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

doi:10.1016/j.bbmt.2018.09.036

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

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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 language	English (US)
Pages (from-to)	538-548
Number of pages	11
Journal	Biology of Blood and Marrow Transplantation
Volume	25
Issue number	3
DOIs	https://doi.org/10.1016/j.bbmt.2018.09.036
State	Published - Mar 2019

Bibliographical note

Funding Information:
The authors acknowledge the editorial assistance of Frances Smith, PhD, Katherine Lewis, MA, Andrew Dietz, MD, MSCR, and Joe Biedenkapp, PhD, who are employed by bluebird bio, Inc. Financial disclosure: This study was funded by bluebird bio. Conflict of interest statement: A.F. G.M. J.K. P.A. S.B. and V.P. have no relevant conflicts of interest. J.B. and S.P. are employees of Veristat, a company contracted for statistical consulting by the study sponsor, bluebird bio. A.B. reports that funds from bluebird bio were provided to his institution to support costs associated with the clinical trial described in this manuscript; personal fees for attendance at advisory boards for Celgene, Novartis, Servier, and Jazz Pharma; personal fees from Shire and Jazz Pharma for attending satellite symposia; and a grant from Shire for performing a clinical trial. J.H.D. has received personal fees from bluebird bio in relation to the work performed in the manuscript; outside of the reported work he has received honorarium for attendance at advisory boards for Jazz Pharma, Mallinckrodt, Sanofi Genzyme, Gilead, Chimerix, Astellas, Incyte, and Elsalys; personal fees from Jazz Pharma; and nonfinancial support from Novartis. M.E. has received personal fees from bluebird bio for attendance at advisory boards and as a consultant outside of the reported work. W.M. reports that funds from bluebird bio were provided to his institution to support costs associated with the clinical trial described in this manuscript, and outside of the reported work he is an employee of Sangamo Therapeutics. G.R. reports that funds from bluebird bio were provided to his institution to support costs associated with the clinical trial described in this manuscript, and he received grants and consultancy fees from bluebird bio outside of the reported work. P.O. and T.L. report that funds were provided to their institution from bluebird bio to support costs associated with the clinical trial described in this manuscript. A.P. was an employee of the study sponsor, bluebird bio, at the time this study was conducted. Authorship statement: All authors were involved in acquiring and/or analyzing the data presented in this manuscript, drafting or revising the manuscript, and approving the final version. Financial disclosure: See Acknowledgments on page 547.

Publisher Copyright:
© 2018 American Society for Blood and Marrow Transplantation

Keywords

Cerebral adrenoleukodystrophy
Hematopoietic stem cell transplantation
Natural history

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10.1016/j.bbmt.2018.09.036

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Raymond, G. V., Aubourg, P., Paker, A., Escolar, M., Fischer, A., Blanche, S., Baruchel, A., Dalle, J. H., Michel, G., Prasad, V., Miller, W., Paadre, S., Balser, J., Kurtzberg, J., Nascene, D. R., Orchard, P. J., & 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, 25(3), 538-548. https://doi.org/10.1016/j.bbmt.2018.09.036

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

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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{\textquoteright} 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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author = "Raymond, {Gerald V.} and Patrick Aubourg and Asif Paker and Maria Escolar and Alain Fischer and Stephane Blanche and Andr{\'e} Baruchel and Dalle, {Jean Hugues} and G{\'e}rard Michel and Vinod Prasad and Weston Miller and Susan Paadre and John Balser and Joanne Kurtzberg and Nascene, {David R.} and Orchard, {Paul J.} and Troy Lund",

