KYMRIAH perfusable dispersion medication leaflet

Kymriah 1.2 × 106 - 6 × 108 cells dispersion for infusion

2.1 General description

Kymriah (tisagenlecleucel) is a genetically modified autologous cell-based product containing T cellstransduced ex vivo using a lentiviral vector expressing an anti-CD19 chimeric antigen receptor (CAR)comprising a murine anti-CD19 single chain variable fragment (scFv) linked via a human CD8 hingeand transmembrane region to an intracellular signalling chain of human 4-1BB (CD137) co-stimulatory domain and CD3-zeta signalling domain.

2.2 Qualitative and quantitative composition

Each patient-specific infusion bag of Kymriah contains tisagenlecleucel at a batch-dependentconcentration of autologous T cells genetically modified to express an anti-CD19 chimeric antigenreceptor (CAR-positive viable T cells). The medicinal product is packaged in one or more infusionbags overall containing a cell dispersion of 1.2 × 106 to 6 × 108 CAR-positive viable T cells in acryopreservative solution.

The cellular composition and the final cell number varies between individual patient batches. Inaddition to T cells, natural killer (NK) cells may be present.

Each infusion bag contains 10-30 mL or 30-50 mL of cell dispersion.

The quantitative information of medicinal product, including the number of infusion bags (seesection 6) to be administered, is presented on the batch-specific documentation accompanying themedicinal product for treatment.

This medicinal product contains 2.43 mg sodium per mL and 24.3 to 121.5 mg sodium per dose.

Each bag contains 11 mg dextran 40 and 82.5 mg dimethyl sulfoxide (DMSO) per mL.

For the full list of excipients, see section 6.1.

Dispersion for infusion

A colourless to slightly yellow dispersion

Kymriah is indicated for the treatment of:

* Paediatric and young adult patients up to and including 25 years of age with B-cell acutelymphoblastic leukaemia (ALL) that is refractory, in relapse post-transplant or in second or laterrelapse.

* Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two ormore lines of systemic therapy.

* Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines ofsystemic therapy.

Kymriah must be administered in a qualified treatment centre. Therapy should be initiated under thedirection of and supervised by a healthcare professional experienced in the treatment ofhaematological malignancies and trained for administration and management of patients treated withthe medicinal product.

In the event of cytokine release syndrome (CRS), at least one dose of tocilizumab and emergencyequipment must be available per patient prior to infusion. The treatment centre must have access toadditional doses of tocilizumab within 8 hours. In the exceptional case where tocilizumab is notavailable due to a shortage that is listed in the European Medicines Agency shortage catalogue,suitable alternative measures to treat CRS instead of tocilizumab must be available prior to infusion.

Manufacture and release of Kymriah usually takes about 3-4 weeks.

Kymriah is intended for autologous use only (see section 4.4).

Treatment consists of a single dose for infusion containing a dispersion for infusion of CAR-positiveviable T cells in one or more infusion bags.

Dose in paediatric and young adult B-cell ALL patients

The concentration of CAR-positive viable T cells is dependent on indication and patient body weight.

- For patients 50 kg and below: The dose is within a range of 0.2 to 5 × 106 CAR-positive viable

T cells per kg body weight.

- For patients above 50 kg: The dose is within a range of 0.1 to 2.5 × 108 CAR-positive viable Tcells (non-weight based).

Dose in adult DLBCL and FL patients

- The dose is within a range of 0.6 to 6 × 108 CAR-positive viable T cells (non-weight based).

See the accompanying batch specific documentation for additional information pertaining to dose.

Pre-treatment conditioning (lymphodepleting chemotherapy)

The availability of Kymriah must be confirmed prior to starting the lymphodepleting regimen. For B-cell ALL and DLBCL indications, Kymriah is recommended to be infused 2 to 14 days aftercompletion of the lymphodepleting chemotherapy. For FL, Kymriah is recommended to be infused 2to 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 theinfusion and the WBC count is >1 000 cells/μL, then the patient should be re-treated withlymphodepleting chemotherapy prior to receiving Kymriah.

B-cell ALL

The recommended lymphodepleting chemotherapy regimen is:

- Fludarabine (30 mg/m2 intravenous daily for 4 days) and cyclophosphamide (500 mg/m2intravenous daily for 2 days starting with the first dose of fludarabine).

If the patient experienced a previous Grade 4 haemorrhagic cystitis with cyclophosphamide, ordemonstrated a chemorefractory state to a cyclophosphamide-containing regimen administered shortlybefore lymphodepleting chemotherapy, then the following should be used:

- Cytarabine (500 mg/m2 intravenous daily for 2 days) and etoposide (150 mg/m2 intravenousdaily for 3 days starting with the first dose of cytarabine).

DLBCL and FL

The recommended lymphodepleting chemotherapy regimen is:

- Fludarabine (25 mg/m2 intravenous daily for 3 days) and cyclophosphamide (250 mg/m2intravenous daily for 3 days starting with the first dose of fludarabine).

If the patient experienced a previous Grade 4 haemorrhagic cystitis with cyclophosphamide, ordemonstrated a chemorefractory state to a cyclophosphamide-containing regimen administered shortlybefore lymphodepleting chemotherapy, then the following should be used:

- Bendamustine (90 mg/m2 intravenous daily for 2 days).

Pre-medication

To minimise potential acute infusion reactions, it is recommended that patients be pre-medicated withparacetamol and diphenhydramine or another H1 antihistamine within approximately 30 to 60 minutesprior to Kymriah infusion. Corticosteroids should not be used at any time except in the case of a life-threatening emergency (see section 4.4).

Clinical assessment prior to infusion

Kymriah treatment should be delayed in some patient groups at risk (see section 4.4).

Monitoring after infusion

- In the first week following infusion, patients should be monitored 2 to 3 times, or morefrequently at the physician’s discretion, for signs and symptoms of potential cytokine releasesyndrome, neurological events and other toxicities.

- After the first week following the infusion, the patient should be monitored at the physician’sdiscretion.

- Physicians should consider hospitalisation at the first signs/symptoms of cytokine releasesyndrome and/or neurological events.

- Patients should be instructed to remain within proximity (within 2 hours of travel) of a qualifiedclinical facility for at least 4 weeks following infusion.

B-cell ALL

The safety and efficacy of Kymriah in this population have not been established.

DLBCL and FL

No dose adjustment is required in patients over 65 years of age.

Patients seropositive for hepatitis B virus (HBV), hepatitis C virus (HCV), or humanimmunodeficiency virus (HIV)

There is no experience with manufacturing Kymriah for patients with a positive test for HIV, active

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

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

B-cell ALL

There is limited experience with Kymriah in paediatric patients below the age of 3 years. Currentlyavailable data in this age group are described in sections 4.8 and 5.1.

DLBCL

The safety and efficacy of Kymriah in children and adolescents below 18 years of age have not yetbeen established. Currently available data are described in section 5.1 but no recommendation on aposology can be made.

FL

The safety and efficacy of Kymriah in children and adolescents below 18 years of age have not yetbeen established. No data are available.

Kymriah is for intravenous use only.

Kymriah is intended for autologous use only. Before administration, it must be confirmed that thepatient’s identity matches the unique patient information on the Kymriah infusion bags andaccompanying documentation. The total number of infusion bags to be administered should also beconfirmed with the patient-specific information on the batch-specific documentation (see section 4.4).

The timing of thaw of Kymriah and infusion should be coordinated (please refer to section 6.6).

Kymriah should be administered as an intravenous infusion through latex-free intravenous tubingwithout a leukocyte depleting filter, at approximately 10 to 20 mL per minute by gravity flow.

If the volume of Kymriah to be administered is ≤20 mL, intravenous push may be used as analternative method of administration.

For detailed instructions on preparation, administration, measures to take in case of accidentalexposure and disposal of Kymriah, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (seesection 4.4).

Contraindications of the lymphodepleting chemotherapy must be considered.

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

Autologous use

Kymriah is intended solely for autologous use and must not, under any circumstances, be administeredto other patients. Kymriah must not be administered if the information on the product labels and batchspecific documentation do not match the patient’s identity.

Reasons to delay treatment

Due to the risks associated with tisagenlecleucel treatment, infusion should be delayed if a patient hasany of the following conditions:

- Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions orhypotension) from preceding chemotherapies.

- Active uncontrolled infection.

- Active graft-versus-host disease (GVHD).

- Significant clinical worsening of leukaemia burden or rapid progression of lymphoma followinglymphodepleting chemotherapy.

Transmission of an infectious agent

Although Kymriah is tested for sterility and mycoplasma, a risk of transmission of infectious agentsexists. Healthcare professionals administering Kymriah must, therefore, monitor patients for signs andsymptoms of infections after treatment and treat appropriately, if needed.

Blood, organ, tissue and cell donation

Patients treated with Kymriah must not donate blood, organs, tissues or cells for transplantation. Thisinformation is provided in the Patient Alert Card which should be given to the patient after treatment.

Active central nervous system (CNS) leukaemia or lymphoma

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

Cytokine release syndrome

Cytokine release syndrome (CRS), including fatal or life-threatening events, has been frequentlyobserved after Kymriah infusion (see section 4.8). In almost all cases, development of CRS occurredbetween 1 to 10 days (median onset 3 days) after Kymriah infusion in paediatric and young adult B-cell ALL patients, between 1 and 9 days (median onset 3 days) after Kymriah infusion in adult

DLBCL patients and between 1 to 14 days (median onset 4 days) after Kymriah infusion in adult FLpatients. In some cases onset of CRS occurred after that period. The median time to resolution ofcytokine release syndrome was 8 days in B-cell ALL patients, 7 days in DLBCL patients and 4 days in

FL patients.

