prior to starting the lymphodepleting regimen. For B-cell ALL and DLBCL indications, Tisagenlecleucel is recommended to be infused 2 to 14 days after completion of the lymphodepleting chemotherapy. For FL, Tisagenlecleucel is recommended to be infused 2 to 6 days after completion of the lymphodepleting chemotherapy.
Lymphodepleting chemotherapy may be omitted if a patient is experiencing significant cytopenia, e.g., white blood cell (WBC) count ≤1 000 cells/μL within one week prior to infusion.
If there is a delay of more than 4 weeks between completing lymphodepleting chemotherapy and the infusion and the WBC count is >1 000 cells/μL, then the patient should be re-treated with lymphodepleting chemotherapy prior to receiving Tisagenlecleucel.
See prescribing information about lymphodepleting chemotherapy regimen prior to receiving Tisagenlecleucel.

* Pediatric and young adult patients up to and including 25 years of age with CD19+ B-cell acute lymphoblastic leukaemia (ALL) that is refractory, in relapse post-transplant or in second or later relapse.
* Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy.
This product is not indicated for treatment of patients with primary or secondary central nervous system lymphoma.
* Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.

* Hypersensitivity to the active substance or to any of the excipients
* Contraindications of the lymphodepleting chemotherapy must be considered

Reasons to delay treatment
* 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 rapid progression of lymphoma following lymphodepleting chemotherapy.
Transmission of an infectious agent
Although Tisagenlecleucel is tested for sterility and mycoplasma, a risk of transmission of infectious agents exists. Healthcare professionals administering Tisagenlecleucel must, therefore, monitor patients for signs and symptoms of infections after treatment and treat appropriately, if needed.
Blood, organ, tissue and cell donation
Patients treated with Tisagenlecleucel must not donate blood, organs, tissues or cells for transplantation.
Cytokine release syndrome
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 in paediatric and young adult B-cell ALL patients, between 1 and 9 days (median onset 3 days) after Tisagenlecleucel infusion in adult DLBCL patients and between 1 to 14 days (median onset 4 days) after Tisagenlecleucel infusion in adult FL patients. The median time to resolution of cytokine release syndrome was 8 days in B-cell ALL patients, 7 days in DLBCL patients and 4 days in FL patients.
Symptoms of cytokine release syndrome may include high fever, rigors, myalgia, arthralgia, nausea, vomiting, diarrhoea, diaphoresis, rash, anorexia, fatigue, headache, hypotension, dyspnoea, tachypnoea, hypoxia, and tachycardia. Organ dysfunction, including cardiac insufficiency, renal insufficiency and liver injury with accompanying elevated aspartate aminotransferase (AST), elevated alanine aminotransferase (ALT) or elevated total bilirubin may also be observed. In some cases, disseminated intravascular coagulation (DIC) with low fibrinogen levels, capillary leak syndrome (CLS), macrophage activation syndrome (MAS) and haemophagocytic lymphohistiocytosis (HLH) may occur in the setting of cytokine release syndrome. Patients should be closely monitored for signs or symptoms of these events, including fever.
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.
Neurological adverse reactions
Neurological events, in particular encephalopathy, confusional state or delirium, occur frequently with Tisagenlecleucel and can be severe or life-threatening. Other manifestations included depressed level of consciousness, seizures, aphasia and speech disorder. The majority of neurological events occurred within 8 weeks following Tisagenlecleucel infusion and were transient. 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 Tisagenlecleucel treatment until the infection is resolved.
Serious infections, including life-threatening or fatal infections, in some cases with late onset, occurred frequently in patients after Tisagenlecleucel infusion. Patients should be monitored for signs and symptoms of infection and treated appropriately.
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.
Prolonged cytopenias
Patients may continue to exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Tisagenlecleucel infusion and should be managed according to standard guidelines.
Secondary malignancies
Patients treated with Tisagenlecleucel 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 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)
TLS, which may be severe, has occasionally been observed. To minimise risk of TLS, patients with elevated uric acid or high tumor 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.
Prior stem cell transplantation
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.
Serological testing
Screening for HBV, HCV and HIV must be performed in accordance with clinical guidelines before collection of cells for manufacturing. Hepatitis B virus (HBV) reactivation, can occur in patients treated with medicinal products directed against B cells and could result in fulminant hepatitis, hepatic failure and death.
Prior treatment with anti-CD19 therapy
Tisagenlecleucel is not recommended if the patient has relapsed with CD19-negative leukaemia after prior anti-CD19 therapy.
Interference with virological testing
Due to limited and short spans of identical genetic information between the lentiviral vector used to create Tisagenlecleucel and HIV, some commercial HIV nucleic acid tests (NAT) may give a false positive result.
Hypersensitivity reactions
Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) and dextran 40 in this medical product. All patients should be observed closely during the infusion period.
See prescribing information for full details.

