Yescarta

/ Gilead

A single dose of Yescarta contains 2 × 10⁶ CAR-positive viable T cells per kg of body weight (or maximum of 2 × 10⁸ CAR-positive viable T cells for patients 100 kg and above) in approximately 68 mL dispersion in an infusion bag.
The availability of Yescarta must be confirmed prior to starting the lymphodepleting regimen.
Pre-treatment (lymphodepleting chemotherapy)
A lymphodepleting chemotherapy regimen consisting of cyclophosphamide 500 mg/m² intravenous and fludarabine 30 mg/m² intravenous must be administered on the 5^th, 4^th, and 3^rd day before infusion of Yescarta.
Pre-medication
Paracetamol 500‑1,000 mg given orally and diphenhydramine 12.5 to 25 mg intravenous or oral (or equivalent) approximately 1 hour before Yescarta infusion is recommended.
Prophylactic use of systemic corticosteroids is not recommended as it may interfere with the activity of Yescarta.
Monitoring
Patients must be monitored daily for the first 10 days following infusion for signs and symptoms of potential CRS, neurologic events and other toxicities.  Physicians should consider hospitalisation for the first 10 days post infusion or at the first signs or symptoms of CRS and/or neurologic events.
After the first 10 days following the infusion, the patient is to be monitored at the physician’s discretion.
Patients must be instructed to remain within proximity of a qualified clinical facility for at least 4 weeks following infusion.
Special populations:
Patients with human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection: There is no clinical experience in patients with active HIV, HBV or HCV infection.
Paediatric population
The safety and efficacy of YESCARTA in children and adolescents below 18 years of age have not yet been established.  No data are available.
Elderly: No dose adjustment is required in patients ≥ 65 years of age.  Efficacy was consistent with the overall treated patient population.
Method of administration:
YESCARTA is to be administered via intravenous infusion.
YESCARTA must not be irradiated.  Do NOT use a leukodepleting filter.
Precautions to be taken before handling or administering the medicinal product:
This medicinal product contains genetically modified human blood cells.  Healthcare professionals handling Yescarta must take appropriate precautions (wearing gloves and glasses) to avoid potential transmission of infectious diseases.
Preparation of Yescarta:
Verify that the patient’s identity (ID) matches the patient identifiers on the Yescarta cassette.
The Yescarta bag must not be removed from the metal cassette if the information on the patient-specific label does not match the intended patient.
Once the patient ID is confirmed, remove the Yescarta bag from the metal cassette.
Check that the patient information on the metal cassette label matches that on the bag label.
Inspect the product bag for any breaches of container integrity before thawing.  If the bag is compromised, follow the local guidelines for the handling of waste of human-derived material (or immediately contact Kite).
Place the infusion bag inside a second bag.
Thaw Yescarta at approximately 37°C using either a water bath or dry thaw method until there is no visible ice in the infusion bag. Gently mix the contents of the bag to disperse clumps of cellular material.  If visible cell clumps remain, continue to gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing.  Yescarta must not be washed, spun down, and/or re‑suspended in new medium prior to infusion. Thawing takes approximately 3 to 5 minutes.
Once thawed, Yescarta is stable at room temperature (20°C‑25°C) for up to 3 hours. However, Yescarta infusion must begin within 30 minutes of thaw completion.
Administration: For autologous use only.
Tocilizumab and emergency equipment must be available prior to infusion and during the monitoring period.
A leukodepleting filter must not be used.
Central venous access is recommended for the administration of Yescarta.
Verify the patient ID again to match the patient identifiers on the Yescarta bag.
Prime the tubing with 0.9% sodium chloride solution (0.154 mmol sodium per mL) prior to infusion.
Infuse the entire content of the Yescarta bag within 30 minutes by either gravity or a peristaltic pump.
Gently agitate the bag during Yescarta infusion to prevent cell clumping.
After the entire content of the bag is infused, rinse the tubing at the same infusion rate with 0.9% sodium chloride solution (0.154 mmol sodium per mL) to ensure all Yescarta is delivered.

Treatment of adult patients with relapsed or refractory diffuse  Large B cell lymphoma (DLBCL) and primary mediastinal Large B cell lymphoma (PMBCL) after two or more lines of systemic therapy.
Limitation of Use: Yescarta not indicated for the treatment of patients with primary or secondary central nervous system lymphoma.