Patients should be closely monitored for signs or symptoms of CRS and patients and caregivers shouldbe informed about potential late onset of signs or symptoms and instructed accordingly. Symptoms of

CRS 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 withaccompanying elevated aspartate aminotransferase (AST), elevated alanine aminotransferase (ALT) orelevated 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 CRS.

Risk factors for severe CRS in paediatric and young adult B-cell ALL patients are: high pre-infusiontumour burden, uncontrolled or accelerating tumour burden following lymphodepleting chemotherapy,active infection and early onset of fever or CRS following Kymriah infusion. High tumour burdenprior to Kymriah infusion was identified as a risk factor for developing severe cytokine releasesyndrome in adult DLBCL patients.

Prior to administration of Kymriah in paediatric and young adult B-cell ALL patients, efforts shouldbe made to lower and control the patient’s tumour burden.

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 duringcytokine release syndrome and may increase the risk of a fatal event.

Management of cytokine release syndrome associated with Kymriah

To reduce the risk of or manage CRS complications (see above), patients treated with Kymriah mayreceive anti-interleukin-6-based intervention (e.g. tocilizumab) with or without a corticosteroid-basedtherapy. CRS management strategies may be implemented based on the most recent relevant treatmentguidelines, including appropriate local institutional/academic guidelines.

One dose of tocilizumab per patient must be on site and available for administration prior to Kymriahinfusion. The treatment centre should have access to additional doses of tocilizumab within 8 hours. Inthe exceptional case where tocilizumab is not available due to a shortage that is listed in the European

Medicines Agency shortage catalogue, the treatment centre must have access to suitable alternativemeasures instead of tocilizumab to treat CRS.

Tisagenlecleucel continues to expand and persist following administration of tocilizumab andcorticosteroids. Patients with medically significant cardiac dysfunction should be managed bystandards of critical care and measures such as echocardiography should be considered. Tumournecrosis factor (TNF) antagonists are not recommended for management of Kymriah-associated CRS.

Neurological adverse reactions

Neurological events (also known as immune effector cell-associated neurotoxicity syndrome[ICANS]), in particular encephalopathy, confusional state or delirium, occur frequently with Kymriahand can be severe or life-threatening (see section 4.8). Other manifestations included depressed levelof consciousness, seizures, aphasia and speech disorder. The majority of neurological events occurredwithin 8 weeks following Kymriah infusion and were transient. In some cases onset of neurologicalevents occurred after that period. The median time to onset of the first neurological events occurring atany time following Kymriah infusion was 9 days in B-cell ALL, 6 days in DLBCL, and 9 days in FL.

The median time to resolution was 7 days for B-cell ALL, 13 days for DLBCL, and 2 days for FL.

Neurological events can be concurrent with cytokine release syndrome, following resolution ofcytokine release syndrome or in the absence of cytokine release syndrome.

Patients should be monitored for neurological events and patients and caregivers should be informedabout the potential late onset of events and instructed accordingly. To reduce the risk of or manageneurological toxicities (including ICANS) (see above), patients treated with Kymriah may receivesupportive treatment based on the most recent relevant guidelines, including appropriate localinstitutional/academic guidelines.

Infections and febrile neutropenia

Patients with active, uncontrolled infection should not start Kymriah treatment until the infection isresolved. Prior to Kymriah infusion, infection prophylaxis should follow standard guidelines based onthe degree of preceding immunosuppression.

Serious infections, including life-threatening or fatal infections, in some cases with late onset,occurred frequently in patients after Kymriah infusion (see section 4.8). Patients should be monitoredfor signs and symptoms of infection and treated appropriately. As appropriate, prophylactic antibioticsshould 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 cytokinerelease syndrome. The possibility of opportunistic infections of the central nervous system should beconsidered in patients with neurological adverse events and appropriate diagnostic evaluations shouldbe performed.

Febrile neutropenia was frequently observed in patients after Kymriah infusion (see section 4.8) andmay be concurrent with cytokine release syndrome. In the event of febrile neutropenia, infectionshould be evaluated and managed appropriately with broad-spectrum antibiotics, fluids and othersupportive care, as medically indicated.

In patients achieving complete remission following Kymriah, resulting low immunoglobulin levels canincrease the risk for infections. Attention to signs and symptoms of infection should be implementedaccording to age and standard specific guidelines.

Prolonged cytopenias

Patients may continue to exhibit cytopenias for several weeks following lymphodepletingchemotherapy and Kymriah infusion and should be managed according to standard guidelines. Themajority of patients who had cytopenias at day 28 following Kymriah treatment resolved to Grade 2 orbelow within three months after treatment for paediatric ALL and DLBCL patients, and within sixmonths for FL patients. 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 duringthe first 3 weeks after Kymriah infusion or until cytokine release syndrome has resolved.

Secondary malignancies including of T-cell origin

Patients treated with Kymriah may develop secondary malignancies or recurrence of their cancer. T-cell malignancies have been reported following treatment of haematological malignancies with a

BCMA- or CD19-directed CAR T-cell therapy, including Kymriah. T-cell malignancies, including

CAR-positive malignancies, have been reported within weeks and up to several years followingadministration of a CD19- or BCMA-directed CAR T-cell therapy. There have been fatal outcomes.

Patients should be monitored life-long for secondary malignancies. In the event that a secondarymalignancy occurs, the company should be contacted to obtain instructions on patient samples tocollect for testing.

Hypogammaglobulinaemia and agammaglobulinaemia can occur in patients after Kymriah infusion.

Immunoglobulin levels should be monitored after treatment with Kymriah. In patients with lowimmunoglobulin levels pre-emptive measures such as infection precautions, antibiotic prophylaxis andimmunoglobulin replacement should be taken according to age and standard guidelines.

TLS, which may be severe, has occasionally been observed. To minimise risk of TLS, patients withelevated 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 managedaccording to standard guidelines.

Concomitant disease

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

Prior stem cell transplantation

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

Serological testing

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 beforecollection of cells for manufacturing. Hepatitis B virus (HBV) reactivation, can occur in patientstreated with medicinal products directed against B cells and could result in fulminant hepatitis, hepaticfailure and death.

CD19-negative B-cell ALL disease

Kymriah is not recommended if the B-cell ALL patient has CD19-negative disease or an unconfirmed

CD19 status.

Prior treatment with anti-CD19 therapy

There is limited experience with Kymriah in patients exposed to prior CD19-directed therapy. Whileactivity of tisagenlecleucel has been observed, data are currently too limited to make an adequateassessment of the benefit-risk profile in these patients. Kymriah is not recommended if the patient hasrelapsed 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 tocreate Kymriah and HIV, some commercial HIV nucleic acid tests (NAT) may give a false positiveresult.

Serious hypersensitivity reactions, including anaphylaxis, have been reported and may be due todimethyl sulfoxide (DMSO) and dextran 40 in Kymriah. All patients should be observed closelyduring the infusion period.

Long-term follow-up

Patients are expected to be enrolled in a registry in order to better understand the long-term safety andefficacy of Kymriah.

Sodium and potassium content

This medicinal product contains 24.3 to 121.5 mg sodium per dose, equivalent to 1 to 6% of the WHOrecommended 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”.

No pharmacokinetic or pharmacodynamic drug interaction studies with tisagenlecleucel have beenperformed in either the paediatric or adult population. The co-administration of agents known toinhibit T-cell function has not been formally studied. Administration of low-dose steroids as per thecytokine 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 beeninvestigated and the effects are unknown.

Live vaccines

The safety of immunisation with live vaccines during or following Kymriah treatment has not beenstudied. As a precautionary measure, vaccination with live vaccines is not recommended for at least6 weeks prior to the start of lymphodepleting chemotherapy, during Kymriah treatment, and untilimmune recovery following treatment.

Pregnancy status for females of childbearing age should be verified prior to starting treatment with

Kymriah.

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

There are insufficient exposure data to provide a recommendation concerning duration ofcontraception following treatment with Kymriah.

There are no data from the use of tisagenlecleucel in pregnant women. No animal studies have beenconducted with tisagenlecleucel to assess whether it can cause foetal harm when administered to apregnant woman (see section 5.3). It is not known whether tisagenlecleucel has the potential to betransferred to the foetus via the placenta and could cause foetal toxicity, including B-celllymphocytopenia. Kymriah is not recommended during pregnancy and in women of childbearingpotential not using contraception.

Pregnant women should be advised on the potential risks to the foetus. Pregnancy after Kymriahtherapy should be discussed with the treating physician. Pregnant women who have received Kymriahmay have hypogammaglobulinaemia. Assessment of immunoglobulin levels is indicated in newbornsof mothers treated with Kymriah.

It is unknown whether tisagenlecleucel cells are excreted in human milk. A risk to the breast-fed infantcannot be excluded. Women who are breast-feeding should be advised of the potential risk to thebreast-fed infant.

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

There are no data on the effect of Kymriah on fertility. Effects of Kymriah on male and female fertilityhave 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, patientsreceiving Kymriah are at risk for altered or decreased consciousness or coordination and must refrainfrom driving or operating heavy or potentially dangerous machines for 8 weeks following Kymriahinfusion.

Safety assessment was based on a total of 424 patients (with paediatric and young adult B-cell ALL,

DLBCL and FL) who received Kymriah in three multicentre pivotal clinical studies.

B-cell ALL

The adverse reactions described in this section were characterised in 212 patients infused with

Kymriah in the pivotal clinical study CCTL019B2202 and in the supportive studies CCTL019B2205Jand CCTL019B2001X.

