Etuvetidigene Autotemcel

Etuvetidigene autotemcel is an autologous hematopoietic stem cell-based gene therapy indicated for the treatment of pediatric patients aged 6 months and older and adults with Wiskott-Aldrich Syndrome (WAS) who have a WAS gene mutation and for whom hematopoietic stem cell transplantation (HSCT) is appropriate and no suitable human leukocyte antigen (HLA)-matched related stem cell donor is available.

• Etuvetidigene autotemcel is available under the following different brand names: Waskyra

Common side effects of Etuvetidigene autotemcel include:

• diarrhea
• vomiting 
• stomatitis 
• rhinitis
• cough 
• rash
• petechiae 
• hypersensitivity 
• anemia
• febrile neutropenia 
• epistaxis
• pyrexia
• catheter-related infections
• catheter site complications
• bacterial and viral infections 
• liver injury 
• head injury

Serious side effects of Etuvetidigene autotemcel include:

• catheter-related infection
• bacterial and viral infections
• febrile neutropenia/prolonged neutropenia
• veno-occlusive disease
• serious fungal infection (e.g., Aspergillus infection)

Rare side effects of Etuvetidigene autotemcel include:

• none 

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult & Pediatric Dosage

Injection, suspension

• Packaged in 1-8 infusion bags overall containing an autologous CD34+cell suspension of 2-11.4 x 10^6 cells/mL (1.9-11.4 x 10^6 CD34+ cells/mL) in a cryopreservative solution

Wiskott-Aldrich Syndrome

Adult & Pediatric dosage

• For autologous use only as a single-dose intravenous infusion
• Recommended dose
  • Minimum recommended dose: 7 x 10^6 CD34+ cells/kg based on the patient’s body weight at the time of infusion
  • Maximum volume: Less than 20% of the patient’s estimated plasma volume
  • Patient preparation before intravenous infusion
• Mobilization and apheresis
  • Mobilize hematopoietic stem and progenitor cells (HSPC) using Granulocyte Colony-Stimulating Factor(G-CSF) with plerixafor according to established protocols
  • Perform apheresis to collect CD34+ cells required for etuvetidigene autotemcel manufacturing following the mobilization procedure
  • Collect and cryopreserve a back-up supply of CD34+ stem cells containing at least 3 x 10^6 CD34+ cells/kg from the patient; complete this collection before initiating reduced intensity conditioning and etuvetidigene autotemcel infusion
  • Store back-up collection for potential rescue treatment in the following scenarios: etuvetidigene autotemcel compromise after reduced intensity conditioning initiation but before scheduled infusion, primary engraftment failure, or prolonged bone marrow aplasia following treatment
• Pretreatment and conditioning
  • Administer rituximab (anti-CD20 monoclonal antibody) approximately 22 days before etuvetidigene autotemcel administration to deplete autoreactive B-cells and provide pre-emptive treatment for potential lymphoproliferative disorder due to Epstein-Barr Virus infection (risk factor in patients with WAS)
  • Administer busulfan and fludarabine for reduced intensity conditioning before etuvetidigene autotemcel infusion to promote engraftment of genetically modified autologous CD34+ cells
  • Do not begin conditioning until a complete set of infusion bag(s) constituting etuvetidigene autotemcel dose has been received and stored at the administration site
  • Confirm the availability of a backup collection of CD34+ stem cells
• Premedication
  • Administer chlorpheniramine (0.2 mg/kg intravenously, not to exceed 10 mg/dose) or an equivalent 15-30 minutes before etuvetidigene autotemcel infusion to reduce possible allergic reaction to infusion

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, healthcare provider, or pharmacist first.

Drug Interaction Overview

Effect of vaccines on etuvetidigene autotemcel

• Safety and effectiveness of vaccination during or following treatment have not been studied
• Vaccination with live virus vaccines is not recommended until immune reconstitution is completed following treatment

Effect of antiretrovirals on etuvetidigene autotemcel

• Anti-retroviral medications may interfere with etuvetidigene autotemcel manufacturing
• Patients should not take antiretroviral medications for at least 1 month before mobilization and until at least 7 days after infusion
• If a patient requires antiretroviral treatment following exposure to HIV/HTLV (Human T-cell Lymphotropic Virus), delay initiation of etuvetidigene autotemcel treatment until an HIV/HTLV western blot and viral load assay have been performed at 6 months post-exposure

Contraindications

• Hypersensitivity to active substance or to any of the excipients
• Previous treatment with HSCT within 6 months before screening or HSCT with evidence of residual donor cells
• Previous treatment with HST gene therapy
• Contraindications to the mobilization and conditioning regimen

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Etuvetidigene autotemcel?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Etuvetidigene autotemcel?”

