Active Ingredient: Etuvetidigene autotemcel
Etuvetidigene autotemcel is indicated for the treatment of patients aged 6 months and older with Wiskott-Aldrich Syndrome (WAS) who have a mutation in the WAS gene for whom haematopoietic stem cell (HSC) transplantation is appropriate and no suitable human leukocyte antigen (HLA)-matched related haematopoietic stem cell donor is available.
For this indication, competent medicine agencies globally authorize below treatments:
For:
In case that patient age in months is ≥ 6
Intravenous, 7,000,000 cells etuvetidigene autotemcel, one dose.
Etuvetidigene autotemcel must be administered in a qualified treatment centre by a physician with experience in haematopoietic stem cell transplantation (HSCT) and trained for administration and management of patients treated with the medicinal product.
Before mobilisation, apheresis and reduced intensity conditioning are initiated, it must be confirmed that haematopoietic stem cell (HSC) transplantation is appropriate for the patient.
Physicians should refer to the SmPCs of medicinal products used for pre-treatment, peripheral blood mobilisation and conditioning to ensure appropriate guidance to the patient.
Etuvetidigene autotemcel is intended for autologous use only and should be administered once.
Treatment consists of a single dose for infusion containing a dispersion of viable CD34+ cells in one or more infusion bags.
The dose of etuvetidigene autotemcel to be administered is defined based on the patient's body weight at the time of infusion.
The minimum recommended dose is 7 × 106 CD34+ cells/kg of body weight.
The maximum volume of etuvetidigene autotemcel to be administered should remain <20% of the patient's estimated plasma volume.
The treating physician should confirm that autologous HSPC gene therapy administration is clinically appropriate for the patient before rituximab and conditioning is initiated.
Conditioning should not begin until the complete set of infusion bag(s) constituting the dose of etuvetidigene autotemcel has been received and stored at the administration site, and the availability of the back-up collection is confirmed.
The autologous CD34+ cells are isolated from mobilised peripheral blood. This is achieved by apheresis procedure(s) following peripheral blood mobilisation.
To obtain CD34+ cells for medicinal product manufacturing and for autologous back up, patients are required to undergo haematopoietic stem and progenitor cell (HSPC) mobilisation with granulocyte-colony stimulation factor (G-CSF) and plerixafor followed by leukapheresis.
A total HSPC collection target of 40 × 106 CD34+ cells/kg is recommended for medicinal product manufacture. In addition to this, at least 3 × 106 CD34+ cells/kg should be collected as autologous back-up The back-up cells may be harvested either through mobilised peripheral blood apheresis or bone marrow harvest.
Busulfan and fludarabine are the recommended conditioning medicinal products.
| Days before the treatment infusion | Dosing regimen | Dose | |
| Rituximab | Day-22 (+/- 1 day) | The infusion of a single dose of IV Rituximab, a monoclonal antibody anti-CD20, is recommended at Day –22 (+/- 1 day) before the infusion of etuvetidigene autotemcel, with the aim to deplete B cells pre-treatment. Infusion rate is in accordance with the summary of product characteristics (SmPC) To reduce the occurrence of potential adverse reactions, Rituximab infusion should be preceded by appropriate premedication with IV antihistaminic medicinal product, paracetamol, and steroids, following standard procedures. These should be repeated after 6 hours. | 375 mg/m² |
| Busulfan | Day-4 to Day-2 | Patients will receive body weight-based doses of IV busulfan. Patients are scheduled to receive a total of 8 doses, given every 6 hours from Day-4 to Day-2. If the target AUC of 48 000 ng/mL*h (± 10%) is not achieved with 8 doses, additional doses may be administered. Dosing will be stopped if the target AUC was reached prior to the eighth dose. Dose adjustment will be performed according to busulfan PK levels to achieve the target cumulative AUC of 48 000 ng/mL*h (± 10%). The etuvetidigene autotemcel cell infusion will be scheduled to allow a washout time of at least 24 hours from the last dose of busulfan. | The starting dose of busulfan is based on patient's weight according to the following scheme: • 1 mg/kg/dose (<9 kg); • 1.2 mg/kg/dose (9 - 16 kg); • 1.1 mg/kg/dose (>16 - 23 kg); • 0.95 mg/kg/dose (>23 - 34 kg); • 0.8 mg/kg/dose (>34 kg). The subsequent doses of busulfan should be estimated from pharmacokinetics (PK) sampling and adjusted accordingly. The busulfan PK analysis should be performed by serial blood sampling before and after the infusion of at least two separate doses usually the first and fifth dose. Special attention should be kept on the busulfan dosing in order to achieve the target cumulative AUC of 48 000 ng/ml*h (± 10%). A dose adjustment should be performed if the total predicted AUC shows more than 10% deviation from the target (total predicted AUC is <43 200 ng/mL*h or >52 800 ng/mL*h). The number of doses of Busulfan may be decreased if the cumulative predicted AUC is too high. |
| Fludarabine | Day-4 and Day-3 | Fludarabine is administered IV once daily in Day-4 and Day-3. The infusion rate should be in accordance with the fludarabine Summary of Product Characteristics (SmPC). | 30 mg/m²/day |
AUC = area under the curve; IV=intravenous; PK=pharmacokinetic; m² = square meter
Prophylactic and empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the prevention and management of infections especially during the neutropenic period following conditioning. Infection control measures and isolation procedures should be employed during the hospitalisation according to local standards.
Antiallergic medicinal products, such as intravenous chlorpheniramine, are recommended be administered 15-30 minutes before the infusion of etuvetidigene autotemcel to reduce the possibility of an allergic reaction to the infusion.
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