The most common non-haematological adverse reactions were cytokine release syndrome (75%),infections (70%), hypogammaglobulinaemia (49%), pyrexia (43%) and decreased appetite (28%).

The most common haematological laboratory abnormalities were decreased white blood cells (100%),decreased haemoglobin (99%), decreased neutrophils (98%), decreased lymphocytes (98%) anddecreased platelets (95%).

Grade 3 and 4 adverse reactions were reported in 86% of patients. The most common Grade 3 and 4non-haematological adverse reaction was cytokine release syndrome (37%).

The most common Grade 3 and 4 haematological laboratory abnormalities were white blood cellsdecreased (97%), lymphocytes decreased (94%), neutrophils decreased (96%), platelets decreased(70%) and haemoglobin decreased (46%).

Grade 3 and 4 adverse reactions were more often observed within the initial 8 weeks post infusion(78% of patients) compared to after 8 weeks post infusion (49% of patients).

DLBCL

The adverse reactions described in this section were characterised in 115 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 (57%),infections (58%), pyrexia (35%), diarrhoea (31%), nausea (29%), fatigue (27%) and hypotension(25%).

The most common haematological laboratory abnormalities were decreased lymphocytes (100%),decreased white blood cells (99%), decreased haemoglobin (99%), decreased neutrophils (97%), anddecreased platelets (95%).

Grade 3 and 4 adverse reactions were reported in 88% of patients. The most common Grade 3 and 4non-haematological adverse reactions were infections (34%) and cytokine release syndrome (23%).

The most common (>25%) Grade 3 and 4 haematological laboratory abnormalities were lymphocytecount decreased (95%), neutrophil count decreased (82%), white blood cell count decreased (78%),haemoglobin decreased (59%) and platelet count decreased (56%).

Grade 3 and 4 adverse reactions were more often observed within the initial 8 weeks post infusion(82%) compared to after 8 weeks post infusion (48%).

FL

The adverse reactions described in this section were characterised in 97 patients infused with Kymriahin one global multicentre international study, i.e. the ongoing pivotal clinical study CCTL019E2202.

The most common non-haematological adverse reactions (>25%) were cytokine release syndrome(50%), infections (50%) and headache (26%).

The most common haematological laboratory abnormalities were decreased haemoglobin (94%),decreased lymphocytes (92%), decreased white blood cells (91%), decreased neutrophils (89%) anddecreased platelets (89%).

Grade 3 and 4 adverse reactions were reported in 75% of patients. The most common Grade 3 and 4non-haematological adverse reactions were infections (16%).

The most common (>25%) Grade 3 and 4 haematological laboratory abnormalities were lymphocytecount decreased (87%), white blood cell count decreased (74%), neutrophil count decreased (71%),platelet count decreased (26%) and haemoglobin decreased (25%).

Grade 3 and 4 adverse reactions were more often observed within the initial 8 weeks post infusion(70%) compared to after 8 weeks post infusion (40%).

The adverse reactions described in this section were identified in 79, 115 and 97 patients in theongoing multicentre pivotal clinical studies (CCTL019B2202, CCTL019C2201 and CCTL019E2202),as well as 64 and 69 patients in the supportive studies (CCTL019B2205J and CCTL019B2001X), andfrom post-marketing reporting. Adverse drug reactions (Table 1) are listed by MedDRA system organclass. Within each system organ class, the adverse drug reactions are ranked by frequency, with themost frequent reactions first, using the following convention: very common (≥1/10); common (≥1/100to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); notknown (cannot be estimated from the available data). Within each frequency grouping, adverse drugreactions are presented in order of decreasing seriousness.

Table 1 Adverse drug reactions

Infections and infestations1)

Very common: Infections - pathogen unspecified, viral infections, bacterial infections

Common: Fungal infections

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Rare: Secondary malignancy of T-cell origin

Very common: Anaemia, febrile neutropenia, neutropenia, thrombocytopenia

Common: Leukopenia, pancytopenia, coagulopathy, lymphopenia

Uncommon: B-cell aplasia

Very common: Cytokine release syndrome, hypogammaglobulinaemia2)

Common: Infusion-related reaction, graft-versus-host disease3), haemophagocyticlymphohistiocytosis

Not known: Anaphylactic reaction

Very common: Decreased appetite, hypokalaemia, hypophosphataemia

Common: Hypomagnesaemia, hypoalbuminaemia4), hyperglycaemia, hyponatraemia,hyperuricaemia5), hypercalcaemia, tumour lysis syndrome, hyperkalaemia,hyperphosphataemia6), hypernatraemia, hyperferritinaemia7), hypocalcaemia

Uncommon: Hypermagnesaemia

Common: Anxiety, delirium8), sleep disorder9)

Very common: Headache10), encephalopathy11)

Common: Dizziness12), peripheral neuropathy13), tremor14), motor dysfunction15), seizure16),immune effector cell-associated neurotoxicity syndrome**, speech disorders17),neuralgia18)

Uncommon: Ischaemic cerebral infarction, ataxia19)

Not known: Neurotoxicity

Common: Visual impairment20)

Very common: Tachycardia21)

Common: Cardiac failure22), cardiac arrest, atrial fibrillation

Uncommon: Ventricular extrasystoles

Very common: Haemorrhage23), hypotension24), hypertension

Common: Thrombosis25), capillary leak syndrome

Uncommon: Flushing

Very common: Cough26), dyspnoea27), hypoxia

Common: Oropharyngeal pain28), pulmonary oedema29), nasal congestion, pleuraleffusion, tachypnoea

Uncommon: Acute respiratory distress syndrome, lung infiltration

Very common: Diarrhoea, nausea, vomiting, constipation, abdominal pain30)

Common: Stomatitis, abdominal distension, dry mouth, ascites

Common: Hyperbilirubinaemia

Very common: Rash31)

Common: Pruritus, erythema, hyperhidrosis, night sweats

Very common: Arthralgia, musculoskeletal pain32)

Common: Myalgia

Very common: Acute kidney injury33)

Very common: Pyrexia, fatigue34), oedema35), pain36)

Common: Influenza-like illness, asthenia, multiple organ dysfunction syndrome, chills

Very common: Lymphocyte count decreased*, white blood cell count decreased*,haemoglobin decreased*, neutrophil count decreased*, platelet countdecreased*, hepatic enzyme increased37)

Common: Blood bilirubin increased, weight decreased, blood fibrinogen decreased,international normalised ratio increased, fibrin D dimer increased, activatedpartial thromboplastin time prolonged, prothrombin time prolonged1) Infections and infestations presented reflect high-level group terms.2) Hypogammaglobulinaemia includes blood immunoglobulin A decreased, bloodimmunoglobulin G decreased, blood immunoglobulin M decreased,hypogammaglobulinaemia, immunodeficiency, immunodeficiency common variable andimmunoglobulins decreased.3) Graft-versus-host disease (GvHD) includes GvHD, GvHD in gastrointestinal tract, GvHD inskin4) Hypoalbuminaemia includes blood albumin decreased, hypoalbuminaemia5) Hyperuricaemia includes blood uric acid increased, hyperuricaemia6) Hyperphosphataemia includes blood phosphorus increased, hyperphosphataemia7) Hyperferritinaemia includes hyperferritinaemia, serum ferritin increased8) Delirium includes agitation, delirium, hallucination, hallucination visual, irritability andrestlessness.9) Sleep disorder includes insomnia, nightmare and sleep disorder.10) Headache includes headache and migraine.11) Encephalopathy includes automatism, cognitive disorder, confusional state, depressed levelof consciousness, disturbance in attention, encephalopathy, lethargy, memory impairment,mental status changes, metabolic encephalopathy, somnolence and thinking abnormal.

Encephalopathy is a dominant feature of immune effector cell-associated neurotoxicitysyndrome (ICANS), along with other symptoms.12) Dizziness includes dizziness, presyncope and syncope.13) Peripheral neuropathy includes dysaesthesia, hyperaesthesia, hypoaesthesia, neuropathyperipheral, paraesthesia and peripheral sensory neuropathy.14) Tremor includes dyskinesia and tremor.15) Motor dysfunction includes muscle spasms, muscle twitching, myoclonus and myopathy.16) Seizure includes generalised tonic-clonic seizures, seizure and status epilepticus.17) Speech disorders includes aphasia, dysarthria and speech disorders.18) Neuralgia includes neuralgia and sciatica.19) Ataxia includes ataxia and dysmetria.20) Visual impairment includes vision blurred and visual impairment.21) Tachycardia includes sinus tachycardia, supraventricular tachycardia, tachycardia22) Cardiac failure includes cardiac failure, cardiac failure congestive, left ventriculardysfunction and right ventricular dysfunction.23) Haemorrhage includes anal haemorrhage, blood blister, blood urine present, catheter sitehaemorrhage, cerebral haemorrhage, conjunctival haemorrhage, contusion, cystitishaemorrhagic, disseminated intravascular coagulation, duodenal ulcer haemorrhage,ecchymosis, epistaxis, eye contusion, gastrointestinal haemorrhage, gingival bleeding,haemarthrosis, haematemesis, haematochezia, haematoma, haematuria, haemoptysis, heavymenstrual bleeding, injection site haematoma, intermenstrual bleeding, large intestinalhaemorrhage, lip haemorrhage, melaena, mouth haemorrhage, mucosal haemorrhage, oralblood blister, periorbital haematoma, peritoneal haematoma, petechiae, pharyngealhaemorrhage, post-procedural haemorrhage, pulmonary haemorrhage, purpura, rectalhaemorrhage, retinal haemorrhage, stoma site haemorrhage, subcutaneous haematoma,subdural haematoma, subdural haemorrhage, tooth socket haemorrhage, trachealhaemorrhage, traumatic haematoma, tumour haemorrhage, upper gastrointestinalhaemorrhage and vaginal haemorrhage.24) Hypotension includes hypotension and orthostatic hypotension.25) Thrombosis includes deep vein thrombosis, embolism, pulmonary embolism, thrombosis,vena cava thrombosis and venous thrombosis.26) Cough includes cough, productive cough and upper-airway cough syndrome.

