Sickle cell disease

Active Ingredient: Exagamglogene autotemcel

Indication for Exagamglogene autotemcel

Population group: only adolescents (12 years - 18 years old) , adults (18 years old or older)
Therapeutic intent: Curative procedure

Exagamglogene autotemcel is indicated for the treatment of severe sickle cell disease (SCD) in patients 12 years of age and older with recurrent vaso-occlusive crises (VOCs) for whom haematopoietic stem cell (HSC) transplantation is appropriate and a human leukocyte antigen (HLA)-matched related HSC donor is not available.

For this indication, competent medicine agencies globally authorize below treatments:

3 × 10⁶ CD34+ cells/kg of body weight once

For:

Dosage regimens

Intravenous, 3,000,000 cells exagamglogene autotemcel per kilogram of body weight, one dose.

Detailed description

Exagamglogene autotemcel is intended for autologous use.

Treatment consists of a single dose containing a dispersion for infusion of viable CD34+ cells in one or more vials.

The minimum recommended dose is 3 × 106 CD34+ cells/kg of body weight.

Mobilisation and apheresis

Patients are required to undergo CD34+ HSPC mobilisation followed by apheresis to isolate the CD34+ cells for medicinal product manufacturing.

Maximise CD34+ cell collection for product manufacturing during each mobilisation and apheresis cycle. Perform two consecutive days of cell collection for product manufacturing per cycle, if clinically tolerated. A total collection target of at least 20 × 106 CD34+ cells/kg is recommended for product manufacture. Collected cells should be sent for product manufacturing even if the total collection target is not achieved. In addition, at least 2 × 106 CD34+ cells/kg are required to be collected for back-up unmodified rescue cells. A third day of cell collection can be used to obtain back-up rescue cells, if needed.

If the minimum dose of exagamglogene autotemcel is not met after initial medicinal product manufacturing, the patient will need to undergo additional cycles of mobilisation and apheresis to obtain more cells for additional product manufacture. Each mobilisation and apheresis cycle must be separated by a minimum of 14 days.

The back-up collection of ≥2 × 106 CD34+ cells/kg of unmodified rescue cells must be collected from the patient and be cryopreserved prior to myeloablative conditioning and infusion with exagamglogene autotemcel.

The unmodified cells may be needed for rescue treatment under any one of the following conditions: compromise of exagamglogene autotemcel after initiation of myeloablative conditioning and before exagamglogene autotemcel infusion; neutrophil engraftment failure; or loss of engraftment after infusion with exagamglogene autotemcel.

Refer to the Summary of Product Characteristics for the mobilisation medicinal product(s) prior to treatment with exagamglogene autotemcel.

Prior to apheresis it is recommended that patients receive RBC exchange or simple transfusion(s) with a goal of maintaining haemoglobin S (HbS) levels <30% of total Hb while keeping total Hb concentration ≤11 g/dL.

Disease modifying therapies (e.g., hydroxyurea/hydroxycarbamide, crizanlizumab, voxelotor) must be discontinued 8 weeks before the planned start of mobilisation and conditioning.

Granulocyte colony stimulating factor (G-CSF) must not be administered for mobilisation in patients with sickle cell disease.

Pre-treatment conditioning

Full myeloablative conditioning must be administered before infusion of exagamglogene autotemcel. Conditioning must not be initiated until the complete set of vials constituting the full dose of exagamglogene autotemcel has been received at the authorised treatment centre, and the availability of the back-up collection of unmodified CD34+ cells is confirmed. Refer to the Summary of Product Characteristics for the myeloablative conditioning medicinal product(s) prior to treatment.

It is recommended that patients receive RBC exchange or simple transfusion(s) for at least the 8 weeks prior to the initiation of myeloablative conditioning with a goal of maintaining HbS levels <30% of total Hb while keeping total Hb concentration ≤11 g/dL. At initiation of red blood cell exchanges or simple transfusions, discontinue disease modifying therapies (e.g., hydroxyurea/hydroxycarbamide, crizanlizumab, voxelotor).

Iron chelation therapy must be stopped at least 7 days prior to myeloablative conditioning.

Prophylaxis for seizures should also be considered. Refer to the Summary of Product Characteristics for the myeloablative conditioning medicinal product used for information on drug interactions.

Prophylaxis for hepatic veno-occlusive disease (VOD)/hepatic sinusoidal obstruction syndrome should be considered, per institutional guidelines.

Prior to starting the myeloablative conditioning regimen, confirm availability of the complete set of vials constituting the dose of exagamglogene autotemcel, and unmodified rescue cells. See the Lot information sheet (LIS) provided with the product shipment for confirmation of the number of vials and total dose of exagamglogene autotemcel.

Pre-medication

It is recommended that pre-medication with paracetamol and diphenhydramine, or equivalent medicinal products, be administered per institutional guidelines, before the infusion of exagamglogene autotemcel, to reduce the possibility of an infusion reaction.

Patients aged 35 years and older

Exagamglogene autotemcel has not been studied in patients >35 years of age. The safety and efficacy of exagamglogene autotemcel in this population has not been established. The benefit of treatment in individual patients should be considered against the risks of HSC transplantation.

Dosage considerations

After completion of the myeloablative conditioning regimen, a minimum of 48 hours must elapse before exagamglogene autotemcel infusion. Exagamglogene autotemcel must be administered between a minimum of 48 hours and a maximum of 7 days after the last dose of myeloablative conditioning.

After exagamglogene autotemcel administration

Standard procedures for patient monitoring and management after HSC transplantation must be followed after exagamglogene autotemcel infusion, including monitoring of complete blood counts and transfusion needs.

Blood products required within the first 3 months after exagamglogene autotemcel infusion must be irradiated.

Restarting iron chelation after exagamglogene autotemcel infusion may be necessary. Avoid the use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after exagamglogene autotemcel infusion. Phlebotomy can be used in lieu of iron chelation, when appropriate.

Active ingredient

Exagamglogene autotemcel

Exagamglogene autotemcel is a cell therapy consisting of autologous CD34+ HSPCs ex vivo edited by CRISPR/Cas9-technology. The highly specific guide RNA enables CRISPR/Cas9 to make a precise DNA double-strand break at the critical transcription factor binding site (GATA1) in the erythroid specific enhancer region of the BCL11A gene. As a result of the editing, GATA1 binding is irreversibly disrupted and BCL11A expression reduced. Reduced BCL11A expression results in an increase in γ-globin expression and foetal haemoglobin (HbF) protein production in erythroid cells, addressing the absent globin in transfusion-dependent β-thalassemia (TDT) and the aberrant globin in sickle cell disease (SCD), which are the underlying causes of disease.

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