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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.

SUBMITTER: Yoon IC

PROVIDER: S-EPMC8020262 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Importance:Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies. Objective:To evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort. Design, Setting, and Participants:Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015. Exposures:Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen. Main Outcomes and Measures:The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models. Results:Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95). Conclusions and Relevance:In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.

Project description:BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HSCT), a potentially curative therapy for malignant and nonmalignant diseases, is being increasingly used in younger patients. Although allo-HSCT survivors have an established increased risk of cardiovascular disease, there is limited knowledge of the long-term effects on cardiac function in survivors.ObjectivesThe purpose of this study was to describe left ventricular (LV) systolic function in long-term allo-HSCT survivors treated in childhood, adolescence, or early adulthood.MethodsOur cross-sectional cohort study included 104 patients (56% women), age 18 ± 10 years at time allo-HSCT with 17 ± 6 years of follow-up. Echocardiography included 2-dimensional (2D) and 3-dimensional (3D) analyses and speckle tracking imaging. In total, 55 healthy control subjects with a similar age, sex, and body mass index were used for comparison. Left ventricular systolic dysfunction (LVSD) was defined as reduced 2D left ventricular ejection fraction (LVEF) of <52% in men and <54% in women, and/or a reduced global longitudinal strain (GLS) of ≥-17%. Multivariable linear regression was used to determine independent predictors of 2D-LVEF and GLS.ResultsAllo-HSCT survivors had significantly reduced LV systolic function compared with control subjects: 2D-LVEF (55.2 ± 5.8% vs. 59.0 ± 2.9%; p < 0.001), 3D LVEF (54.0 ± 5.1% vs. 57.6 ± 2.7%; p < 0.001), and GLS (-17.5 ± 2.2% vs. -19.8 ± 1.4%; p < 0.001). LVSD was found in 44.2%, of whom 28.3% were symptomatic. Clinical factors independently associated with 2D-LVEF and/or GLS included age, anthracyclines, graft versus host disease (GVHD), heart rate, and hypertension. In the 45% of survivors pre-treated with anthracyclines, the effect of anthracyclines on 2D-LVEF and GLS was dose-dependent.ConclusionsLVSD is common in long-term survivors of allo-HSCT treated in their youth. Pre-HSCT therapies with anthracyclines, age, heart rate, hypertension, and graft versus host disease are associated with measures of LV function.

Project description:ObjectiveIntraspinal human spinal cord-derived neural stem cell (HSSC) transplantation is a potential therapy for amyotrophic lateral sclerosis (ALS); however, previous trials lack controls. This post hoc analysis compared ambulatory limb-onset ALS participants in Phase 1 and 2 (Ph1/2) open-label intraspinal HSSC transplantation studies up to 3 years after transplant to matched participants in Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) and ceftriaxone datasets to provide required analyses to inform future clinical trial designs.MethodsSurvival, ALSFRS-R, and a composite statistic (ALS/SURV) combining survival and ALS Functional Rating Scale revised (ALSFRS-R) functional status were assessed for matched participant subsets: PRO-ACT n = 1108, Ph1/2 n = 21 and ceftriaxone n = 177, Ph1/2 n = 20.ResultsSurvival did not differ significantly between cohorts: Ph1/2 median survival 4.7 years, 95% CI (1.2, ∞) versus PRO-ACT 2.3 years (1.9, 2.5), P = 1.0; Ph1/2 3.0 years (1.2, 5.6) versus ceftriaxone 2.3 years (1.8, 2.8), P = 0.88. Mean ALSFRS-R at 24 months significantly differed between Ph1/2 and both comparison cohorts (Ph1/2 30.1 ± 8.6 vs. PRO-ACT 24.0 ± 10.2, P = 0.048; Ph1/2 30.7 ± 8.8 vs. ceftriaxone 19.2 ± 9.5, P = 0.0023). Using ALS/SURV, median PRO-ACT and ceftriaxone participants died by 24 months, whereas median Ph1/2 participant ALSFRS-Rs were 23 (P = 0.0038) and 19 (P = 0.14) in PRO-ACT and ceftriaxone comparisons at 24 months, respectively, supporting improved functional outcomes in the Ph1/2 study.InterpretationComparison of Ph1/2 studies to historical datasets revealed significantly improved survival and function using ALS/SURV versus PRO-ACT controls. While results are encouraging, comparison against historical populations demonstrate limitations in noncontrolled studies. These findings support continued evaluation of HSSC transplantation in ALS, support the benefit of control populations, and enable necessary power calculations to design a randomized, sham surgery-controlled efficacy study.

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

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