27) Dyspnoea includes acute respiratory failure, dyspnoea, dyspnoea exertional, respiratorydistress and respiratory failure.28) Oropharyngeal pain includes oral pain and oropharyngeal pain.29) Pulmonary oedema includes acute pulmonary oedema and pulmonary oedema.30) Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower,abdominal pain upper and gastrointestinal pain.31) Rash includes dermatitis, dermatitis acneiform, dermatitis contact, rash, rash maculo-papular,rash papular and rash pruritic.32) Musculoskeletal pain includes back pain, bone pain, flank pain, musculoskeletal chest pain,musculoskeletal pain, neck pain, non-cardiac chest pain.33) Acute kidney injury includes acute kidney injury, anuria, azotaemia, blood creatinineabnormal, blood creatinine increased, blood urea increased, renal failure, renal tubulardysfunction and renal tubular necrosis.34) Fatigue includes fatigue and malaise.35) Oedema includes face oedema, fluid retention, generalised oedema, hypervolaemia, localisedoedema, oedema peripheral, periorbital oedema and peripheral swelling.36) Pain includes pain and pain in extremity.37) Hepatic enzyme increased includes alanine aminotransferase increased, aspartateaminotransferase increased, blood alkaline phosphatase increased, hepatic enzyme increased,transaminases increased.

* Frequency is based on laboratory values. Patients are counted only for the worst gradeobserved post baseline.

** Abbreviated as ICANS. Symptoms or signs can be progressive and may include aphasia,altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, andcerebral oedema.

Description of selected adverse drug reactions

Cytokine release syndrome

In the clinical studies in paediatric and young adult B-cell ALL (N=212), cytokine release syndromewas reported in 75% of patients (37% with Grade 3 or 4; 0.5% [1 patient] with fatal outcome).

In the ongoing clinical study in DLBCL (N=115), cytokine release syndrome was reported in 57% ofpatients (23% with Grade 3 or 4).

In the ongoing clinical study in FL (N=97), cytokine release syndrome was reported in 50% ofpatients. No Grade 3 or 4 events were reported.

Cytokine release syndrome was graded per Penn criteria in the paediatric and young adult B-cell ALLand DLBCL studies as follows: Grade 1: mild reactions, reactions requiring supportive care;

Grade 2: moderate reactions, reactions requiring intravenous therapies; Grade 3: severe reactions,reactions requiring low-dose vasopressors or supplemental oxygen; Grade 4: life-threatening reactions,those requiring high-dose vasopressors or intubation; Grade 5: death.

Cytokine release syndrome was graded per the Lee criteria in the FL study as follows: Grade 1: mildgeneral symptoms requiring symptomatic treatment; Grade 2: symptoms requiring moderateintervention such as low-flow oxygen supplementation or low-dose vasopressor; Grade 3: symptomsrequiring aggressive intervention, such as high-flow oxygen supplementation and high-dosevasopressor; Grade 4: life-threatening symptoms requiring intubation; Grade 5: death.

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

Infections and febrile neutropenia

In B-cell ALL patients severe infections (Grade 3 and higher), which can be life-threatening or fatal,occurred in 36% of patients after Kymriah infusion. The overall incidence (all grades) was 70%(unspecified 55%, viral 31%, bacterial 24% and fungal 12%) (see section 4.4). 41% of the patientsexperienced 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 34% of patients. The overall incidence (all grades) was 58% (unspecified 48%, bacterial15%, fungal 11% and viral 11%) (see section 4.4). 37% of the patients experienced an infection of anytype within 8 weeks.

In FL patients severe infections (Grade 3 or 4), occurred in 16% of patients. The overall incidence (allgrades) was 50% (unspecified 36%, viral 17%, bacterial 6%, and fungal 2%) (see section 4.4). 19% ofthe patients experienced an infection of any type within 8 weeks.

Severe febrile neutropenia (Grade 3 or 4) was observed in 26% of paediatric and young adult B-cell

ALL patients, 17% of DLBCL patients and 12% of FL patients. See section 4.4 for the management offebrile neutropenia before and after Kymriah infusion.

Prolonged cytopenias

Cytopenias are very common based on prior chemotherapies and Kymriah therapy.

All paediatric and young adult B-cell ALL patients had a Grade 3 or 4 cytopenia at some time after

Kymriah infusion. Grade 3 and 4 cytopenias not resolved by day 28 after Kymriah infusion based onlaboratory findings included decreased count of white blood cells (50%), neutrophils (56%),lymphocytes (43%), and thrombocytes (32%) and decreased haemoglobin (11%).

All adult DLBCL patients had Grade 3 and 4 cytopenias at some time after Kymriah infusion. Grade 3and 4 cytopenias not resolved by day 28 based on laboratory findings included decreased count ofthrombocytes (39%), lymphocytes (29%), neutrophils (25%), and white blood cells (21%) anddecreased haemoglobin (14%).

In adult patients with FL, 99% had Grade 3 and 4 cytopenias at any time post Kymriah infusion.

Grade 3 and 4 cytopenias not resolved by day 28 after Kymriah infusion based on laboratory findingsincluded a decreased count of lymphocytes (23%), thrombocytes (17%), neutrophils (16%), whiteblood cells (13%) and decreased haemoglobin (3%).

Neurological adverse reactions

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

In paediatric and young adult B-cell ALL patients, serious neurological adverse reactions includingmanifestations of encephalopathy and/or delirium occurred in 32% of patients (10% were Grade 3 or4) within 8 weeks after Kymriah infusion. In DLBCL patients, manifestations of encephalopathyand/or delirium occurred in 20% of patients (11% were Grade 3 or 4) within 8 weeks after Kymriahinfusion. In FL patients, these occurred in 9% of patients (1% Grade 3 or 4) within 8 weeks after

Kymriah infusion. Among the neurotoxic events in FL patients, immune effector cell-associatedneurotoxicity syndrome (ICANS) occurred in 4% of patients (1% Grade 3 or 4), all within 8 weeks of

Kymriah infusion.

For clinical management of neurological adverse reactions, see section 4.4.

Hypogammaglobulinaemia was reported in 49% of patients treated with Kymriah for r/r ALL, 17% ofpatients with r/r DLBCL and 17% of patients with r/r FL.

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

In clinical studies, humoral immunogenicity of tisagenlecleucel was measured by determination ofanti-murine CAR19 antibodies (anti-mCAR19) in serum pre- and post-administration. The majority ofpatients tested positive for pre-dose anti-mCAR19 antibodies in paediatric and young adult ALL(B2202, B2205J, B2001X, 84.0%), adult DLBCL (C2201, 93.9%) and adult FL (E2202, 66.0%)patients.

Treatment-induced anti-mCAR19 antibodies were found in 40.5% of paediatric and young adult ALL(B2202), 8.7% of adult DLBCL and 28.7% of adult FL patients. Pre-existing and treatment-inducedantibodies were not associated with an impact on clinical response nor did they have an impact on theexpansion and persistence of tisagenlecleucel. There is no evidence that the presence of pre-existingand 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, adultr/r DLBCL and adult FL patients.

The safety of tisagenlecleucel in r/r B-cell ALL paediatric patients from 3 years of age and older wasassessed in 212 patients in the pivotal study B2202 and the supportive studies B2205J and B2001X inwhich the majority of patients (81%) were under 18 years old (65/79 in B2202, 54/64 in B2205 and52/69 in B2001X). The frequency, type and severity of adverse reactions in paediatric patients arereflected in “Summary of the safety profile” and in Table 1 above.

The safety of tisagenlecleucel in r/r B-cell ALL paediatric patients below 3 years of age was assessedin the observational study B2401 (n=43) where the overall safety experience was generally consistentwith the known safety profile of tisagenlecleucel.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdose has not been reported.

In case of overdose, the potential risk is an increased probability of developing CRS including severe

CRS. For close monitoring, see section 4.2; for symptoms and management of CRS, see section 4.4.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XL04.

Tisagenlecleucel is an autologous, immunocellular cancer therapy which involves reprogramming apatient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify andeliminate CD19 expressing cells. The CAR is comprised of a murine single chain antibody fragmentwhich recognises CD19 and is fused to intracellular signalling domains from 4-1BB (CD137) and

CD3 zeta. The CD3 zeta component is critical for initiating T-cell activation and anti-tumour activity,while 4-1BB enhances the expansion and persistence of tisagenlecleucel. Upon binding to CD19-expressing cells, the CAR transmits a signal promoting T-cell expansion and persistence oftisagenlecleucel.

Acute lymphoblastic leukaemia (ALL)

The safety and efficacy of Kymriah treatment in paediatric and young adult patients up to andincluding 25 years of age, with relapsed or refractory (r/r) B-cell ALL were evaluated in a total of203 patients in one pivotal (B2202, N=79) and two supportive (B2205J, N=64, and B2101J, N=60)open-label, single-arm phase I/II studies. All patients had leukapheresis products collected andcryopreserved prior to or during study entry.

