LAUSR

Early treatment with allogeneic hematopoietic stem cell transplantation (allo-HSCT) for cerebral adrenoleukodystrophy (CALD) has a beneficial effect on clinical indices of disease and long-term survival but is associated with immunologic risks. We aim to understand how outcomes of allo-HSCT differ by disease stage, donor cell source, and conditioning regimen. As of February 2019, 47 boys were enrolled in an ongoing observational study of allo-HSCT in CALD. Efficacy was analyzed for advanced (Loes >9 or Neurologic Function Score [NFS] >1; n=10) and two early disease cohorts (ED1, Loes ≤4 and NFS ≤1 [n=21]; ED2, Loes >4-9, and NFS ≤1 [n=9]). Safety was analyzed by donor source and conditioning regimen. There was no statistical difference in survival and neurologic findings between the ED cohorts. Patients with advanced CALD had the worst outcomes. At 24 months, overall survival and survival free of major functional disabilities were 90.5% (95% CI 67.0, 97.5) and 78.9% (53.2, 91.5) for ED1, 85.7% (33.4, 97.9) and 70.0% (22.5, 91.8) for ED2, and 52.5% (16.8, 79.3) and 35.0% (8.5, 64.0) for advanced CALD, respectively. Most patients in both ED cohorts, and fewer of those with advanced CALD, had stable Loes scores and NFS through last follow up. Of patients with baseline gadolinium enhancement (GdE+) and follow-up data, 9/9 in ED1, 4/5 in ED2, and 2/4 in the advanced disease cohort had resolution of GdE+ throughout follow-up. Acute (Grade ≥2) and chronic graft-versus-host disease (GVHD) occurred in 23.5% (8/34) and 27.6% (8/29) of patients, respectively. One-year transplant-related mortality was 12.1% (4/33), and 21.6% (8/37) of patients had engraftment failure. There were no substantial observed differences in transplant-related outcomes by donor cell source, but more patients who received umbilical cord (UC) cells from an unrelated donor (38.9%, 7/18) had engraftment failure compared to patients who received bone marrow (BM) or UC cells from a matched sibling donor (MSD), or BM cells from an unrelated donor (0% for both [0/8]; p=0.0622). Importantly, while transplants performed using cells from a MSD are considered safe, they resulted in chronic GVHD in 28.6% (2/7) of patients. Trade-offs in transplant-related risks with myeloablative conditioning were noted. Compared to busulfan/ fludarabine (Bu/Flu), the use of busulfan/cyclophosphamide increased the risk of acute and chronic GVHD (6.3% [1/16] vs. 42.9% [6/14] [p=0.0309] and 13.3% [p=2/15] vs. 54.5% [6/11] [p=0.0384], respectively), while myeloablative conditioning with Bu/Flu resulted in higher rates of engraftment failure (28.6% [6/21] vs. 0% [0/11], p=0.0711). These data suggest that treatment in early CALD provides better efficacy outcomes irrespective of the stage of early disease, although neuropsychological outcome data are not yet available. Transplant-related risks highlight an unmet need for improved safety outcomes.