Mobilization and Apheresis Experience in Patients Receiving One-Time Gene Therapy with Beti-Cel for Patients with Transfusion-Dependent β-Thalassemia: A Pooled Analysis

Introduction Betibeglogene autotemcel (beti-cel) gene therapy is approved for the treatment of patients with transfusion-dependent β-thalassemia (TDT). In beti-cel clinical trials, hematopoietic stem cell (HSC) mobilization with granulocyte colony-stimulating factor (G-CSF) and plerixafor have been used to achieve sufficient yields of CD34+ cells for gene therapy in patients with TDT. Objective To evaluate pooled data on the mobilization and collection of HSCs from the intent-to-treat population in 4 studies of beti-cel. Methods Phase 1/2 HGB-204 (NCT01745120) and HGB-205 (NCT02151526) and phase 3 HGB-207 (NCT02906202) and HGB-212 (NCT03207009) were single-arm, open-label, single-dose studies that enrolled pediatric and adult patients with TDT, with or without prior splenectomy. Patients underwent HSC mobilization with G-CSF (5 or 10 μg/kg/day in patients without or with a spleen, respectively) and plerixafor (0.24 mg/kg/day; except for 1 patient [see Results]), followed by CD34+ cell collection by apheresis. The target number of cells to be collected via apheresis was ≥10 × 106 CD34+ cells/kg in HGB-204 and HGB-205, and ≥12 × 106 CD34+ cells/kg in HGB-207 and HGB-212, irrespective of age or genotype, for a minimum drug product dose of 5 × 106 cells/kg. The number of mobilization cycles needed to achieve cell collection target was analyzed; data for various baseline indexes are presented based on number of mobilization cycles and splenectomy status. Results Across the 4 studies, 66 patients initiated mobilization (splenectomized, n=18; nonsplenectomized, n=48; Table 1). Total cell collection target was achieved after 1 mobilization cycle in 52/66 (78.8%) patients and after 2 cycles in 13/66 (19.7%); 1 patient who received only G-CSF had unsuccessful mobilization and withdrew prior to beti-cel infusion. Among patients with available values, baseline median liver iron concentration, hemoglobin, total white blood cells, neutrophil:lymphocyte ratio in blood, and myeloid:erythroid ratio in bone marrow were similar between patients who had 1 mobilization cycle and those who had 2 (Table 2). A greater proportion of splenectomized patients (8/18 [44.4%]) had 2 mobilization cycles vs nonsplenectomized patients (5/48 [10.4%]). Median (min, max) CD34+ cell yield collected for beti-cel manufacturing was 19.44 (8.9, 36.9) × 106 cells/kg in splenectomized patients and 29.46 (16.9, 51.1) × 106 cells/kg in nonsplenectomized patients. Most patients (51/66 [77.3%]) had ≥1 adverse event (AE) attributed to mobilization and apheresis. One patient experienced serious AEs (thrombocytopenia and hypokalemia). Conclusion The mobilization and apheresis protocol used in beti-cel clinical trials for the treatment of patients with TDT was well tolerated and effective and will inform real-world use of beti-cel treatment for achieving optimal CD34+ cell yields for gene therapy.