The pivotal study B2202 (ELIANA) is a multicentre, single-arm phase II study in paediatric andyoung adult patients with r/r B-cell ALL. Of 97 patients enrolled in the main cohort, 79 receivedinfusion with Kymriah; for 8 patients (8%) Kymriah could not be manufactured; reasons fordiscontinuation prior to Kymriah infusion included death (n=7; 7%) or adverse events (n=3; 3%) whileawaiting Kymriah manufacturing in the clinical study. The median duration of study follow-up definedas the time from Kymriah infusion to the date of completion or discontinuation from follow-up prior tothe data cut-off date was 28.5 months (range: 0.4-65.5). The median time from Kymriah infusion tothe data cut-off date was 79.4 months (range: 59.7-90.3).

Key baseline information for enrolled and infused patients is presented in Table 2. The majority ofpatients (69/79, 87%) received bridging therapy while waiting for Kymriah. A total of 76 out of79 patients (96%) who received Kymriah infusion also received lymphodepleting chemotherapy afterenrolment and prior to infusion of a single dose of Kymriah (see section 4.2 for condition oflymphodepleting chemotherapy).

Table 2 Study B2202: Baseline information across the enrolled and the infused patientpopulation

Enrolled Infused

N=97 N=79n (%) n (%)

Age (years)

Mean (standard deviation) 12 (5.48) 12 (5.38)

Median (minimum - maximum) 11 (3 - 27) 11 (3 - 24)

Age category (years) - n (%)<10 years 40 (41.2) 32 (40.5)≥10 years and <18 years 40 (41.2) 33 (41.8)≥18 years 17 (17.5) 14 (17.7)

Sex - n (%)

Male 54 (55.7) 45 (57.0)

Female 43 (44.3) 34 (43)

Disease status - n (%)

Primary refractory1 8 (8.2) 6 (7.6)

Relapsed disease2 89 (91.8) 73 (92.4)

Prior stem-cell transplantation - n (%)0 39 (40.2) 31 (39.2)1 50 (51.5) 42 (53.2)2 8 (8.2) 6 (7.6)1Primary refractory: Never had a morphologic complete remission (CR) prior to the study;2Relapsed disease: Had at least one relapse prior to the study

Efficacy was established through the primary endpoint of overall remission rate (ORR), whichincludes best overall response as complete remission (CR) or complete remission with incompleteblood count recovery (CRi) within 3 months post infusion, as determined by Independent Review

Committee (IRC) assessment, as well as secondary endpoints including duration of remission (DOR)and the proportion of patients who achieved CR or CRi with minimal residual disease (MRD) <0.01%by flow cytometry (MRD-negative). See Table 3 for efficacy results from this study. ORR wasconsistent across all subgroups. Eight patients (10.1%) who achieved CR/CRi after Kymriah infusionwent to haematopoietic stem cell transplant while in remission of which 6 of the patients (7.6%)proceeded to transplant within the first 6 months post infusion while in remission. Kymriah wasadministered in a qualified Kymriah treatment centre in an inpatient and outpatient setting.

Table 3 Study B2202: Efficacy results in paediatric and young adult patients withrelapsed/refractory B-cell acute lymphoblastic leukaemia (ALL)

Enrolled patients Infused patients

Primary endpoint

N=97 N=79

Overall remission rate (ORR) within 3 months1,2, 65 (67.0) 65 (82.3)n (%) (56.7, 76.2) (72.1, 90.0)95% CI p<0.0001 p<0.0001

CR3, n (%) 49 (50.5) 49 (62.0)

CRi4, n (%) 16 (16.5) 16 (20.3)

Key secondary endpoint N=97 N=79

CR or CRi with MRD negative bone marrow5,6, n 64 (66.0) 64 (81.0)(%) (55.7, 75.3) (70.6, 89.0)95% CI p<0.0001 p<0.0001

Duration of remission (DOR)7 N=66 N=66% event-free probability at 12 months 67.4 67.4% event-free probability at 30 months 56.2 56.2

Median (months) (95% CI) 46.8 (17.8, NE9) 46.8 (17.8, NE)

Other secondary endpoint N=97 N=79

Overall survival (OS)8% survival probability at 36 months 52.8 63.5

Median (months) (95% CI) 47.9 (19.4, NE) Not reached (45.6,

NE)1 Requires remission status to be maintained for at least 28 days without clinical evidence ofrelapse.2 Nominal one-sided exact p-value based on H0: ORR ≤20% vs. Ha: ORR >20%3 CR (complete remission) was defined as <5% of blasts in the bone marrow, circulating blastsin blood should be <1%, no evidence of extramedullary disease, and full recovery ofperipheral blood counts (platelets >100 000/μL and absolute neutrophil counts [ANC]>1 000/μL) without blood transfusion.4 CRi (complete remission with incomplete blood count recovery) was defined as <5% ofblasts in the bone marrow, circulating blasts in blood should be <1%, no evidence ofextramedullary disease, and without full recovery of peripheral blood counts with or withoutblood transfusion.5 MRD (minimal residual disease) negative was defined as MRD by flow cytometry <0.01%.6 Nominal one-sided exact p-value based on H0: Rate of MRD negative remission ≤15% vs.

Ha: >15%.7 DOR was defined as time since onset of CR or CRi to relapse or death due to underlyingindication, whichever is earlier (N=66). One patient achieved remission after month 3.8 OS was defined as time from date of Kymriah infusion to the date of death due to any causefor infused patients and from time of date of enrolment to the date of death due to any causefor enrolled patients.9 Not estimable

The supportive study B2205J (ENSIGN) was a multicentre single-arm phase II study in paediatric andyoung adult patients with r/r B‑cell ALL. The study had similar study design and enrolled comparablepatient populations as the pivotal study B2202. The main difference between the two studies was thedefinition of the primary efficacy endpoint ORR, which was measured within 6 months after Kymriahinfusion in study B2205J compared to 3 months in the pivotal study. Of 75 patients enrolled, 64received infusion of Kymriah; for 5 patients (6.7%), Kymriah could not be manufactured and6 patients (8.0%) died while awaiting Kymriah manufacturing in the clinical study. The medianduration of study follow-up defined as the time from Kymriah infusion to the date of completion ordiscontinuation from follow-up prior to the data cut-off date in the final analyses was 12.2 months(range: 0.4-49.3). The median time from Kymriah infusion to the data cut-off date was 31.7 months(range: 17.6-56.0).

Among the patients infused, the median age was 12.5 years (range: 3 to 25), 34 (53.1%) were femaleand 30 (46.9%) were male, 10.9% had primary refractory disease, 89.1% had relapsed disease, and43.8% of patients had at least one prior haematopoietic stem cell transplant. Baseline diseasecharacteristics were similar in the enrolled patients with regard to age (median age 13.0 years, range: 3to 25), gender (46.7% female and 53.3% male), primary refractoriness (10.7%), and prior transplanthistory (42.7%). The majority of infused patients (57/64, 89.1%) received bridging chemotherapywhile waiting for Kymriah. A total of 60 out of 64 patients (93.8%) who received Kymriah infusionalso received lymphodepleting chemotherapy after enrolment and prior to infusion of a single dose of

Kymriah.

Efficacy was established through the primary endpoint of ORR, which included best overall responseas CR or CRi that were maintained for at least 28 days within 6 months post infusion, as determinedby IRC assessment, as well as secondary endpoints including DOR, proportion of patients whoachieved CR or CRi with MRD-negative disease status, and OS. Among the patients infused, ORRwas demonstrated in 45 patients (70.3%; 59.4% CR and 10.9% CRi). CR/CRi with MRD-negativebone marrow was reported in 43 patients (67.2%). The median DOR was not reached and the event-free probability at 12 months was 70.5%. The survival probability at 24 months was 54.7%, and themedian OS was estimated as 29.9 months (95% CI: 15.1, 42.4). The OS results were confirmed in anupdated OS analysis (i.e. median OS 29.9 months [95% CI: 15.2, NE] with 57.6% survival probabilityat 24 months; with a median follow-up for OS of 25.9 months), which included patients transitioned toa separate long-term follow-up study. Seven patients (10.9%) who achieved CR/CRi after Kymriahinfusion proceeded to haematopoietic stem cell transplant while in remission during the study, ofwhich 5 of the patients (7.8%) proceeded to transplant within the first 6 months post infusion. Efficacyresults reported for the enrolled patients (n=75) demonstrate an ORR of 60.0% (50.7% CR and 9.3%

CRi; 57.3% with MRD-negative bone marrow). The reported overall survival in the enrolledpopulation is in accordance with the infused population.

No differences in efficacy or safety were observed between different age subgroups.

Patients with active CNS leukaemia

Of four patients with active CNS leukaemia (i.e. CNS-3) included in study B2101J, three experiencedcytokine release syndrome (Grade 2-4) and transient neurological abnormalities (Grade 1-3) thatresolved within 1-3 months of infusion. One patient died due to disease progression and the remainingthree patients achieved a CR or CRi and remain alive 1.5-2 years after infusion.

Diffuse large B-cell lymphoma (DLBCL)

The safety and efficacy of Kymriah treatment in adult patients with relapsed or refractory (r/r) diffuselarge B-cell lymphoma (DLBCL) who received ≥2 lines of chemotherapy, including rituximab andanthracycline, or relapsed following autologous haematopoietic stem cell transplantation (HSCT), wasevaluated in the multicentre, open-label, pivotal, single-arm phase II study C2201 (JULIET). Patientswith T-cell rich/histiocyte-rich large B-cell lymphoma (THRBCL), primary cutaneous large B-celllymphoma, primary mediastinal B-cell lymphoma (PMBCL), EBV-positive DLBCL of the elderly,

Richter’s transformation, and Burkitt lymphoma were not enrolled in study C2201.

