TY - JOUR
T1 - Presymptomatic Lesion in Childhood Cerebral Adrenoleukodystrophy
T2 - Timing and Treatment
AU - Mallack, Eric James
AU - Van Haren, Keith P.
AU - Torrey, Anna
AU - Van De Stadt, Stephanie
AU - Engelen, Marc
AU - Raymond, Gerald V.
AU - Fatemi, Ali
AU - Eichler, Florian S.
N1 - Funding Information:
E.J. Mallack receives research support from the National Institute of Neurological Disorders and Stroke (K12NS066274, K23NS118044), serves on a DSMB for Lysogene, has institutional contracts with Passage Bio and Viking Therapeutics, and received support for leukodystrophy education from Prime, PCORI, Orchard Therapeutics, and Neurology Alert. K. Van Haren receives research support from Bluebird Bio, Minoryx, and is a scientific consultant for Poxel and Viking Therapeutics. A. Torrey reports no disclosures relevant to the manuscript. S. van de Stadt reports no disclosures relevant to the manuscript. M. Engelen receives research support from the Dutch Research Council (NWO; Vidi grant 016.196.310), Minoryx, Vertex, Autobahn Therapeutics, and SwanBio. G. Raymond is a consultant for Minoryx (Barcelona), Viking, and Bluebird Bio (Cambridge, MA). He serves on the DSMBs for Ionis and Retrophin. A. Fatemi receives research support from the NICHD (P50HD103538), National Institute of Neurological Disorders and Stroke/NCATS (U54NS115052), NCATS (UL1TR003098), NCATS (U01NS103882), Institutional Contract with Minoryx, Viking Therapeutics, Autobahn Therapeutics, Poxel, Personal Contract with Bluebird Bio (DSMB member). F.S. Eichler receives research support from FDA Orphan Disease Group (R01FD004127), National Institute of Neurological Disorders and Stroke (R01NS072446, R01NS082331,U54NS115052), Retrophin, Minoryx, Bluebird Bio, AGTC, and SwanBio. Go to Neurology.org/N for full disclosures.
Funding Information:
Funding was received from the NIH for activities related to this project (E.J.M. K12NS066274, K23NS118044; A.F. P50HD103538, U54NS115052; F.S.E. U54NS115052). A portion of the subject monitoring was funded in part by the Johns Hopkins University School of Medicine General Clinical Research Center Grant M01-RR00052 from the National Center for Research Resources/NIH; Grants HD10981 and HD39276 from the NIH; Grant 685–008 from the Office of Orphan Drug Products of the Food and Drug Administration.
Publisher Copyright:
© American Academy of Neurology.
PY - 2022/8/2
Y1 - 2022/8/2
N2 - Background and ObjectivesWe sought to characterize the natural history and standard-of-care practices between the radiologic appearance of brain lesions, the appearance of lesional enhancement, and treatment with hematopoietic stem-cell transplant or gene therapy among boys diagnosed with presymptomatic childhood-onset cerebral adrenoleukodystrophy (CCALD).MethodsWe analyzed a multicenter, mixed retrospective/prospective cohort of patients diagnosed with presymptomatic CCALD (Neurologic Function Score = 0, Loes Score [LS] = 0.5-9.0, and age <13 years). Two time-to-event survival analyses were conducted: (1) time from CCALD lesion onset-to-lesional enhancement and (2) time from enhancement-to-treatment. The analysis was repeated in the subset of patients with (1) the earliest evidence of CCALD, defined as an MRI LS ≤ 1, and (2) patients diagnosed between 2016 and 2021.ResultsSeventy-one boys were diagnosed with presymptomatic cerebral lesions at a median age of 6.4 years [2.4-12.1] with a LS of 1.5 [0.5-9.0]. Fifty percent of patients had lesional enhancement at diagnosis. In the remaining 50%, the median Kaplan-Meier (KM)-estimate of time from diagnosis-to-lesional enhancement was 6.0 months (95% CI 3.6-17.8). The median KM-estimate of time from enhancement-to-treatment is 3.8 months (95% CI 2.8-5.9); 2 patients (4.2%) developed symptoms before treatment. Patients with a diagnostic LS ≤ 1 were younger (5.8 years [2.4-11.5]), had a time-to-enhancement of 4.7 months (95% CI 2.7-9.30), and were treated in 3.8 months (95% CI 3.1-7.1); no patients developed symptoms before treatment. Time from CCALD diagnosis-to-treatment decreased over the course of the study (ρ =-0.401, p = 0.003).DiscussionOur findings offer a more refined understanding of the timing of lesion formation, enhancement, and treatment among boys with presymptomatic CCALD. These data offer benchmarks for standardizing clinical care and designing future clinical trials.
AB - Background and ObjectivesWe sought to characterize the natural history and standard-of-care practices between the radiologic appearance of brain lesions, the appearance of lesional enhancement, and treatment with hematopoietic stem-cell transplant or gene therapy among boys diagnosed with presymptomatic childhood-onset cerebral adrenoleukodystrophy (CCALD).MethodsWe analyzed a multicenter, mixed retrospective/prospective cohort of patients diagnosed with presymptomatic CCALD (Neurologic Function Score = 0, Loes Score [LS] = 0.5-9.0, and age <13 years). Two time-to-event survival analyses were conducted: (1) time from CCALD lesion onset-to-lesional enhancement and (2) time from enhancement-to-treatment. The analysis was repeated in the subset of patients with (1) the earliest evidence of CCALD, defined as an MRI LS ≤ 1, and (2) patients diagnosed between 2016 and 2021.ResultsSeventy-one boys were diagnosed with presymptomatic cerebral lesions at a median age of 6.4 years [2.4-12.1] with a LS of 1.5 [0.5-9.0]. Fifty percent of patients had lesional enhancement at diagnosis. In the remaining 50%, the median Kaplan-Meier (KM)-estimate of time from diagnosis-to-lesional enhancement was 6.0 months (95% CI 3.6-17.8). The median KM-estimate of time from enhancement-to-treatment is 3.8 months (95% CI 2.8-5.9); 2 patients (4.2%) developed symptoms before treatment. Patients with a diagnostic LS ≤ 1 were younger (5.8 years [2.4-11.5]), had a time-to-enhancement of 4.7 months (95% CI 2.7-9.30), and were treated in 3.8 months (95% CI 3.1-7.1); no patients developed symptoms before treatment. Time from CCALD diagnosis-to-treatment decreased over the course of the study (ρ =-0.401, p = 0.003).DiscussionOur findings offer a more refined understanding of the timing of lesion formation, enhancement, and treatment among boys with presymptomatic CCALD. These data offer benchmarks for standardizing clinical care and designing future clinical trials.
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U2 - 10.1212/WNL.0000000000200571
DO - 10.1212/WNL.0000000000200571
M3 - Article
C2 - 35609989
AN - SCOPUS:85135874156
SN - 0028-3878
VL - 99
SP - E512-E520
JO - Neurology
JF - Neurology
IS - 5
ER -