Cautions

• Hypersensitivity and infusion-related reactions
  • Hypersensitivity and infusion-related reactions, including anaphylaxis, may occur with infusion due to its excipient, dimethylsulfoxide (DMSO)
  • Monitor for signs and symptoms of hypersensitivity and infusion-related reactions during and after infusion
  • When more than 1 bag is needed, ensure that the total volume of product to be infused is compatible with the recommended limit of DMSO (ie, less than 1% of the patient’s estimated plasma volume)
  • Maximum volume of etuvetidigene autotemcel should therefore remain less than 20% of the patient’s estimated plasma volume
  • Also, when more than 1 bag is needed, only 1 bag of the medicinal product should be infused at a time
• Engraftment failure
  • Engraftment failure, defined as failure to reach an absolute neutrophil count (ANC) of more than 500 cells/μL associated with no evidence of bone marrow recovery (ie, hypocellular marrow) by day 60, may potentially occur after infusion
  • Monitor for signs and symptoms of engraftment failure
  • In case of engraftment failure, infuse non-transduced back-up hematopoietic stem cells according to local standards
• Cytopenias
  • Severe cytopenias, including anemia, neutropenia, and thrombocytopenia, have occurred for several weeks following reduced intensity conditioning and etuvetidigene autotemcel infusion
  • Monitor for signs and symptoms of cytopenia for at least 8 weeks after treatment
  • Manage patients with supportive transfusion according to clinical practice
  • If neutropenia persists beyond 6-7 weeks, despite use of G-CSF, consider administration of non-transduced backup stem cells or alternative treatments
• Serious infections
  • Serious infections have occurred
  • Increased susceptibility to infections may occur with concomitant administration of rituximab and conditioning regimen
  • Monitor for signs and symptoms of infection before and after etuvetidigene autotemcel infusion and treat appropriately
  • Administer prophylactic antimicrobials according to local guidelines
  • Maintain serum IgG more than 5 g/L to prevent potential infections associated with severe hypogammaglobulinemia, resulting from disease, related immune deficiency, rituximab administration, and conditioning
  • Irradiate any blood products required after infusion
• Transmission of an infectious agent
  • Transmission of infectious disease or agents may occur with treatment because it is manufactured using human and bovine-derived reagents, which are tested for human and animal viruses, bacteria, fungi, and mycoplasma before use
  • Additionally, it is tested for sterility and mycoplasma at release
  • These measures do not eliminate the risk of transmitting these or other infectious diseases or agents
  • Report all infections thought to be transmitted by etuvetidigene autotemcel to Fondazione Telethon ETS at 1-888-212-6928
• Hepatic veno-occlusive disease
  • Hepatic veno-occlusive disease reported
  • Monitor for signs and symptoms of veno-occlusive disease, including assessment of liver function tests during the first month after infusion
• Risk of oncogenesis
  • There is a lifelong risk of lentiviral vector (LVV)-mediated insertional oncogenesis and secondary malignancy after treatment
  • Monitor after treatment for the development of malignancies
  • If malignancy occurs, contact Fondazione Telethon ETS at 1-888-212-6928 to obtain instructions on collecting patient samples for testing
• Interference with HIV testing
  • Patients may test positive by polymerase chain reaction (PCR) assays for HIV due to LVV provirus insertion, resulting in a false positive test for HIV
  • Do not screen patients for HIV infection using a PCR-based assay
• Blood, organ, tissue, and cell donation
  • Patients should not donate blood, organs, tissues, or cells for transplantation at any time in the future
  • This information is provided in the Patient Alert Card that patients receive after treatment

Pregnancy and Lactation

Pregnancy

• There are no clinical data on use during pregnancy
• No animal reproductive and developmental toxicity studies have been conducted to assess whether etuvetidigene autotemcel can cause fetal harm
• Must not be administered during pregnancy because of the risk associated with conditioning
• Pregnancy after infusion should be discussed with the treating physician

Pregnancy testing

• A negative serum pregnancy test must be confirmed before the start of mobilization and reconfirmed before conditioning procedures and before administration in females of childbearing potential

Contraception

• Males capable of fathering a child and females of childbearing age should use an effective method of contraception from the start of mobilization through at least 6 months after administration

Infertility

• Data are not available regarding the effects on fertility
• Treating physicians should inform patients or patients’ parents/carers in case of minors about options for cryopreservation of spermatogonial stem cells or ovarian tissue prior to application of conditioning

Lactation

• There are no data on the presence of etuvetidigene autotemcel in human or animal milk, effects on breastfed children, or effects on milk production
• Because of potential risks associated with conditioning, breastfeeding should be discontinued
• Consider the developmental and health benefits of breastfeeding, along with the mother’s clinical needs and any potential adverse effects on breastfed children or from underlying maternal condition