Of 167 patients enrolled in study C2201, 115 patients received infusion with Kymriah. Approximately31% of patients discontinued the study prior to Kymriah infusion. For 13 patients (8%) Kymriah couldnot be manufactured. Other reasons for discontinuation prior to Kymriah infusion included death(n=16; 10%), physician decision/primary disease progression (n=16; 10%), patient decision (n=2;1%), protocol deviation (n=1; 1%) or adverse events (n=4; 2%) while awaiting Kymriahmanufacturing in the clinical study. The median duration of study follow-up defined as the time from

Kymriah infusion to date of completion or discontinuation from follow-up prior to the data cut-offdate in the final analysis was 7.7 months (range: 0.4-61.0). The median time from Kymriah infusion tothe data cut-off date in the final analysis was 74.3 months (range: 58.1-86.6).

Key baseline information for enrolled and infused patients is presented in Table 4. All patients hadleukapheresis starting material collected and cryopreserved prior to or during study entry. Themajority of patients (103/115, 90%) received bridging therapy for disease stabilisation. The type andduration of bridging therapy was left to the discretion of the physician. 107/115 patients (93%)received lymphodepleting chemotherapy prior to Kymriah infusion. Kymriah was given as a single-dose (0.6-6.0 × 108 CAR-positive viable T cells) intravenous infusion in a qualified Kymriahtreatment centre in an inpatient and outpatient setting.

Table 4 Study C2201: Baseline information across the enrolled and the infused patientpopulations

Enrolled Infused

N=167 N=115n (%) n (%)

Age (years)

Mean (standard deviation) 56 (12.9) 54 (13.1)

Median (minimum - maximum) 58 (22 - 76) 56 (22 - 76)

Age category (years) - n (%)<65 years 120 (71.9) 89 (77.4)≥65 years 47 (28.1) 26 (22.6)

Sex - n (%)

Male 105 (62.9) 71 (61.7)

Female 62 (37.1) 44 (38.3)

Prior haematopoietic stem cell transplant(SCT) - n (%)

No 93 (55.7) 59 (51.3)

Yes 74 (44.3) 56 (48.7)

Stage III/IV disease at study entry - n (%)

No 36 (21.6) 27 (23.5)

Yes 131 (78.4) 88 (76.5)

Number of prior lines of antineoplastictherapy - n (%)1 6 (3.6) 5 (4.3)2 73 (43.7) 51 (44.3)3 52 (31.1) 36 (31.3)≥4 36 (21.6) 23 (20.0)

Disease status - n (%)

Refractory to last line of therapy 98 (58.7) 63 (54.8)

Relapse to last line of therapy 69 (41.3) 52 (45.2)

The efficacy of Kymriah was evaluated through the primary endpoint of best overall response rate(ORR), which includes complete response (CR) and partial response (PR) as determined by

Independent Review Committee (IRC) assessment as well as secondary endpoints including durationof response (Table 5).

Table 5 Study C2201: Efficacy results in adult patients with relapsed or refractory diffuselarge B-cell lymphoma (DLBCL) after two or more lines of systemic therapy

Enrolled patients Infused patients

N=167 N=115

Primary endpoint1 N=147 N=99

Overall response rate (ORR) (CR+PR)2, n (%) 54 (36.7) 54 (54.5)95% CI (28.9, 45.1) (44.2, 64.6)

CR, n (%) 41 (27.9) 41 (41.4)

PR, n (%) 13 (8.8) 13 (13.1)

Response at month 3 N=147 N=99

ORR (%) 40 (27.2) 40 (40.4)

CR (%) 34 (23.1) 34 (34.3)

Response at month 6 N=147 N=99

ORR (%) 34 (23.1) 34 (34.3)

CR (%) 31 (21.1) 31 (31.3)

Duration of response (DOR)3 N=54 N=54

Median (months) (95% CI) Not reached (10.0, NE5) Not reached (10.0, NE5)% relapse-free probability at 12 months 63.4 63.4% relapse-free probability at 24 months 60.8 60.8% relapse-free probability at 36 months 60.8 60.8% relapse-free probability at 54 months 60.8 60.8

Other secondary endpoints N=167 N=115

Overall survival (OS)4% survival probability at 12 months 41.0 48.2% survival probability at 36 months 29.4 36.6% survival probability at 60 months 25.5 31.7

Median (months) (95% CI) 8.2 (5.8, 11.7) 11.1 (6.6, 23.9)1 The primary endpoint was analysed on all patients whose Kymriah was manufactured at the Novartis

US facility.2 ORR is the proportion of patients with best overall response (BOR) of CR or PR based on the

Lugano response criteria (Cheson 2014); non-infused patients were assigned BOR=Unknown (i.e.

non-responders).3 DOR was defined as time from achievement of CR or PR to relapse or death due to DLBCL,whichever occurs first.4 OS was defined as time from date of Kymriah infusion to the date of death due to any cause (N=115)and time from date of enrolment to the date of death due to any cause for enrolled patients (N=167).5 Not estimable.

Among 41 patients who achieved CR, 16 patients initially had an overall disease response of PRwhich improved to CR over time; most patients (13/16) achieved PR to CR conversion within6 months post tisagenlecleucel infusion. ORR was consistent across subgroups.

Follicular lymphoma (FL)

The safety and efficacy of Kymriah treatment in adult patients with relapsed or refractory (r/r)follicular lymphoma (FL) were evaluated in an open-label, multicentre, single-arm, phase II study(E2202, N=97).

The pivotal study E2202 (ELARA) included patients who were refractory to or relapsed within6 months after completion of a second or later line of systemic therapy (including an anti-CD20antibody and an alkylating agent), relapsed during or within 6 months after completion of anti-CD20antibody maintenance therapy following at least two lines of therapy, or relapsed after autologoushaematopoietic stem cell transplant (HSCT). The study excluded patients with active or seriousinfections, transformed lymphoma or other aggressive lymphomas, including patients with FL

Grade 3b, those who had received prior allogeneic HSCT, or who had disease with active CNSinvolvement.

Of 98 patients who were enrolled and underwent leukapheresis, 97 patients received infusion with

Kymriah. One patient achieved a complete response prior to infusion which was attributed to theirprior last line of therapy and was subsequently discontinued from the study due to physician decisionprior to infusion. All patients had leukapheresis products collected and cryopreserved prior to orduring study entry. Kymriah was delivered for all enrolled patients. The median duration of studyfollow-up defined as the time from Kymriah infusion to date of completion or discontinuation fromfollow-up prior to the data cut-off date was 18.6 months (range: 1.8-29.9). The median time from

Kymriah infusion to the data cut-off date was 20.8 months (range: 14.4-29.9). The study is stillongoing.

Of the 97 patients infused with Kymriah, 94 patients had measurable disease at baseline per

Independent Review Committee (IRC) and are included in the efficacy analysis set (EAS).

Key baseline information for the enrolled set and EAS is presented in Table 6. Approximately half ofthe patients (44/94; 47%) received bridging therapy for disease stabilisation between leukapheresisand administration of Kymriah and all patients received lymphodepleting chemotherapy. For allinfused patients, Kymriah was administered as a single-dose intravenous infusion in a qualifiedtreatment centre in an inpatient or outpatient (18%) setting.

Table 6 Study E2202: Baseline information across the enrolled and the EAS patientpopulations

Enrolled EAS*

N=98 N=94n (%) n (%)

Age (years)

Mean (standard deviation) 56.5 (10.34) 56.4 (10.54)

Median (minimum - maximum) 57.5 (29-73) 57.0 (29-73)

Age category (years) - n (%)<65 years 74 (75.5) 70 (74.5)≥65 years 24 (24.5) 24 (25.5)

Sex - n (%)

Male 65 (66.3) 64 (68.1)

Female 33 (33.7) 30 (31.9)

Stage III/IV disease at study entry - n (%) 84 (85.7) 81 (86.2)

High FLIPI score1 - n (%) 59 (60.2) 57 (60.6)

Bulky disease at baseline2 - n (%) 62 (63.3) 61 (64.9)

Number of prior lines of antineoplastictherapy - n (%)2 24 (24.5) 24 (25.5)3 21 (21.4) 19 (20.2)4 25 (25.5) 24 (25.5)≥5 28 (28.6) 27 (28.7)

Median (minimum - maximum) 4.0 (2.0 -13.0) 4.0 (2.0 - 13.0)

Disease status - n (%)

Refractory to last line of therapy 76 (77.6) 74 (78.7)

Relapse to last line of therapy 17 (17.3) 17 (18.1)

Double refractory3 - n (%) 67 (68.4) 65 (69.1)

Progression of disease within 24 months 61 (62.2) 61 (64.9)(POD24)4 - n (%)

Prior haematopoietic stem cell transplant(HSCT) - n (%) 36 (36.7) 35 (37.2)

Prior PI3K inhibitor - n (%) 21 (21.4) 19 (20.2)

* Infused patients who had measurable disease at baseline per Independent Review Committee(IRC) and are included in the efficacy analysis set.1 FLIPI includes 5 labelled prognostic factors; FLIPI = sum (where prognostic factor = ‘Yes’);

Low: 0-1 criteria met; intermediate: 2 criteria met; high: 3 or more met.2 Bulky disease defined per IRC as imaging showing any nodal or extra nodal tumour mass thatis >7 cm in diameter or involvement of at least 3 nodal sites, each with a diameter >3 cm.3 Double refractory is defined as patients who failed to respond or relapsed within 6 monthsfollowing therapy with anti-CD20 and alkylating agents, any regimen4 POD24: subjects with primary refractory or experiencing progression of disease within24 months from initiation of a first-line anti-CD20 mAb containing treatment.