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

Traceability
The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability the name of the product, the batch number and the name of the treated patient must be kept for a period of 30 years after expiry date of the medicinal product.
Reasons to delay treatment
Due to the risks associated with this treatment, infusion must be delayed if a patient has any of the following conditions:
* Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions, or hypotension) including from preceding chemotherapies.
* Active uncontrolled infection.
* Active graft-versus-host disease (GvHD).
In some cases, the treatment may be delayed after administration of the lymphodepleting chemotherapy regimen. If the infusion is delayed for more than 2 weeks after the patient has received the lymphodepleting chemotherapy, lymphodepleting chemotherapy regimen must be administered again.
Monitoring after infusion
Patients must be monitored daily for the first 10 days following infusion for signs and symptoms of potential CRS, neurologic events and other toxicities. Physicians should consider hospitalisation for the first 10 days post infusion or at the first signs/symptoms of CRS and/or neurologic events.
Transmission of an infectious agent
Monitor patients for signs and symptoms of infection after treatment and treat appropriately, if needed.
Serological testing
Screening for HBV, HCV, and HIV must be performed before collection of cells for manufacturing.
Blood, organ, tissue and cell donation
Patients treated with this medical product must not donate blood, organs, tissues, or cells for transplantation.
Cytokine release syndrome
Nearly all patients experienced some degree of CRS. Severe CRS, including life-threatening and fatal reactions, was very commonly observed with a time to onset of 1 to 12 days in ZUMA-1 and ZUMA-7, and 1 to 11 days in ZUMA-5.
Management of cytokine release syndrome
At least 1 dose per patient of tocilizumab, an interleukin 6 (IL 6) receptor inhibitor, must be on site and available for administration prior to infusion. The qualified treatment center must have access to an additional dose of tocilizumab within 8 hours of each previous dose.
Patients must be monitored daily for signs and symptoms of CRS for at least 10 days following infusion.
This medical product must not be administered to patients with active infections or inflammatory disease until these conditions have resolved.
CRS has been known to be associated with end organ dysfunction (e.g., hepatic, renal, cardiac, and pulmonary). In addition worsening of underlying organ pathologies can occur in the setting of CRS. Patients with medically significant cardiac dysfunction must be managed by standards of critical care and measures such as echocardiography are to be considered.
Evaluation for haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) is to be considered in patients with severe or unresponsive CRS.
This medical product continues to expand and persist following administration of tocilizumab and corticosteroids. Tumour necrosis factor (TNF) antagonists are not recommended for management of CRS.
Neurologic adverse reactions
Severe neurologic adverse reactions, also known as immune effector cell-associated neurotoxicity syndrome (ICANS), have been very commonly observed in patients treated with this medical product, which could be life-threatening or fatal. The median time to onset was 6-7 days following infusion. Patients with a history of CNS disorders such as seizures or cerebrovascular ischaemia may be at increased risk.
Patients must be monitored at least daily for 10 days at the qualified clinical facility following infusion for signs and symptoms of neurologic toxicity/ICANS. After the first 10 days following the infusion, the patient is to be monitored at the physician’s discretion.
Infections and febrile neutropenia
Serious infections have been very commonly observed. Patients must be monitored for signs and symptoms of infection before, during, and after infusion and treated appropriately.
Febrile neutropenia has been observed in patients after infusion and may be concurrent with CRS.
Viral reactivation
HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B-cells.
Reactivation of John Cunningham (JC) virus, leading to progressive multifocal leukoencephalopathy (PML), has been reported in patients treated with this medical product who have also received prior treatment with other immunosuppressive medications. Cases with fatal outcome have been reported.
Other life-threatening and fatal cases of viral reactivation with HHV-6 have been reported.
Prolonged cytopenias
Patients may experience cytopenias for several weeks following lymphodepleting chemotherapy and administration of this medicinal product. Prolonged Grade 3 or higher cytopenias were very common after infusion and included thrombocytopenia, neutropenia, and anemia. Blood counts must be monitored after infusion.
Hypogammaglobulinaemia
B-cell aplasia leading to hypogammaglobulinaemia can occur in patients receiving treatment, hypogammaglobulinaemia has been very commonly observed. Hypogammaglobulinaemia predisposes patients to have infections. Immunoglobulin levels should be monitored after treatment and managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement in case of recurrent infections and must be taken according to standard guidelines.
Hypersensitivity reactions
Allergic reactions may occur with infusion. Serious hypersensitivity reactions including anaphylaxis, may be due to DMSO or residual gentamicin.
Secondary malignancies including of T-cell and myeloid origin
Patients may develop secondary malignancies. T-cell malignancies have been reported following treatment of haematological malignancies with a BCMA- or CD19-directed CAR T-cell therapy. T-cell malignancies, including CAR-positive malignancies, have been reported within weeks and up to several years following administration of a CD19- or BCMA-directed CAR T-cell therapy. There have been fatal outcomes. In the event that a secondary malignancy of T-cell origin occurs, the company is to be contaced to obtain instructions on patient samples to collect for testing.
Myelodysplastic syndrome and acute myeloid leukaemia, including cases with fatal outcomes, have occurred in patients.
Patients are to be monitored life-long for secondary malignancies.
Tumour lysis syndrome (TLS)
To minimise risk of TLS, patients with elevated uric acid or high tumour burden should receive allopurinol, or an alternative prophylaxis, prior to infusion. Signs and symptoms of TLS must be monitored.
CD19-negative disease
There is limited experience with this medical product in patients exposed to prior CD19-directed therapy. This medical product is not recommended if the patient has relapsed with CD19-negative disease after prior anti-CD19 therapy.
See prescribing information for full details.

