Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report

Abstract

BackgroundMetachromatic Leukodystrophy (MLD) is a rare, fatal demyelinating disorder with limited treatment options. Published outcomes after hematopoietic stem cell transplantation (HSCT) are scant and mixed. We report survival and function following HSCT for a large, single-center MLD cohort.MethodsTransplant-related data, survival and serial measures (brain MRI, nerve conduction velocity (NCV), neurologic and neuropsychology evaluations) were reviewed. When possible, parental interviews informed current neurologic status, quality-of-life, and adaptive functioning. Gross motor and expressive functions for late-infantile (LI-MLD) and juvenile (J-MLD) patients were described using previously reported, MLD-specific scales.ResultsForty patients with confirmed MLD have undergone HSCT at our center. Twenty-one (53 %) survive at a median 12 years post-HSCT. Most deaths (n = 17) were treatment-related; two died from disease progression. Survival did not depend upon MLD subtype or symptom status at transplant. LI-MLD patients survive beyond reported life expectancy in untreated disease.Abnormal brain MRI and peripheral nerve conduction velocities (NCV) were common before HSCT. Following transplant, fewer patients experienced MRI progression compared to NCV deterioration.Sixteen LI-MLD and J-MLD survivors were evaluable for long-term gross motor and/or expressive language functioning using existing MLD clinical scoring systems. While most J-MLD patients regressed, the aggregate cohort demonstrated superior retention of function compared to published natural history.Seventeen LI-MLD, J-MLD and adult subtype (A-MLD) survivors were evaluable for long-term adaptive functioning, activities of daily living, and/or cognition. Relative cognitive sparing was observed despite overall global decline.Five sibling pairs (one LI-MLD and four J-MLD), in which at least one underwent transplant in our cohort, were evaluable. Within each familial dyad, survival or function was superior for the treated sibling, or if both siblings were transplanted, for the pre-symptomatic sibling.ConclusionsHSCT is a viable treatment option for MLD, but has significant limitations. Later-onset phenotypes may benefit most from early, pre-symptomatic transplant. Until superior, novel treatment strategies are demonstrated, MLD patients should be carefully considered for HSCT.

Demyelination load as predictor for disease progression in juvenile metachromatic leukodystrophy

“…New therapeutic approaches are currently under investigation 1, 15. There is an increasing body of evidence suggesting that successful therapy is related to early treatment, that is, presymptomatic and early symptomatic,16, 17, 18, 19 and to a slower disease progression, that is, treatments such as HSCT being more effective in the more slowly progressive juvenile form than in the rapidly progressive late‐infantile form 17, 18. Thus, one of the clinical challenges when to recommend HSCT in juvenile MLD is to judge on the dynamics of the disease course.…”

“…Therefore, it seems important to investigate whether the demyelination load is a clinically relevant parameter, not only to describe, but also to predict disease progression in juvenile MLD. Especially, as HSCT was proven to be a beneficial treatment when done at an early stage of the disease before the phase of rapid progression 16, 17, 18, 19. It seems essential to find predictors of disease progression already early during disease course in order to be able to judge on the “window of opportunity,” for example, whether a treatment has enough time to become effective.…”

Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome

“…However, his diagnosis allowed the detection of patient MLD8b before disease onset. And indeed, two recent studies -a prospective cohort and case-control study -have raised evidence that HSCT is associated with a reasonable chance of disease stabilization if performed pre-symptomatically 10,16 . Patient MLD-9 came for HSCT evaluation one year after the beginning of cognitive losses.…”

“…Case reports suggested that HSCT might reduce demyelination in juvenile (onset between two and 14 years) and adult forms of MLD when performed as early as possible 3,4,5,16 . A recent case control study confirmed that HSCT, at a presymptomatic or early symptomatic stage of juvenile MLD, is associated with disease stabilization 10 .…”

Neurological outcome in patients with inborn errors of metabolism submitted to hematopoietic stem cell transplantation. What should we expect?

“…In an individual analyses, for MLD (OMIM #250100), the HSCT performed before symptoms onset could delay the progression of central nervous system compromise, but the response at the peripheral level is still controversial in the litterature 4,5 . For MPS-IH (OMIM #607014), although cerebral damage prior to HSCT remains irreversible, HSCT treatment could still offer an improvement of neurological development, particularly when HSCT is done performed 16 months of age, when a significant reduction of brain atrophy is observed (OR 3.22, 95%CI 1.60-6.50, p = 0.001) 6 .…”