Efficacy was evaluated through the primary endpoint of complete response rate (CRR), recorded frominfusion until progressive disease or start of new therapy. CRR was determined by IRC based on

Lugano classification criteria (Cheson 2014). Secondary endpoints included overall response rate(ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS). Mediantime from enrolment to infusion was 46 days (range: 23 to 127). The first disease assessment wasscheduled to be performed at month 3 post infusion.

Table 7 Study E2202: Efficacy results in adult patients with relapsed or refractory follicularlymphoma (FL) after two or more lines of therapy

Enrolled patients EAS patients*

N=98 N=94

Complete response rate (CRR)1, per IRCn (%) 67 (68.4) 65 (69.1)95% CI (58.2, 77.4) (58.8, 78.3)

Overall response rate (ORR)2, per IRCn (%) 84 (85.7) 81 (86.2)

Duration of response (DOR)3, per IRC N=84 N=81

Median (months) (95% CI) NE (20.9, NE) NE (15.6, NE)% event-free probability at 9 months (95% CI) 75.9 (64.8, 83.9) 76.2 (64.9, 84.3)

CI=Confidence interval, NE=Not estimable

* Infused patients who had measurable disease at baseline per Independent Review Committee (IRC)and are included in the efficacy analysis set.1 The primary endpoint was CRR per IRC based on Lugano response criteria (Cheson 2014) anddefined as the proportion of patients with a best overall response (BOR) of complete response (CR).

The non-infused patient was treated as a non-responder.2 ORR was defined as the proportion of patients with a BOR of CR or partial response (PR). The non-infused patient was treated as a non-responder.3 DOR was defined as time from achievement of CR or PR to relapse or death due to FL, whicheveroccurs first.

All responders achieved their first response (CR or PR) at the first disease assessment performed postinfusion, at 3 months. Of the 65 patients who eventually achieved a CR, 15 patients (16%) initially hada PR. The majority of patients converted from PR to CR within 6 months post infusion. No patientwho received Kymriah infusion went to transplant while in response (CR or PR).

The probability for a patient to remain in response (DOR) ≥9 months was 76% (95% CI: 64.9, 84.3),while the probability for a patient who achieved a CR to remain in response ≥9 months was 87% (95%

CI: 75.6, 93.3).

Subgroup analyses demonstrated a generally consistent CRR across all subgroups, including thefollowing high-risk prognostic subgroups: high FLIPI score (CRR of 63%), prior HSCT (CRR of66%), POD24 (CRR of 59%), and double refractoriness (CRR of 66%).

There are not enough data to determine whether there are any differences in efficacy or safety betweendifferent age subgroups, although the clinical benefit and safety experience in elderly patients with

DLBCL and FL above the age of 65 years (23% and 24.7% of the study population for DLBCL and

FL, respectively) were comparable to the overall population.

Study B2401

An observational study (B2401) was conducted to collect long-term safety and efficacy data inpatients infused with tisagenlecleucel from the Center for International Blood and Marrow Transplant

Research (CIBMTR) and European Society for Blood and Marrow Transplantation (EBMT) registries.

The study included 617 (CIBMTR: 570; EBMT: 47) paediatric and young adult patients with r/r B-cell

ALL at time of the data cut-off. Kymriah manufacture for patients below 3 years of age and with lowweight was feasible; 43 patients (CIBMTR: 40, EBMT: 3) were below 3 years of age at time ofinfusion. The median time from Kymriah infusion to the data cut-off date of the paediatric and youngadult patients with r/r B-cell ALL was 11.8 months for CIBMTR and 9.0 months for EBMT.

Among the patients below 3 years of age included in the efficacy set (n=33), CR (including CRi) as

BOR was reported for 26 patients (78.8%) (95% CI: 61.1, 91.0) and all 15 patients in CR (including

CRi) and with reported MRD data were MRD-negative during follow-up. The estimated DOR rate atmonth 12 was 62.7% (95% CI: 35.0, 81.3).

The overall safety experience in patients below 3 years of age with r/r B-cell ALL was generallyconsistent with the known safety profile of tisagenlecleucel.

Study C2202

A phase II study of tisagenlecleucel (C2202, BIANCA) was conducted in 33 infused patients withrelapsed or refractory mature B-cell non-Hodgkin lymphoma (NHL) in children and young adults. Ofthe 33 patients infused with tisagenlecleucel, 28 patients (24 patients, aged 3-17 years old and4 patients, aged 20-22 years old) had measurable disease prior to infusion and are included in theefficacy analysis set (EAS).

The EAS included patients with Burkitt lymphoma (n=15), diffuse large B-cell lymphoma (n=8),primary mediastinal B-cell lymphoma (n=3), grey zone lymphoma (n=1) and high-grade lymphomawith MYC and BCL2 rearrangements (n=1). Among these patients, the median age was 14.0 years(range: 3 to 22), 9 (32.1%) were female and 19 (67.9%) were male. The median number of prior linesof therapy was 1 (range:1-3), 17.9% of patients had one prior haematopoietic stem cell transplant. Allpatients except one (96.4%) received bridging chemotherapy while waiting for tisagenlecleucel.

Patients received the approved tisagenlecleucel dose for the paediatric ALL indication.

Results in the EAS showed an ORR of 32.1% (95% CI: 15.9, 52.4), with a CR of 7.1%. Subgroupanalysis indicated a lower ORR in patients with Burkitt lymphoma (20%, 95% CI pct. 4.3, 48.1) comparedto patients with diffuse large B-cell lymphoma (37.5%, 95% CI: 8.5, 75.5) or other diagnoses includedin the study (60.0%, 95% CI: 14.7, 94.7).

The overall safety experience in paediatric and young adult patients with CD19+ r/r mature B-cell

NHL infused with tisagenlecleucel in Study C2202 was consistent with the known safety profile oftisagenlecleucel. No new safety signals were observed.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Kymriah in one or more subsets of the paediatric population in the treatment of B-cell lymphoblasticlymphoma (see section 4.2 for information on paediatric use).

Following infusion of Kymriah into paediatric and young adult r/r B-cell ALL, r/r DLBCL and r/r FLpatients, tisagenlecleucel typically exhibited an initial rapid expansion followed by a slower bi-exponential decline. High inter-subject variability was associated with the in vivo exposure metrics(AUC0-28d and Cmax) across all indications.

Cellular kinetics in paediatric and young adult B-cell ALL patients

A summary of cellular kinetic parameters of tisagenlecleucel in paediatric and young adult B-cell ALLpatients is provided in Table 8 below. The maximal expansion (Cmax) was approximately 1.5-foldhigher in CR/CRi patients (n=114) compared with non-responding (NR) patients (n=10) as measuredby qPCR. Delayed and lower expansion was observed in NR patients compared to CR/CRi patients.

Table 8 Cellular kinetic parameters of tisagenlecleucel in paediatric and young adult r/r B-cell ALL (Studies B2202 and B2205J)

Parameter Summary statistics Responding patients Non-responding(CR/CRi) patients (NR)

N=114 N=12

Cmax (copies/μg) Geometric mean 32 900 (173.8), 114 21 900 (80.7), 10(CV%), n

T ‡max (day) Median [min;max], n 9.85 [5.70; 54.8], 114 20.1 [12.6; 62.7], 10

AUC0-28d Geometric mean 286 000 (194.9), 114 232 000 (104.5), 8(copies/μg*day) (CV%), n

T½ (day) Geometric mean 40.0 (436.8), 72 3.78 (222.0), 4(CV%), n

Tlast (day) Median [min;max], n 190 [17.8; 1 860], 114 28.8 [13.9; 888], 11

Cellular kinetics in adult DLBCL patients

A summary of cellular kinetic parameters of tisagenlecleucel in DLBCL patients is provided in

Table 9 below.

Table 9 Cellular kinetic parameters of tisagenlecleucel in r/r DLBCL patients

Parameter Summary statistics Responding patients Non-responding patients(CR and PR) (SD/PD/Unknown)

N=44 N=71

Cmax (copies/μg) Geometric mean 6 070 (256.8), 44 5 000 (391.7), 67(CV%), n

Tmax (day) Median [min;max], n 9.02 [5.78; 27.7], 44 8.84 [0.994; 26.7], 67

AUC0-28d Geometric mean 63 000 (177.7), 43 52 300 (321.4), 62(copies/μg*day) (CV%), n

T½ (day) Geometric mean 151 (487.5), 31 11.6 (196.2), 49(CV%), n

Tlast (day) Median [min;max], n 930 [17.1; 1 830], 44 41.9 [0.994; 1 480], 67

Cellular kinetics in FL patients

A summary of cellular kinetic parameters of tisagenlecleucel in FL patients by BOR is provided in

Table 10 below.

The geometric mean AUC0-28d value of responders was 2.9 fold higher compared to non-responders,while the geometric mean Cmax value was 2.1 fold higher in responders compared to non-responders.

