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

Abstract

Background: Metachromatic 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.

Methods: Transplant-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.

Results: Forty 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.

Conclusions: HSCT 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.

Fig. 1

Gross Motor Function Classification (GMFC-MLD) and Expressive Language Function Classification (ELFC-MLD) scales in metachromatic leukodystrophy. The previously reported scales describe both gross motor and expressive language deterioration over time for late-infantile and juvenile subtypes of MLD. Long-term survivors in the HSCT cohort were evaluated for scores at most recent follow-up and age-to-entry into various levels over time

Fig. 2

Kaplan-Meier survival estimates following HSCT for MLD. a Probability of survival at 5 years following HSCT for the entire cohort (n = 40). b Probability of survival at 5 years following HSCT for individual MLD subtypes: LI-MLD (n = 4); J-MLD (n = 27), and A-MLD (n = 9)

Fig. 3

Age to entry into GMFC-MLD levels for LI-MLD and J-MLD patients in the HSCT cohort. Numbers preceding each line refer to the Patient ID (see Tables 1 and 2). Circles represent time at entry into a respective level. Each line ends at most recent follow-up. Some patients had evaluable gross motor function data prior to HSCT. See Fig. 1 for GMFC-MLD level definitions. Patients were labeled symptomatic at the time of HSCT if they exhibited any clinical manifestation of MLD

Fig. 4

Age to entry into ELFC-MLD levels for LI-MLD and J-MLD patients in the HSCT cohort. Numbers preceding each line refer to the Patient ID (see Tables 1 and 2). Circles represent time at entry into a respective level. Each line ends at most recent follow-up. Some patients had evaluable expressive language function data prior to HSCT. See Fig. 1 for ELFC-MLD level definitions. Patients were labeled symptomatic at the time of HSCT if they exhibited any clinical manifestation of MLD

Fig. 5

Brain MRI and NCV trends over time. All available clinical reports of brain MRI and peripheral nerve conduction velocity studies for the cohort were reviewed. Each MRI time-point was evaluated for change in white matter disease from the previous study as classified by the interpreting neuroradiologist. Each NCV time-point was evaluated for change in function from the previous study as classified by the interpreting neurologist. Each line represents a unique patient, while each circle represents an assessment. The dashed vertical line at time 0 reflects the time of transplant. Negative time points denote pre-HSCT studies. Red, yellow and green circles and preceding line segments indicate MRI or NCV studies that were worse than, the same as, or better than the previous assessment, respectively. Of evaluable patients at pre-transplant baseline, 97 % had an abnormal MRI while 92 % demonstrated peripheral neuropathy

Fig. 6

Vineland Adaptive Behavior Scale (VABS) scores over time. Serial trends in composite VABS over years for all long-term survivors after HSCT are shown by MLD subtype. A triangle represents a pre-HSCT score while a circle represents a post-HSCT score. Green indicates patients pre-symptomatic at the time of HSCT. Red indicates patients symptomatic at the time of HSCT. Calendar and functional age equivalence in years is shown by the solid diagonal line, with the dashed lines representing two standard deviations from the mean

Fig. 7

Intelligent Quotient (IQ) Trends over time for MLD subtypes. Trends in IQ scores over time for all long-term survivors after HSCT are shown by MLD subtype. A triangle represents a pre-HSCT score while a circle represents a post-HSCT score. Green indicates patients who were pre-symptomatic at the time of HSCT. Red indicates patients who were symptomatic at the time of HSCT. All but two of the scores shown (both for one J-MLD patient, indicated by asterisk) denote Verbal IQ. The solid line represents a mean IQ score of 100 and the dashed lines are two standard deviations from the mean