Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report
Weston P. MillerSteven M. RothmanDavid NasceneTeresa KivistoTodd E. DeForRichard ZieglerJulie B. EisengartKara LeiserGerald V. RaymondTroy C. LundJakub TolarPaul J. Orchard
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Adrenoleukodystrophy
Cumulative incidence
Adrenoleukodystrophy
Peroxisomal disorder
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To evaluate the efficacy and safety of haploidentical (from family member donors) hematopoietic stem cell transplantation (HSCT) for children with hematologic malignancies.Fifty-eight children under fourteen years with hematological malignancies underwent haploidentical HSCT. All patients had poor-risk clinical or cytogenetic features and reclassified into high-risk and standard-risk groups. Transplantation outcomes were analyzed.Of fifty-eight patient/donor pairs, seven (12.1%) were mismatched in two HLA loci, twenty (34.5%) in three loci, and thirty-one (53.4%) in four loci. Follow-ups were performed for a median of 1,663 (752-2,664) days after transplantation. All patients achieved stable engraftments. The cumulative incidence of acute graft-versus-host disease (GVHD) of grades 2-4 was (54.8+/-7.6)%, and that of grades 3-4 was (11.4+/-4.8)%. The cumulative incidence of chronic GVHD was (45.6+/-7.8)% for the total and (19.6+/-6.5)% for the extensive. Thirty-eight patients survived with a 2-year actual overall rate of survival 59.0% and 78.9% in the high-risk and standard-risk group, respectively. The 3-year probability of LFS was (58.6+/-8.0)% and (68.4+/-10.7)%, respectively.The results encourage extending haploidentical HSCT without T-cell depletion treatments to children with an indication for transplantation.
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Importance
Allogeneic hematopoietic stem cell transplantation is the standard intervention for childhood cerebral X-linked adrenoleukodystrophy. However, the pretransplant conditions, demyelination patterns, complications, and neurological outcomes of this therapy are not well characterized.Objectives
To identify the risks to stable neurocognitive survival after hematopoietic stem cell transplantation and to describe subgroups of patients with distinct clinical long-term outcomes.Design, Setting, and Participants
This case series analyzed the treatment and outcome of a cohort of 36 boys who underwent hematopoietic stem cell transplantation at Charité Universitätsmedizin Berlin, Germany, between January 1, 1997, and October 31, 2014. Case analysis was performed from January 1, 2016, through November 30, 2017. During this retrospective review, the adrenoleukodystrophy-disability rating score and the neurological function score were used. Demyelinating lesions in the brain were quantified by the Loes score.Main Outcomes and Measures
Overall survival, survival without major functional disabilities, and event-free survival were analyzed. Patients' clinical symptoms, demyelination patterns, and stem cell source were stratified.Results
Of the 36 boys who underwent hematopoietic stem cell transplantation, the median (range) age was 7.2 (4.2-15.4) years; 18 were presymptomatic and 18 were symptomatic. Twenty-seven patients (75%) were alive at a median (interquartile range [IQR]) follow-up of 108 (40-157) months. Sixteen of 18 presymptomatic patients (89%) survived, and 13 (72%) had an event-free survival with a median (IQR) survival time of 49 (37-115) months. Among the symptomatic patients, 11 of 18 (61%) survived, but only 1 was an event-free survival (6%) (median [IQR] time, 9 [3-22] months). Of the 9 patients who received a bone marrow transplant from a matched family donor, all survived. Among the 36 patients, 6 disease-related deaths (17%) and 3 transplant-related deaths (8%) occurred. Deaths from disease progression (n = 6) occurred only in patients with demyelination patterns other than parieto-occipital. In total, 18 patients (50%) displayed limited parieto-occipital (Loes score <9) or frontal (Loes score <4) demyelination before transplant (favorable). None of these patients died of progressive disease or developed major functional disabilities, 15 of them were characterized by stable neuroimaging after the transplant, and event-free survival was 77% (95% CI, 60%-100%). In contrast, the other 18 patients with more extended parieto-occipital demyelination (n = 6), frontal involvement (n = 4), or other demyelination patterns (n = 8) progressed (unfavorable): 13 patients developed epilepsy and 10 developed major functional disabilities, and their event-free survival was 0%. This newly defined neuroimaging assessment correlated best with neurocognitive deterioration after transplant (hazard ratio, 16.7; 95% CI, 4.7-59.6).Conclusions and Relevance
All patients with favorable neuroimaging who received matched bone marrow remained stable after transplant, while some of the other patients developed major functional disabilities. Newborn screening for the disease and regular neuroimaging are recommended, and patients who lack a matched bone marrow donor may need to find new therapeutic options.Adrenoleukodystrophy
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Introduction Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder with an incidence of 1 in 14–17,000 male births, caused by pathogenic variants within the ABCD1 gene. By adulthood, approximately 40% of the patients develop cerebral ALD, a severe, neuroinflammatory condition that is generally progressive and fatal without intervention.Areas covered Historically, only allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to halt progression of cerebral ALD, with superior outcomes obtained when HSCT is performed early in the disease process. More recently, a lentiviral-based gene therapy approach has been investigated as therapy for cerebral ALD as an alternative to allogeneic transplantation. A focused literature review was performed using the terms 'hematopoietic stem cell transplantation,' 'gene therapy' and 'adrenoleukodystrophy' to include relevant literature, especially comparing the experience with gene therapy and HSCT outcomes. We review the history and experience with HSCT in cerebral ALD and its limitations, as well as the information currently available in association with the gene therapy trials for cerebral ALD.Expert opinion The data regarding this lentiviral-based gene therapy approach and its relative risks and benefits is still being evaluated. This information is explored in the context of the experience with allogeneic HSCT for cerebral ALD.
