Long-term neurodevelopmental outcomes of hematopoietic stem cell transplantation for late-infantile Krabbe disease

Abstract

Krabbe disease is a rare neurodegenerative disorder caused by a deficiency in galactocerebrosidase. The only effective treatment is hematopoietic stem cell transplantation (HSCT). Approximately 85% of Krabbe disease cases are the infantile subtypes, among which ∼20% are late infantile. Prior studies have demonstrated that HSCT is effective for early-infantile patients (0-6 months of age) who undergo transplantation while asymptomatic, compared with those receiving transplants while symptomatic. However, no studies evaluated the efficacy of HSCT for late-infantile patients (6-36 months). In this prospective, longitudinal study, patients were evaluated at a single site according to a standardized protocol. Survival analysis was performed using the Kaplan-Meier method. Differences between groups were estimated using mixed regression models to account for within-person repeated measures. Nineteen late-infantile patients underwent HSCT (March 1997 to January 2020). Compared with untreated patients, transplant recipients had a longer survival probability and improved cognitive and language function. Gross and fine motor development were most affected, with variable results. Asymptomatic patients benefitted the most from transplantation, with normal to near-normal development in all domains and some gross motor delays. Among symptomatic patients, those with disease onset at >12 months of age had better cognitive outcomes than untreated patients. Those with disease onset at ≤12 months were comparable to untreated patients. We found that HSCT prolonged the lifespan and improved the functional abilities of late-infantile patients with Krabbe disease, particularly those who underwent transplantation before onset of symptoms. In addition, our findings support prior literature that reclassifies late-infantile Krabbe disease to be symptom onset at 12 to 36 months of age.

Conflict of interest statement

Conflict-of-interest-disclosure: M.L.E. and P.S. have financial interest in Forge Biologics, and M.L.E. is a part-time employee. The remaining authors declare no competing financial interests.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Kaplan-Meier curves for overall survival.

Figure 2.

Psychosine levels at various ages in the patients with data available. Each line represents a single patient, and each circle indicates an individual measurement.

Figure 3.

Height, weight, and head circumference of the patients. Each line represents a patient, and each circle indicates an individual measurement. The gray lines show the standard growth curves for the 3rd, 5th, 10th, 25th, 50th, 75th, 90th, 95th, and 99th percentiles. In the graphs on the left (A-C), blue lines indicate boys, and in the graphs on the right (D-F), red lines indicate the girls.

Figure 4.

Neurodevelopmental outcomes of transplant recipients. Neurodevelopmental domains shown are cognitive development (A), adaptive behavior (B), receptive language (C), expressive language (D), gross motor (E), and fine motor (F). The developmental ages were determined by age-equivalent scores from tests. Each line represents a patient and each circle indicates an individual measurement. Gray lines and areas indicate normal development at the 95th, 50th, and fifth percentiles.