Very common: Unspecified pathogen infections, viral infections, bacterial infections, febrile neutropenia, neutropenia, lymphopenia, leukopenia, anaemia, thrombocytopenia, cytokine Release Syndrome, hypogammaglobulinaemia, hyponatraemia, hypophosphatemia, hyperuricemia, decreased appetite, weight decrease, delirium , insomnia, encephalopathy, tremor, headache, dizziness, tachycardia, arrhythmia, hypotension, hypertension, dyspnoea, cough, nausea, vomiting, constipation, abdominal pain, diarrhoea, rash, motor dysfunction, musculoskeletal pain, fever, oedema, fatigue, chills, transaminases increased.
Common:  Fungal infections, coagulopathy, hypersensitivity, hypokalemia,
hypocalcaemia, hypoalbuminaemia, dehydration, affective disorder, seizure
hemiparesis, ataxia, neuropathy peripheral, cardiac arrest, cardiac failure, thrombosis, hypoxia, pleural effusion, nasal inflammation, dysphagia,
dry mouth, renal impairment, pain, visual impairment, hyperbilirubinemia.
See prescribing information for full details.

No interaction studies have been performed with Yescarta.

Pregnancy:
Women of childbearing potential/Contraception
The pregnancy status of women of child bearing potential must be verified before starting YESCARTA treatment.
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 Yescarta.
There are no available data with Yescarta use in pregnant women.  No reproductive and developmental toxicity animal studies have been conducted with YESCARTA to assess whether it can cause foetal harm when administered to a pregnant woman.
It is not known if Yescarta has the potential to be transferred to the foetus.  Based on the mechanism of action, if the transduced cells cross the placenta, they may cause foetal toxicity, including B‑cell lymphocytopenia.  Therefore, Yescarta is not recommended for women who are pregnant, or for women of childbearing potential not using contraception.  Pregnant women should be advised on the potential risks to the foetus
Lactation:
It is unknown whether Yescatra is excreted in human milk or transferred to the breast‑feeding child.  Breast‑feeding women should be advised of the potential risk to the breast‑fed child.

There are no data regarding the signs of overdose.

Storage:
The expiry date of the product is indicated on the packaging materials.
Yescarta must be stored frozen in the vapour phase of liquid nitrogen (≤ -150 ˚C).
The stability of Yescarta upon completion of thawing is up to 3 hours at room temperature (20 ˚C to 25 °C).  However, Yescarta infusion must begin within 30 minutes of thaw completion and the total Yescarta infusion time must not exceed 30 minutes.  Thawed product must not be refrozen.
The Yescarta bag must be stored in the vapour phase of liquid nitrogen (≤ -150 ˚C) and Yescarta must remain frozen until the patient is ready for treatment to ensure viable live autologous cells are administered to the patient.
Effects on ability to drive and use machines
Yescarta has major influence on the ability to drive and use machines. Due to the potential for neurologic events, including altered mental status or seizures, patients must refrain from driving or operating heavy or potentially dangerous machines until at least 8 weeks after infusion or until resolution of neurologic adverse reactions.