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Adrenoleukodystrophy
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Adrenoleukodystrophy
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Adrenoleukodystrophy
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To investigate the efficacy and safety of haploidentical (from family member donors) hematopoietic stem cell transplantation (HSCT) for children. 42 children under 14 yrs old with hematological malignancies underwent haploidentical HSCT. Outcomes were analyzed. Thirty-three children were classified as high-risk candidates. Of 42 patient/donor pairs, 4 (9.5%) were mismatched in 2 HLA loci, 15 (35.7%) in 3 loci, and 23 (54.8%) in 4 loci. Follow-ups were performed for a median of 1110 (449-1959) days after transplantation. All patients achieved stable engraftments. The cumulative incidence of acute graft-versus-host disease (aGVHD) of grade 2-4 was 57.2%, and that of grade 3-4 was 13.8%. The cumulative incidence of chronic graft-versus-host disease (cGVHD) was 56.7% for total and 29.5% for extensive. Twenty-seven patients survived with a 3-yr probability of leukemia-free survival (LFS), 57.3+/-8%, 18 of them were in the high-risk group. Fifteen patients died, 4 from infection, 7 from relapse of leukemia, 2 from heart failure, one from severe aGVHD, and one from lymphoproliferative disorders. The results encourage extending haploidentical HSCT without T cell depletion treatments to children with an indication for transplantation.
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Cerebral X-linked adrenoleukodystrophy (cALD) is an inflammatory demyelination of the brain that can lead to death unless treated by hematopoietic stem cell transplantation. Survival and improved outcomes for cerebral adrenoleukodystrophy are associated with hematopoietic stem cell transplantation at earliest evidence of disease on magnetic resonance imaging (MRI). Our goal was to determine average duration between diagnosis of cALD and hematopoietic stem cell transplantation.This was a retrospective review of data of patients aged 18 years or younger, using a nationwide administrative health care database (Pediatric Health Information System), with an International Classification of Diseases, Tenth Revision (ICD-10) diagnosis of adrenoleukodystrophy. Time range was October 1, 2015, through June 30, 2021. We determined time to hematopoietic stem cell transplantation by duration between index brain MRI and a code for hematopoietic stem cell transplantation.We identified 27 patients with cerebral adrenoleukodystrophy. Total charges for the cohort was $53 million. Time to transplant averaged 97 days. For Hispanic patients, time to transplant was 117 days, compared with 80 days for White, non-Hispanic patients. Comparison of different hospitals showed significant variability in time to hematopoietic stem cell transplantation.We found that time to hematopoietic stem cell transplantation was >3 months for patients with cerebral adrenoleukodystrophy in the hospitals we evaluated. We noted differences in average time by race/ethnicity and by hospital. Our findings suggest opportunity to reduce time to transplant in cerebral adrenoleukodystrophy.
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Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is the only therapeutic approach that can arrest cerebral demyelination of X‐linked adrenoleukodystrophy (ALD) in boys and results in long‐term in a good quality of life, provided the procedure is performed at an early stage of disease. Similar benefits of allogeneic HSCT have been demonstrated in adults with cerebral ALD. However, it is not yet known whether allogeneic HSCT can prevent or rescue adrenomyeloneuropathy. Allogeneic HSCT remains associated with significant morbidity and mortality risks, particularly in adults, and not all ALD patients have donors despite the availability of cord blood. The absence of biological markers that can predict the evolutivity of cerebral disease is a major limitation to propose in due time allogeneic HSCT to ALD patients. Recently, HSC gene therapy using lentiviral vector was shown to have comparable efficacy than allogeneic HSCT in two boys with cerebral ALD who had no Human‐leukocyte‐antigen (HLA)‐matched donor. If these results are confirmed in an extended series of patients, HSC gene therapy may become the first therapeutic option for all ALD male patients who develop cerebral demyelination.
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