Tisagenlecleucel

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.

There is limited experience with tisagenlecleucel in patients exposed to prior CD19-directed therapy. While activity of tisagenlecleucel has been observed, data are currently too limited to make an adequate assessment of the benefit-risk profile in these patients. Tisagenlecleucel is not recommended if the patient has relapsed with CD19-negative leukaemia after prior anti-CD19 therapy.

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

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

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

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

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

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

Women of childbearing potential/Contraception in males and females

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

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

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

Fertility

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

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

Due to the potential for neurological events, including altered mental status or seizures, patients receiving tisagenlecleucel are at risk for altered or decreased consciousness or coordination and must refrain from driving or operating heavy or potentially dangerous machines for 8 weeks following tisagenlecleucel infusion.

Summary of the safety profile

Safety assessment was based on a total of 424 patients (with paediatric and young adult B-cell ALL, DLBCL and FL) who received tisagenlecleucel in three multicentre pivotal clinical studies.

B-cell ALL

The adverse reactions described in this section were characterised in 212 patients infused with tisagenlecleucel in the pivotal clinical study CCTL019B2202 and in the supportive studies CCTL019B2205J and 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%) and decreased platelets (95%).

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

The most common Grade 3 and 4 haematological laboratory abnormalities were white blood cells decreased (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 tisagenlecleucel in one global multicentre international study, i.e. the ongoing pivotal clinical study CCTL019C2201.

The most common non-haematological adverse reactions were cytokine release syndrome (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%), and decreased platelets (95%).

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

The most common (>25%) Grade 3 and 4 haematological laboratory abnormalities were lymphocyte count 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 tisagenlecleucel in 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%) and decreased platelets (89%).

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

The most common (>25%) Grade 3 and 4 haematological laboratory abnormalities were lymphocyte count 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%).

Tabulated list of adverse reactions

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

Adverse drug reactions:

¹ Infections and infestations presented reflect high-level group terms.
² Hypogammaglobulinaemia includes blood immunoglobulin A decreased, blood immunoglobulin G decreased, blood immunoglobulin M decreased, hypogammaglobulinaemia, immunodeficiency, immunodeficiency common variable and immunoglobulins decreased.
³ Graft-versus-host disease (GvHD) includes GvHD, GvHD in gastrointestinal tract, GvHD in skin.
⁴ Hypoalbuminaemia includes blood albumin decreased, hypoalbuminaemia.
⁵ Hyperuricaemia includes blood uric acid increased, hyperuricaemia.
⁶ Hyperphosphataemia includes blood phosphorus increased, hyperphosphataemia.
⁷ Hyperferritinaemia includes hyperferritinaemia, serum ferritin increased.
⁸ Delirium includes agitation, delirium, hallucination, hallucination visual, irritability and restlessness.
⁹ Sleep disorder includes insomnia, nightmare and sleep disorder.
¹⁰ Headache includes headache and migraine.
¹¹ Encephalopathy includes automatism, cognitive disorder, confusional state, depressed level of 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 neurotoxicity syndrome (ICANS), along with other symptoms.
¹² Dizziness includes dizziness, presyncope and syncope.
¹³ Peripheral neuropathy includes dysaesthesia, hyperaesthesia, hypoaesthesia, neuropathy peripheral, 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, tachycardia.
²² Cardiac failure includes cardiac failure, cardiac failure congestive, left ventricular dysfunction and right ventricular dysfunction.
²³ Haemorrhage includes anal haemorrhage, blood blister, blood urine present, catheter site haemorrhage, cerebral haemorrhage, conjunctival haemorrhage, contusion, cystitis haemorrhagic, disseminated intravascular coagulation, duodenal ulcer haemorrhage, ecchymosis, epistaxis, eye contusion, gastrointestinal haemorrhage, gingival bleeding, haemarthrosis, haematemesis, haematochezia, haematoma, haematuria, haemoptysis, heavy menstrual bleeding, injection site haematoma, intermenstrual bleeding, large intestinal haemorrhage, lip haemorrhage, melaena, mouth haemorrhage, mucosal haemorrhage, oral blood blister, periorbital haematoma, peritoneal haematoma, petechiae, pharyngeal haemorrhage, postprocedural haemorrhage, pulmonary haemorrhage, purpura, rectal.

