Variables affecting outcomes after allogeneic hematopoietic stem cell transplant for cerebral adrenoleukodystrophy

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in early cerebral adrenoleukodystrophy can stabilize neurologic function and improve survival but has associated risks including transplant-related mortality (TRM), graft failure, and graft-versus-host disease (GVHD). An observational study of 59 patients with median age at allo-HSCT of 8 years addressed impact of donor source, donor match, conditioning regimen, and cerebral disease stage on first allo-HSCT outcomes. Efficacy analyses included 53 patients stratified by disease category: advanced disease (AD; n = 16) with Loes score >9 or neurological function score (NFS) >1 and 2 early disease (ED) cohorts (ED1 [Loes ≤4 and NFS ≤1; n = 24] and ED2 [Loes >4-9 and NFS ≤1; n = 13]). Survival free of major functional disabilities and without second allo-HSCT at 4 years was significantly higher in the ED (66%) vs AD (41%) cohort (P = .015) and comparable between ED1 and ED2 cohorts (P = .991). The stabilization of neurologic function posttransplant was greater in the ED vs AD cohort, with a median change from baseline at 24 months after allo-HSCT in NFS and Loes score, respectively, of 0 and 0.5 in ED1 (n = 13), 0.5 and 0 in ED2 (n = 6), and 2.5 and 3.0 (n = 4) in AD cohort. TRM was lower in the ED (7%) compared with the AD (22%) cohort; however, the difference was not significant (P = .094). Transplant-related safety outcomes were also affected by transplant-related characteristics: graft failure incidence was significantly higher with unrelated umbilical cord grafts vs matched related donors (P = .039), and acute GVHD and graft failure incidences varied by conditioning regimen. This study was registered at www://clinicaltrials.gov as #NCT02204904.

Graphical abstract

Figure 1.

Kaplan-Meier analyses of overall survival (A) MFD-free survival and (B) by disease severity cohorts. Time of origin was the first allo-HSCT and patients alive without an event were censored at the last follow-up or at the time of study termination. MFD-free survival included survival without second allo-HSCT or major functional disabilities (MFDs).

Figure 2.

Loes score and Neurological Function Score (NFS) over time. Median change from baseline by disease stage is shown for Loes score (A) and NFS (B). Number of evaluable patients at each time point are shown below the x-axis (data availability for each patient at each visit was influenced by a number of factors, including the survival status, retransplantation status, length of follow-up, whether the visit took place, and whether the assessment was performed). (C-D) Individual patient Loes scores and NFS by disease stage.

Figure 2.

Loes score and Neurological Function Score (NFS) over time. Median change from baseline by disease stage is shown for Loes score (A) and NFS (B). Number of evaluable patients at each time point are shown below the x-axis (data availability for each patient at each visit was influenced by a number of factors, including the survival status, retransplantation status, length of follow-up, whether the visit took place, and whether the assessment was performed). (C-D) Individual patient Loes scores and NFS by disease stage.

Figure 3.

Gadolinium enhancement (GdE) status over time. Results for individual patients are stratified by disease severity. Patients with graft failure/rejection or chimerism <90% are indicated.