Evaluation of Mobilization, Apheresis, and Conditioning Regimen and Engraftment in Patients Receiving One-Time Gene Therapy with Elivaldogene Autotemcel (Eli-cel) for Cerebral Adrenoleukodystrophy (CALD)

Introduction Eli-cel, an autologous hematopoietic stem cell (HSC) gene therapy consisting of CD34+ cells transduced with ABCD1 cDNA using a Lenti-D lentiviral vector (LVV), is approved for the treatment of CALD. Objective To describe conditioning and engraftment data from patients with CALD treated with eli-cel in two consecutive studies, ALD-102 (NCT01896102) and ALD-104 (NCT03852498). Methods ALD-102 and ALD-104 enrolled boys aged ≤17 y with active CALD to undergo HSC mobilization with granulocyte colony-stimulating factor with or without plerixafor (mandated in ALD-104; physician discretion in ALD-102). Mobilization was followed by CD34+ cell collection by apheresis and enrichment. CD34+ HSCs were transduced ex vivo with Lenti-D LVV and tested to ensure drug product quality. Transduced cells (eli-cel) were infused following myeloablation conditioning with intravenous (IV) busulfan (1.1 mg/kg [≤12 kg] or 0.8 mg/kg [>12 kg] every 6 hours × 4 days with level monitoring) with IV cyclophosphamide (50 mg/kg × 4 days; ALD-102) or IV fludarabine (40 mg/m2 × 4 days; ALD-104). Patients were followed 24 mo post infusion in ALD-102 and ALD-104, with 13 y of long-term follow-up in LTF-304 (ongoing). Engraftment definitions—neutrophil: achieving 3 consecutive laboratory values of ≥0.5 × 109 cells/L obtained on different days by 43 days post infusion; platelet: achieving 3 consecutive unsupported values of ≥20 × 109 cells/L obtained on different days post infusion. Safety was evaluated throughout the studies. Results ALD-102 (data cutoff: Mar 26, 2021) enrolled 32 patients (median [min, max] age: 6 y [3, 13]; median [min, max] follow-up: 60.2 mo [13.4, 106.9]), and ALD-104 (data cutoff: Jun 12, 2023) enrolled 35 patients (median [min, max] age: 7 y [5, 13]; median [min, max] follow-up: 23.8 mo [17.6, 31.3]). Patients collected sufficient HSCs for transduction and back-up in 1 cycle and received eli-cel infusion at the prescribed dose (≥5.0 × 106 CD34+ cells/kg). All 67 patients achieved neutrophil and platelet engraftment (Table 1); 9 (13.4%) had platelet count ≤50 × 109 cells/L >60 days post infusion. Serious adverse events (SAEs) are provided in Table 2. Few SAEs were reported during mobilization/apheresis; incidence was expectedly higher in conditioning and neutropenic periods, consistent with myeloablative transplant. No patients developed sinusoidal obstruction syndrome or new seizures; all survived to hospital discharge. As of Sep 6, 2023, 5 patients who received eli-cel were subsequently diagnosed with myelodysplastic syndrome. Conclusion In ALD-102 and ALD-104, the mobilization, apheresis, and conditioning protocols used were effective. The AE profile was consistent with the expected effects of mobilization, apheresis, and myeloablation. These data demonstrate the utility of these approaches in achieving sufficient CD34+ cell yields and engraftment for CALD gene therapy.