note = "Funding Information: The authors acknowledge the editorial assistance of Frances Smith, PhD, Katherine Lewis, MA, Andrew Dietz, MD, MSCR, and Joe Biedenkapp, PhD, who are employed by bluebird bio, Inc. Financial disclosure: This study was funded by bluebird bio. Conflict of interest statement: A.F. G.M. J.K. P.A. S.B. and V.P. have no relevant conflicts of interest. J.B. and S.P. are employees of Veristat, a company contracted for statistical consulting by the study sponsor, bluebird bio. A.B. reports that funds from bluebird bio were provided to his institution to support costs associated with the clinical trial described in this manuscript; personal fees for attendance at advisory boards for Celgene, Novartis, Servier, and Jazz Pharma; personal fees from Shire and Jazz Pharma for attending satellite symposia; and a grant from Shire for performing a clinical trial. J.H.D. has received personal fees from bluebird bio in relation to the work performed in the manuscript; outside of the reported work he has received honorarium for attendance at advisory boards for Jazz Pharma, Mallinckrodt, Sanofi Genzyme, Gilead, Chimerix, Astellas, Incyte, and Elsalys; personal fees from Jazz Pharma; and nonfinancial support from Novartis. M.E. has received personal fees from bluebird bio for attendance at advisory boards and as a consultant outside of the reported work. W.M. reports that funds from bluebird bio were provided to his institution to support costs associated with the clinical trial described in this manuscript, and outside of the reported work he is an employee of Sangamo Therapeutics. G.R. reports that funds from bluebird bio were provided to his institution to support costs associated with the clinical trial described in this manuscript, and he received grants and consultancy fees from bluebird bio outside of the reported work. P.O. and T.L. report that funds were provided to their institution from bluebird bio to support costs associated with the clinical trial described in this manuscript. A.P. was an employee of the study sponsor, bluebird bio, at the time this study was conducted. Authorship statement: All authors were involved in acquiring and/or analyzing the data presented in this manuscript, drafting or revising the manuscript, and approving the final version. Financial disclosure: See Acknowledgments on page 547. Publisher Copyright: {\textcopyright} 2018 American Society for Blood and Marrow Transplantation",

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doi = "10.1016/j.bbmt.2018.09.036",

language = "English (US)",

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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

N1 - Funding Information: The authors acknowledge the editorial assistance of Frances Smith, PhD, Katherine Lewis, MA, Andrew Dietz, MD, MSCR, and Joe Biedenkapp, PhD, who are employed by bluebird bio, Inc. Financial disclosure: This study was funded by bluebird bio. Conflict of interest statement: A.F. G.M. J.K. P.A. S.B. and V.P. have no relevant conflicts of interest. J.B. and S.P. are employees of Veristat, a company contracted for statistical consulting by the study sponsor, bluebird bio. A.B. reports that funds from bluebird bio were provided to his institution to support costs associated with the clinical trial described in this manuscript; personal fees for attendance at advisory boards for Celgene, Novartis, Servier, and Jazz Pharma; personal fees from Shire and Jazz Pharma for attending satellite symposia; and a grant from Shire for performing a clinical trial. J.H.D. has received personal fees from bluebird bio in relation to the work performed in the manuscript; outside of the reported work he has received honorarium for attendance at advisory boards for Jazz Pharma, Mallinckrodt, Sanofi Genzyme, Gilead, Chimerix, Astellas, Incyte, and Elsalys; personal fees from Jazz Pharma; and nonfinancial support from Novartis. M.E. has received personal fees from bluebird bio for attendance at advisory boards and as a consultant outside of the reported work. W.M. reports that funds from bluebird bio were provided to his institution to support costs associated with the clinical trial described in this manuscript, and outside of the reported work he is an employee of Sangamo Therapeutics. G.R. reports that funds from bluebird bio were provided to his institution to support costs associated with the clinical trial described in this manuscript, and he received grants and consultancy fees from bluebird bio outside of the reported work. P.O. and T.L. report that funds were provided to their institution from bluebird bio to support costs associated with the clinical trial described in this manuscript. A.P. was an employee of the study sponsor, bluebird bio, at the time this study was conducted. Authorship statement: All authors were involved in acquiring and/or analyzing the data presented in this manuscript, drafting or revising the manuscript, and approving the final version. Financial disclosure: See Acknowledgments on page 547. Publisher Copyright: © 2018 American Society for Blood and Marrow Transplantation

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

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