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Original Investigation |

Long-term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Juvenile Metachromatic Leukodystrophy Compared With Nontransplanted Control Patients

Samuel Groeschel, MD1; Jörn-Sven Kühl, MD2; Annette E. Bley, MD3; Christiane Kehrer, MD1; Bernhard Weschke, MD4; Michaela Döring, MD5; Judith Böhringer, PhD1; Johanna Schrum, MD6; René Santer, PhD3; Alfried Kohlschütter, PhD3; Ingeborg Krägeloh-Mann, MD, PhD1; Ingo Müller, MD5,6
[+] Author Affiliations
1Department of Pediatric Neurology and Developmental Medicine, University Children’s Hospital of Tübingen, Tübingen, Germany
2Department of Pediatric Oncology, Charité University Medicine Berlin, Berlin, Germany
3Department of Pediatrics, University Children’s Hospital Hamburg-Eppendorf, Hamburg, Germany
4Department of Neuropediatrics, Charité University Medicine Berlin, Berlin, Germany
5Department of Pediatric Hematology and Oncology, University Children’s Hospital of Tübingen, Tübingen, Germany
6Department of Pediatric Hematology and Oncology, University Children’s Hospital Hamburg-Eppendorf, Hamburg, Germany
JAMA Neurol. 2016;73(9):1133-1140. doi:10.1001/jamaneurol.2016.2067.
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Importance  Allogeneic hematopoietic stem cell transplantation (HSCT) has been the only treatment option clinically available during the last 20 years for juvenile metachromatic leukodystrophy (MLD), reported with variable outcome and without comparison with the natural course of the disease.

Objective  To compare the long-term outcome of patients who underwent allogeneic HSCT with control patients who did not among a cohort with juvenile MLD.

Design, Setting, and Participants  Patients with juvenile MLD born between 1975 and 2009 and who received HSCT at a median age of 7 years (age range, 1.5-18.2 years) and nontransplanted patients with juvenile MLD born between 1967 and 2007 were included in this case-control study. The median follow-up after HSCT was 7.5 years (range, 3.0-19.7 years). Patients underwent HSCT at 3 German centers between 1991 and 2012. The analysis was done between July 2014 and August 2015.

Main Outcomes and Measures  Survival and transplantation-related mortality, loss of gross motor function (Gross Motor Function Classification in MLD), loss of any language function, and magnetic resonance imaging (MRI) severity score for cerebral changes. To explore prognostic factors at baseline, patients who underwent HSCT (hereafter, transplanted patients) were a priori divided into stable vs progressive disease, according to gross motor and cognitive function.

Results  Participants were 24 transplanted patients (11 boys, 13 girls) and 41 control patients (22 boys, 19 girls) who did not receive transplantation (hereafter, nontransplanted patients) with juvenile MLD. Among the transplanted patients, 4 children died of transplantation-related mortality, and 2 additional children died of rapid MLD progression 1.5 and 8.6 years after HSCT, resulting in a 5-year survival of 79% (19 of 24). Among the nontransplanted patients, 5-year survival after disease onset was 100% (41 of 41). However, 11 died of MLD progression, resulting in similar overall survival within the observation period. Nine of the long-term survivors after HSCT had disease progression, while 11 showed stable disease. Compared with the nontransplanted patients, the transplanted patients were less likely to lose their gross motor or language function and demonstrated significantly lower MRI severity scores at the latest examination. Patients after HSCT were more likely to have a stable disease course when undergoing HSCT at an early stage with no or only mild gross motor deficits (Gross Motor Function Classification in MLD level 0 or 1) and an IQ of at least 85, when age at disease onset was older than 4 years, or when MRI severity scores were low (preferably ≤17).

Conclusions and Relevance  Among patients with juvenile MLD, patients who underwent HSCT had a better gross motor and language outcome and lower MRI severity scores compared with nontransplanted patients. Transplantation at a presymptomatic or early symptomatic stage of juvenile MLD is associated with a reasonable chance for disease stabilization.

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Figure 1.
Clinical Course of 24 Patients With Juvenile Metachromatic Leukodystrophy (MLD) Before and After Hematopoietic Stem Cell Transplantation

The age at transplantation is denoted by horizontal red lines. The key provides the explanations for the colored portions of the bars that indicate the change in clinical status over time. GMFC-MLD indicates Gross Motor Function Classification in MLD (MLD levels 1-6).

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Figure 2.
Survival Analyses of Transplanted Patients and Nontransplanted Patients

A, Kaplan-Meier plots of overall survival of transplanted patients after hematopoietic stem cell transplantation (HSCT). Causes of mortality were transplantation related (n = 4) within the first weeks after HSCT, as well as due to progression of the disease (n = 2). B and C, Kaplan-Meier plots of survival of transplanted and nontransplanted patients with respect to the time after disease onset (B) and to age (C). MLD indicates metachromatic leukodystrophy.

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Figure 3.
Deterioration of Gross Motor Function and Language Function of Transplanted Patients and Nontransplanted Patients

Kaplan-Meier plots of patients surviving without deterioration to Gross Motor Function Classification in metachromatic leukodystrophy (GMFC-MLD) level 5 and more28 (A and B) and without complete loss of language function5 (C and D). In this outcome analysis, transplanted patients who died of transplantation-related complications (n = 4) were excluded.

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Figure 4.
Magnetic Resonance Imaging (MRI) Severity Scores of Transplanted Patients and Nontransplanted Patients

The MRI severity scores are plotted with respect to the time after disease onset (A) and to age (B). The mean (SE) of 36 MRIs from 36 nontransplanted patients is shown in blue. While transplanted patients with stable disease (n = 11) showed scores on follow-up below the mean of the natural history study patients, transplanted patients with progressive disease (n = 9) showed scores above the mean. In this outcome analysis, transplanted patients who died of transplantation-related complications (n = 4) were excluded. HSCT indicates hematopoietic stem cell transplantation.

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