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 syndrome was 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% of patients (23% with Grade 3 or 4).

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

Cytokine release syndrome was graded per Penn criteria in the paediatric and young adult B-cell ALL and 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: mild general symptoms requiring symptomatic treatment; Grade 2: symptoms requiring moderate intervention such as low-flow oxygen supplementation or low-dose vasopressor; Grade 3: symptoms requiring aggressive intervention, such as high-flow oxygen supplementation and high-dose vasopressor; Grade 4: life-threatening symptoms requiring intubation; Grade 5: death.

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 tisagenlecleucel infusion. The overall incidence (all grades) was 70% (unspecified 55%, viral 31%, bacterial 24% and fungal 12%). 41% of the patients experienced an infection of any type within 8 weeks after tisagenlecleucel infusion.

In DLBCL patients severe infections (Grade 3 and higher), which can be life-threatening or fatal, occurred in 34% of patients. The overall incidence (all grades) was 58% (unspecified 48%, bacterial 15%, fungal 11% and viral 11%). 37% of the patients experienced an infection of any type within 8 weeks.

In FL patients severe infections (Grade 3 or 4), occurred in 16% of patients. The overall incidence (all grades) was 50% (unspecified 36%, viral 17%, bacterial 6%, and fungal 2%). 19% of the 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.

Prolonged cytopenias

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

All paediatric and young adult B-cell ALL patients had a Grade 3 or 4 cytopenia at some time after tisagenlecleucel infusion. Grade 3 and 4 cytopenias not resolved by day 28 after tisagenlecleucel infusion based on laboratory 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 tisagenlecleucel infusion. Grade 3 and 4 cytopenias not resolved by day 28 based on laboratory findings included decreased count of thrombocytes (39%), lymphocytes (29%), neutrophils (25%), and white blood cells (21%) and decreased haemoglobin (14%).

In adult patients with FL, 99% had Grade 3 and 4 cytopenias at any time post tisagenlecleucel infusion. Grade 3 and 4 cytopenias not resolved by day 28 after tisagenlecleucel infusion based on laboratory findings included a decreased count of lymphocytes (23%), thrombocytes (17%), neutrophils (16%), white blood 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 including manifestations of encephalopathy and/or delirium occurred in 32% of patients (10% were Grade 3 or 4) within 8 weeks after tisagenlecleucel infusion. In DLBCL patients, manifestations of encephalopathy and/or delirium occurred in 20% of patients (11% were Grade 3 or 4) within 8 weeks after tisagenlecleucel infusion. In FL patients, these occurred in 9% of patients (1% Grade 3 or 4) within 8 weeks after tisagenlecleucel infusion. Among the neurotoxic events in FL patients, immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 4% of patients (1% Grade 3 or 4), all within 8 weeks of tisagenlecleucel infusion.

Hypogammaglobulinaemia

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

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

Immunogenicity

In clinical studies, humoral immunogenicity of tisagenlecleucel was measured by determination of anti-murine CAR19 antibodies (anti-mCAR19) in serum pre and postadministration. The majority of patients 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-induced antibodies were not associated with an impact on clinical response nor did they have an impact on the expansion and persistence of tisagenlecleucel. There is no evidence that the presence of pre-existing and treatment-induced anti-mCAR19 antibodies impacts the safety or effectiveness of tisagenlecleucel.

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

Paediatric population

The safety of tisagenlecleucel in r/r B-cell ALL paediatric patients from 3 years of age and older was assessed in 212 patients in the pivotal study B2202 and the supportive studies B2205J and B2001X in which the majority of patients (81%) were under 18 years old (65/79 in B2202, 54/64 in B2205 and 52/69 in B2001X). The frequency, type and severity of adverse reactions in paediatric patients are reflected in “Summary of the safety profile” and in the table above.

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