Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation

Gerald V. Raymond, Patrick Aubourg, Asif Paker, Maria Escolar, Alain Fischer, Stephane Blanche, André Baruchel, Jean Hugues Dalle, Gérard Michel, Vinod Prasad, Weston Miller, Susan Paadre, John Balser, Joanne Kurtzberg, David R. Nascene, Paul J. Orchard, Troy Lund

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a large multicenter retrospective chart review to characterize the natural history of CALD, to describe outcomes after HSCT, and to identify predictors of treatment outcomes. Major functional disabilities (MFDs) were identified as having the most significant impact on patients’ abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes magnetic resonance imaging score were assessed. Data were collected on 72 patients with CALD who did not undergo HSCT (untreated cohort) and on 65 patients who underwent transplantation (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) from the time of CALD diagnosis were 55% (95% confidence interval [CI], 42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HSCT cohort overall (P =.01). KM estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE + ) were 29% (95% CI, 11.7% to 48.2%) for untreated patients (n = 21). For patients who underwent HSCT with GdE + at baseline, with an NFS ≤1 and Loes score of 0.5 to ≤9 (n = 27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%). Mortality rates post-HSCT were 8% (5 of 65) at 100days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor-recipient HLA matching and lack of GVHD, and early disease treatment was predictive of MFD-free survival. GdE + status is a strong predictor of disease progression in untreated patients.‎ This study confirms HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than solely assessing OS as an indicator of treatment success.

Original languageEnglish (US)
Pages (from-to)538-548
Number of pages11
JournalBiology of Blood and Marrow Transplantation
Volume25
Issue number3
DOIs
StatePublished - Mar 2019

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Adrenoleukodystrophy
Hematopoietic Stem Cell Transplantation
Survival
Graft vs Host Disease
Confidence Intervals
Kaplan-Meier Estimate
Nervous System
Disease Progression
Protein Deficiency
Gadolinium
Therapeutics
Infection
Natural History
Neurodegenerative Diseases
Cause of Death

All Science Journal Classification (ASJC) codes

  • Hematology
  • Transplantation

Cite this

Raymond, Gerald V. ; Aubourg, Patrick ; Paker, Asif ; Escolar, Maria ; Fischer, Alain ; Blanche, Stephane ; Baruchel, André ; Dalle, Jean Hugues ; Michel, Gérard ; Prasad, Vinod ; Miller, Weston ; Paadre, Susan ; Balser, John ; Kurtzberg, Joanne ; Nascene, David R. ; Orchard, Paul J. ; Lund, Troy. / Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation. In: Biology of Blood and Marrow Transplantation. 2019 ; Vol. 25, No. 3. pp. 538-548.
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Raymond, GV, Aubourg, P, Paker, A, Escolar, M, Fischer, A, Blanche, S, Baruchel, A, Dalle, JH, Michel, G, Prasad, V, Miller, W, Paadre, S, Balser, J, Kurtzberg, J, Nascene, DR, Orchard, PJ & Lund, T 2019, 'Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation', Biology of Blood and Marrow Transplantation, vol. 25, no. 3, pp. 538-548. https://doi.org/10.1016/j.bbmt.2018.09.036

Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation. / Raymond, Gerald V.; Aubourg, Patrick; Paker, Asif; Escolar, Maria; Fischer, Alain; Blanche, Stephane; Baruchel, André; Dalle, Jean Hugues; Michel, Gérard; Prasad, Vinod; Miller, Weston; Paadre, Susan; Balser, John; Kurtzberg, Joanne; Nascene, David R.; Orchard, Paul J.; Lund, Troy.

In: Biology of Blood and Marrow Transplantation, Vol. 25, No. 3, 03.2019, p. 538-548.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation

AU - Raymond, Gerald V.

AU - Aubourg, Patrick

AU - Paker, Asif

AU - Escolar, Maria

AU - Fischer, Alain

AU - Blanche, Stephane

AU - Baruchel, André

AU - Dalle, Jean Hugues

AU - Michel, Gérard

AU - Prasad, Vinod

AU - Miller, Weston

AU - Paadre, Susan

AU - Balser, John

AU - Kurtzberg, Joanne

AU - Nascene, David R.

AU - Orchard, Paul J.

AU - Lund, Troy

PY - 2019/3

Y1 - 2019/3

N2 - Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a large multicenter retrospective chart review to characterize the natural history of CALD, to describe outcomes after HSCT, and to identify predictors of treatment outcomes. Major functional disabilities (MFDs) were identified as having the most significant impact on patients’ abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes magnetic resonance imaging score were assessed. Data were collected on 72 patients with CALD who did not undergo HSCT (untreated cohort) and on 65 patients who underwent transplantation (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) from the time of CALD diagnosis were 55% (95% confidence interval [CI], 42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HSCT cohort overall (P =.01). KM estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE + ) were 29% (95% CI, 11.7% to 48.2%) for untreated patients (n = 21). For patients who underwent HSCT with GdE + at baseline, with an NFS ≤1 and Loes score of 0.5 to ≤9 (n = 27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%). Mortality rates post-HSCT were 8% (5 of 65) at 100days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor-recipient HLA matching and lack of GVHD, and early disease treatment was predictive of MFD-free survival. GdE + status is a strong predictor of disease progression in untreated patients.‎ This study confirms HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than solely assessing OS as an indicator of treatment success.

AB - Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a large multicenter retrospective chart review to characterize the natural history of CALD, to describe outcomes after HSCT, and to identify predictors of treatment outcomes. Major functional disabilities (MFDs) were identified as having the most significant impact on patients’ abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes magnetic resonance imaging score were assessed. Data were collected on 72 patients with CALD who did not undergo HSCT (untreated cohort) and on 65 patients who underwent transplantation (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) from the time of CALD diagnosis were 55% (95% confidence interval [CI], 42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HSCT cohort overall (P =.01). KM estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE + ) were 29% (95% CI, 11.7% to 48.2%) for untreated patients (n = 21). For patients who underwent HSCT with GdE + at baseline, with an NFS ≤1 and Loes score of 0.5 to ≤9 (n = 27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%). Mortality rates post-HSCT were 8% (5 of 65) at 100days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor-recipient HLA matching and lack of GVHD, and early disease treatment was predictive of MFD-free survival. GdE + status is a strong predictor of disease progression in untreated patients.‎ This study confirms HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than solely assessing OS as an indicator of treatment success.

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