Table 10 Cellular kinetic parameters of tisagenlecleucel in r/r FL patients

Parameter Summary statistics Responding patients Non-responding(CR and PR) patients

N=81 (SD/PD)

N=12

Cmax

Geometric mean (CV%), n 6 280 (331), 67 3 000 (1 190), 8(copies/micrograms)

Tmax (day) Median [min;max], n 9.92 [2.62; 28.0], 67 13.0 [7.73; 16.0], 8

AUC0-28d

Geometric mean (CV%), n 57 500 (261), 66 20 100 (18 100), 7(copies/micrograms*day)

T½ (day) Geometric mean (CV%), n 43.8 (287), 43 24.4 (180), 6

Tlast (day) Median [min;max], n 191 [19.9; 558], 73 107 [18.7; 366], 10

Biodistribution

In paediatric and young adult B-cell ALL patients, tisagenlecleucel has been shown to be present inthe blood and bone marrow for up to 5 years and 6 months, respectively. The blood to bone marrowpartitioning of tisagenlecleucel in bone marrow was 50% of that present in blood at day 28 while atboth months 3 and 6 it distributes at 67% (Studies B2202 and B2205J). Tisagenlecleucel also trafficsand persists in cerebrospinal fluid in paediatric and young adult B-cell ALL patients (Study B2101J)for up to 1 year.

In adult DLBCL patients (Study C2201), tisagenlecleucel has been detected for up to 5 years inperipheral blood and up to month 9 in bone marrow for complete responder patients. The blood tobone marrow partitioning in bone marrow was nearly 70% of that present in blood at day 28 and 50%at month 3 in both responder and non-responder patients.

In adult FL patients (Study E2202), tisagenlecleucel has been detected for up to 18 months inperipheral blood and up to month 3 in bone marrow for complete responder patients. The blood tobone marrow partitioning in bone marrow was nearly 54% of that present in blood at month 3 in bothresponder and non-responder patients.

The elimination profile of Kymriah includes a bi-exponential decline in peripheral blood and bonemarrow.

There is no apparent relationship between dose and AUC0-28d or Cmax.

The scatter plots of cellular kinetic parameters versus age (22 to 76 years in DLBCL patients and 29 to73 years in FL patients) revealed no relevant relationship between cellular kinetic parameters (AUC0-28d and Cmax) with age.

Gender has not been identified as a significant characteristic influencing tisagenlecleucel expansion in

B-cell ALL, DLBCL and FL patients. In Study B2202, there were 43% female and 57% male patients,in Study C2201 38% female and 62% male patients and in Study E2202 34% female and 66% malepatients who received Kymriah. Further, in Study E2202, the geometric means of the exposureparameters (Cmax and AUC0-28d) were shown to be 111% and 106% higher, respectively, in femalepatients compared to male patients. Although the interpretation of expansion in relation to gender isdifficult due to overlapping ranges and high inter-subject variability.

There is limited evidence that race/ethnicity impact the expansion of Kymriah in paediatric and youngadult ALL, DLBCL and FL patients. In Study B2202 there were 73.4% Caucasian, 12.7% Asian and13.9% other ethnic patients. In Study C2201 there were 85% Caucasian, 9% Asian, 4% Black or

African American patients, and 3 patients (3%) of unknown race. In Study E2202, there were 75%

Caucasian, 13% Asian, 1% Black or African American patients, and 10% of unknown race.

In ALL, DLBCL and FL patients, across the weight ranges (ALL; 14.4 to 137 kg; DLBCL: 38.3 to186.7 kg; FL: 44.3 to 127.7 kg), the scatter plots of qPCR cellular kinetic parameters versus weightrevealed no apparent relationship between cellular kinetic parameters with weight.

Prior transplantation

Prior transplantation did not impact the expansion/persistence of Kymriah in paediatric and youngadult B-cell ALL patients, adult DLBCL or adult FL patients.

Non-clinical safety assessment of Kymriah addressed the safety concerns of potential uncontrolled cellgrowth of transduced T cells in vitro and in vivo as well as dose-related toxicity, biodistribution andpersistence. No such risks were identified based on these studies.

Genotoxicity assays and carcinogenicity studies in rodents are not appropriate to assess the risk ofinsertional mutagenesis for genetically-modified cell therapy products. No alternative adequate animalmodels are available.

In vitro expansion studies with CAR-positive T cells (Kymriah) from healthy donors and patientsshowed no evidence for transformation and/or immortalisation of T cells. In vivo studies inimmunocompromised mice did not show signs of abnormal cell growth or signs of clonal cellexpansion for up to 7 months, which represents the longest meaningful observation period forimmunocompromised mouse models. A genomic insertion site analysis of the lentiviral vector wasperformed on Kymriah products from 14 individual donors (12 patients and 2 healthy volunteers).

There was no evidence for preferential integration near genes of concern or preferential outgrowth ofcells harbouring integration sites of concern.

No non-clinical reproductive safety studies were conducted as no adequate animal model is available.

Juvenile toxicity studies were not conducted.

Glucose

Sodium chloride

Human albumin solution

Dextran 40 for injection

Dimethyl sulfoxide

Sodium gluconate

Sodium acetate

Potassium chloride

Magnesium chloride

Sodium-N-acetyltryptophanate

Sodium caprylate

Aluminium

Water for injections

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

9 months.

The medicinal product should be administered immediately after thawing. After thawing, the productshould be kept at room temperature (20°C-25°C) and infused within 30 minutes to maintain maximumproduct viability, including any interruption during the infusion.

Kymriah must be stored and transported ≤ -120°C, e.g. in a container for cryogenic storage in thevapour phase of liquid nitrogen, and must remain frozen until the patient is ready for treatment toensure viable cells are available for patient administration. Do not re-freeze after thawing.

For storage conditions after thawing of the medicinal product, see section 6.3.

implantation

Ethylene vinyl acetate (EVA) infusion bag with polyvinyl chloride (PVC) tubing and a luer spikeinterconnector closed by a luer-lock cap containing either 10-30 mL (50 mL bags) or 30-50 mL(250 mL bags) cell dispersion.

Each infusion bag is placed into a protective layer.

One individual treatment dose comprises 1 or more infusion bags.

Kymriah should be transported within the facility in closed, break-proof, leak-proof containers.

This medicinal product contains human blood cells. Healthcare professionals handling Kymriah musttake appropriate precautions (wearing gloves and eye protection) to avoid potential transmission ofinfectious diseases.

Preparation prior to administration

Before administration, it must be confirmed that the patient’s identity matches the unique patientinformation on the Kymriah infusion bags and accompanying documentation. The total number ofinfusion bags to be administered should also be confirmed with the patient-specific information on thebatch-specific documentation accompanying the medicinal product.

The timing of thaw of Kymriah and infusion should be coordinated. The infusion start time should beconfirmed in advance and adjusted for thaw so that Kymriah is available for infusion when therecipient is ready. Once Kymriah has been thawed and is at room temperature (20°C-25°C), it shouldbe infused within 30 minutes to maintain maximum product viability, including any interruptionduring the infusion.

Inspection and thawing of the infusion bag(s)

Do not thaw the product until it is ready to be used.

The infusion bag should be placed inside a second sterile bag during thawing to protect ports fromcontamination and avoid spills in the unlikely event of the bag leaking. Kymriah should be thawed at37°C using either a water bath or dry thaw method until there is no visible ice in the infusion bag. Thebag should be removed immediately from the thawing device and kept at room temperature (20°C-25°C) until infusion. If more than one infusion bag has been received for the treatment dose (refer tothe batch certificate for number of bags constituting one dose), the next bag should only be thawedafter the contents of the preceding bag have been infused.

Kymriah should not be manipulated. For example, Kymriah should not be washed (spun down andresuspended in new media) prior to infusion.

The infusion bag(s) should be examined for any breaks or cracks prior to thawing. If the infusion bagappears to have been damaged or to be leaking, it should not be infused and should be disposed ofaccording to local procedures on handling of biological waste.

Kymriah intravenous infusion should be administered by a healthcare professional experienced withimmunosuppressed patients and prepared to manage anaphylaxis. In the event of cytokine releasesyndrome (CRS), ensure that at least one dose of tocilizumab per patient and emergency equipmentare available prior to infusion. Hospitals must have access to additional doses of tocilizumab within8 hours. In the exceptional case where tocilizumab is not available due to a shortage that is listed in the

European Medicines Agency shortage catalogue, ensure that suitable alternative measures to treatcytokine release syndrome are available on site.

The patient’s identity should be matched with the patient identifiers on the infusion bag. Kymriah isintended solely for autologous use and must not, under any circumstances, be administered to otherpatients.

Kymriah should be administered as an intravenous infusion through latex-free intravenous tubingwithout a leukocyte depleting filter, at approximately 10 to 20 mL per minute by gravity flow. Allcontents of the infusion bag(s) should be infused. Sterile sodium chloride 9 mg/mL (0.9%) solution forinjection should be used to prime the tubing prior to infusion and to rinse it after infusion. When thefull volume of Kymriah has been infused, the infusion bag should be rinsed with 10 to 30 mL sodiumchloride 9 mg/mL (0.9%) solution for injection by back priming to ensure as many cells as possibleare infused into the patient.

If the volume of Kymriah to be administered is ≤20 mL, intravenous push may be used as analternative method of administration.

Measures to take in case of accidental exposure

In case of accidental exposure local guidelines on handling of human-derived material should befollowed. Work surfaces and materials which have potentially been in contact with Kymriah must bedecontaminated with appropriate disinfectant.

Precautions to be taken for the disposal of the medicinal product

Unused medicinal product and all material that has been in contact with Kymriah (solid and liquidwaste) should be handled and disposed of as potentially infectious waste in accordance with localguidelines on handling of human-derived material.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/18/1297/001

Date of first authorisation: 23 August 2018

Date of latest renewal: 26 April 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu