Abstract Introduction CRISPR-Cas9 based gene therapy has been the first cellular therapy approved in the UK since September 2024 for the treatment of transfusion dependant β-thalassemia (TDT). Through its mechanism of action, the underlying defect in TDT is corrected directly by downregulating BCL11A expression, leading to increased fetal hemoglobin (HbF) production. Obtaining adequate CD34⁺ hematopoietic stem cells (HSC) is a crucial step in order to proceed with this curative treatment. Following collection, CD34⁺ cells require approximately 5-6 months to undergo gene editing and processing before reinfusion. The edited CD34⁺ hematopoietic stem cells are then reinfused into the patient following a four-day regimen of myeloablative busulfan conditioning chemotherapy. Method All eligible patients were evaluated and approved through the regional Hemoglobinopathy Coordinating Centre (HCC) and the National Hemoglobinopathy Panel (NHP). Seven patients underwent hematopoietic stem cell mobilization with plerixafor and granulocyte colony stimulating factor (G-CSF) followed by leukapheresis over a three-day period. Data on patient characteristics, apheresis parameters, and procedure related complications were collected and analyzed retrospectively. Results The study cohort comprised seven patients (four males, three females) aged 13 to 37 years. One patient had undergone splenectomy, while the remaining six patients had intact spleens. All patients underwent leukapheresis over a three-day period. G-CSF was administered at a dose of 10 µg/kg/day for 5 to 7 days, and plerixafor at 0.24 mg/kg was given on the day of apheresis. In the splenectomized patient, a reduced G-CSF dose of 5 µg/kg/day was used. Six of seven patients achieved adequate stem cell collection with a single cycle of apheresis, while one required a second cycle. Patient 1: White blood cell (WBC) count ranged from 65.6 × 10⁹/L to 91.4 × 10⁹/L. A total CD34⁺ cell dose of 70.24 × 10⁶/kg was collected, of which 18.5 × 10⁶/kg comprised gene-edited cells. Patient 2: WBC count ranged from 73.2 × 10⁹/L to 122.7 × 10⁹/L. The total CD34⁺ cell dose collected for manufacturing was 38.8 × 10⁶/kg, and the final gene-modified product yielded 16.5 × 10⁶/kg. Patient 3: WBC count ranged from 132.2 × 10⁹/L to 152.5 × 10⁹/L. The CD34⁺ cell dose collected was 22.54 × 10⁶/kg. The cells were deemed insufficient by the manufacturer, necessitating a repeat procedure, which has been scheduled. Patient 4: WBC count ranged from 56.8 × 10⁹/L to 85.7 × 10⁹/L. The total CD34⁺ cell dose collected for manufacturing was 29.22 × 10⁶/kg. Patient 5: WBC count ranged from 68.0 × 10⁹/L to 99.4 × 10⁹/L. A CD34⁺ cell dose of 21.96 × 10⁶/kg was collected and sent for manufacturing. Patient 6: WBC count ranged from 71.7 × 10⁹/L to 95.5 × 10⁹/L. The total CD34⁺ cell dose collected was 77.39 × 10⁶/kg, and the gene-edited cell dose was 15.5 × 10⁶/kg. Patient 7: WBC count ranged from 48.8 × 10⁹/L to 60.8 × 10⁹/L. A total CD34⁺ cell dose of 37.8 × 10⁶/kg was collected and is currently undergoing gene modification. Conclusion We successfully achieved adequate CD34⁺ stem cell collections in six out of seven patients. A repeat cycle of apheresis was required in one patient due to insufficient collection and is currently awaiting completion. In two out of the seven patients, the final CD34⁺ gene edited cell doses were 18.5 × 10⁶/kg and 15.5 × 10⁶/kg, both exceeding the minimum target threshold of 15 × 10⁶/kg. Final cell dose quantification is pending for the remaining four patients.Patient 1 has successfully undergone gene therapy and represents the first treated TDT patient within the National Health Service (NHS). He achieved timely engraftment and was discharged home within four weeks. Adverse events observed were consistent with expected toxicities from myeloablative conditioning. To our knowledge, this is the largest single-centre series of its kind reported to date.
Deshani et al. (Mon,) studied this question.