Very common: Infections – pathogen unspecified, viral infections, bacterial infections, anemia, febrile neutropenia, neutropenia, thrombocytopenia, cytokine release syndrome, hypogammaglobulinaemia, decreased appetite, hypokalaemia, hypophosphataemia, headache, encephalopathy, tachycardia, haemorrhage, hypotension, hypertension, cough, dyspnea, hypoxia, diarrhoea, nausea, vomiting, constipation, abdominal pain, rash, arthralgia, musculoskeletal pain, acute kidney injury, pyrexia, fatigue, oedema, pain, lymphocyte count decreased, white blood cell count decreased, haemoglobin decreased, neutrophil count decreased, platelet count decreased, hepatic enzyme increased.
Common: Fungal infections, Leukopenia, pancytopenia, coagulopathy, lymphopenia, infusion-related reaction, graft-versus-host disease, haemophagocytic lymphohistiocytosis, hypomagnesaemia, hypoalbuminaemia, hyperglycaemia, hyponatraemia, hyperuricaemia, hypercalcaemia, tumour lysis syndrome, hyperkalaemia, hyperphosphataemia, hypernatraemia, hyperferritinaemia, hypocalcaemia, anxiety, delirium, sleep disorder, dizziness, peripheral neuropathy, tremor, motor dysfunction, seizure, speech disorders, neuralgia, visual impairment, cardiac failure, cardiac arrest, atrial fibrillation, thrombosis, capillary leak syndrome, oropharyngeal pain, pulmonary oedema, nasal congestion, pleural effusion, tachypnea, stomatitis, abdominal distension, dry mouth, ascites, hyperbilirubinaemia, pruritus, erythema, hyperhidrosis, night sweats, myalgia, influenza-like illness, asthenia, multiple organ dysfunction syndrome, chills, blood bilirubin increased, weight decreased, blood fibrinogen decreased, international normalised ratio increased, fibrin D dimer increased, activated partial thromboplastin time prolonged, prothrombin time prolonged.
See prescribing information for full details.

No pharmacokinetic or pharmacodynamic drug interaction studies with tisagenlecleucel have been performed in either the paediatric or adult population. The co-administration of agents known to inhibit T-cell function has not been formally studied.
Live vaccines:
The safety of immunisation with live vaccines during or following Tisagenlecleucel treatment 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 lymphodepleting chemotherapy, during Tisagenlecleucel treatment, and until immune recovery following treatment.
See prescribing information for full details.

Women of childbearing potential: See the prescribing information for lymphodepleting chemotherapy for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy
Pregnancy: There are no data from the use of tisagenlecleucel in pregnant women. Pregnant women who have received Tisagenlecleucel may have hypogammaglobulinaemia. Assessment of immunoglobulin levels is indicated in newborns of mothers treated with Tisagenlecleucel.
Lactation: It is unknown whether tisagenlecleucel cells are excreted in human milk

Overdose has not been reported. In case of overdose, the potential risk is an increased probability of developing CRS including severe CRS.

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 and must refrain from driving or operating heavy or potentially dangerous machines for 8 weeks following Tisagenlecleucel infusion.