Outcomes of Allogeneic Cord Blood Transplantation for Leukodystrophies; A Joint Study of Eurocord and 'Inborn Errors WP-EBMT'

Background This study aims to describe transplant outcomes and disease-specific clinical outcomes of allogeneic cord blood transplantation (CBT) in leukodystrophies. Leukodystrophies are rare inborn errors of metabolism (IEM) in which the development and maintenance of brain myelin is primarily affected. They are characterized by rapid neurological deterioration. Hematopoietic stem cell transplantation (HSCT) has been shown to halt disease progression for selected leukodystrophies, including adrenoleukodystrophy (ALD), Krabbe disease (globoid cell leukodystrophy) and metachromatic leukodystrophy (MLD). The fast availability of unrelated cord blood (UCB) makes HSCT feasible in leukodystrophy patients who lack an HLA-matched sibling. Patients and methods All patients transplanted for leukodystrophies with related and unrelated umbilical cord blood in EBMT centers between 1996 and 2012 were included. HSCT data were collected from the EUROCORD database. An additional questionnaire on disease-specific clinical outcomes was sent to participating centers. Included in the questionnaire were enzyme- and (for ALD) fatty acid levels, general disease status, performance score, MRI/MRS status, peripheral neuropathy, school attendance and performance, mental development testing, adrenal insufficiency (for ALD only), vision and hearing. Kaplan-Meier estimates were used to calculate overall survival (OS) and cumulative incidence methods for secondary outcomes, including neutrophil and platelet engraftment, incidence of graft-versus-host disease (GvHD), donor chimerism and disease-specific characteristics at most recent follow-up. The two-sided log-rank test was used for univariate comparisons. Results Seventy patients (31 ALD, 5 Krabbe, 34 MLD) were available for analysis, with a median age at transplant of 6.5 years (range 0-43 years). Median follow-up for survivors was 46 months. Overall survival at 4 years was 60% (±6%). Cumulative incidences of neutrophil and platelet engraftment were 88% (±4%) at day 60, and 73% (±6%) at day 180, respectively. Ten patients experienced graft failure and 5 had autologous recovery; 4 received a 2nd HSCT (2 CBT, 1 Haplo, 1 BM) and of those 3 were alive in a median of 60 months after HSCT. Acute-GvHD (grade II-IV) occurred in 16 patients (22% ±5%) at day 100 and chronic GvHD in 9 patients (13% ±5%). Out of the 24 patients who died, 18 (67%) died of transplant-related causes and 6 (33%) died of disease progression. Higher survival was seen in patients who had no or 1 HLA mismatch (OS 81%), compared to patients who received UCBT with 2 HLA mismatches (OS 47%, p 0.02). On 37 patients (53%), information on disease-specific characteristics was available. OS among these patients was 68% (±8), which was not significantly different from patients without disease-specific information (p=0,307). Of the 37 patients, 19 (51%) were asymptomatic at transplant, 14 (38%) had mild disease and 4 (11%) were severely affected. Overall survival was dramatically worse in patients with severe disease at transplant; all 4 severely affected patients died, while 79% of patients with mild disease and 76% of asymptomatic patients survived. At most recent follow-up, disease status was stable in 15 (57.7%), had improved in 2 (7.7%) and worsened in 9 (34.6%) surviving patients. The majority of patients showed abnormalities on MRI-scanning pre-HSCT (n=25, 68%). In patients with normal MRI-scans pre-transplant OS was 69%; in patients with abnormal MRI-scans 75%. At most recent follow-up, MRI-scans were stable in 12 (43.9%), improved in 5 (17.8%) and worsened in 11 (39.3%) patients. Eighteen patients (50%) showed peripheral neuropathy pre-HSCT, of which 13 were mildly affected and 5 severely affected. Of patients who had no signs of peripheral neuropathy pre-HSCT, 70% survived, versus 77% of patients who were mildly affected and 40% of those severely affected. At most recent follow-up, peripheral neuropathy was stable in 14 (56%), had improved in 3 (12%) and worsened in 8 (32%) patients. Conclusion We found an overall survival of 60% at 4 years after CBT for leukodystrophies, with relatively low rates of GvHD. Use of a mismatched donor (>1 HLA mismatch) negatively impacts survival. Data on clinical characteristics suggest that overall survival is strongly influenced by disease status at transplant. Disclosures: No relevant conflicts of interest to declare.