- Email: [email protected]
Combination of a Haploidentical Stem Cell Transplant With Umbilical Cord Blood for Cerebral X-Linked Adrenoleukodystrophy
Pediatric Neurology xxx (2015) 1e3
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Combination of a Haploidentical Stem Cell Transplant With Umbilical Cord Blood for Cerebral X-Linked Adrenoleukodystrophy Hua Jiang MD a,1, Min-yan Jiang MD b,1, Sha Liu MD a, Yan-na Cai PhD b, Cui-li Liang MD b, Li Liu MD b, * a
Department of Pediatric Hematology, Guangzhou Women and Children’s Medical Center, Guangzhou, China Department of Pediatric Endocrinology and Genetic Metabolism, Guangzhou Women and Children’s Medical Center, Guangzhou, China b
abstract BACKGROUND: Childhood cerebral X-linked adrenoleukodystrophy is a rapidly progressive neurodegenerative disorder that affects central nervous system myelin and the adrenal cortex. Hematopoietic stem cell transplantation is the best available curative therapy if performed during the early stages of disease. Only 30% of patients who might benefit from a hematopoietic stem cell transplant will have a full human leukocyte antigenematched donor, which is considered to be the best choice. PATIENT DESCRIPTION: We present a 5-year-old boy with cerebral X-linked adrenoleukodystrophy whose brain magnetic resonance imaging severity score was 7 and who needed an immediate transplantation without an available full human leukocyte antigenematched donor. We combined haploidentical and umbilical cord blood sources for transplantation and saw encouraging results. After transplantation, the patient showed neurological stability for 6 months and the level of very long chain fatty acids had decreased. By 1 year, the patient appeared to gradually develop cognition, motor, and visual disturbances resulting from possible mix chimerism. CONCLUSION: Transplantation of haploidentical stem cells combined with the infusion of umbilical cord blood is a novel approach for treating cerebral X-linked adrenoleukodystrophy. It is critical to monitor posttransplant chimerism and carry out antirejection therapy timely for a beneficial clinical outcome. Keywords: X-linked adrenoleukodystrophy, CCALD, haploidentical transplantation, ABCD1
Pediatr Neurol 2015; -: 1-3 Ó 2015 Elsevier Inc. All rights reserved. Introduction
X-linked adrenoleukodystrophy (MIM 300100) is the most common peroxisomal disease, with an estimated birth incidence of 1 in 17,000 newborns (male and female).1 X-linked adrenoleukodystrophy affects the nervous system, adrenal cortex, and testis as a result of inactivating mutations in the ABCD1 gene located on the X chromosome. Childhood cerebral adrenoleukodystrophy (CCALD) is rapidly progressive and devastating, accounting for >50% of
Article History: Received January 21, 2015; Accepted in final form May 1, 2015 * Communications should be addressed to: Dr. Liu; Department of Endocrinology and Metabolism; Guangzhou Women and Children’s Medical Center; Guangzhou, China. E-mail address: [email protected] 1
HJ and M-YJ are the co-first authors.
0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.05.002
all cases. The only effective treatment to date has been allogeneic hematopoietic stem cell transplants (HSCT).2 Beneficial clinical results are obtained when HSCT is performed during the very early stages of CCALD. Hence, early diagnosis and emergent HSCT are crucial. However, it is time-consuming to find a full human leukocyte antigen (HLA)-matched donor. For patients that have no full HLAmatched donor, a haploidentical family donor is an attractive source.3,4 However, this therapeutic source has been limited by the risk of severe graft-versus-host disease (GVHD).5 To avoid this, several studies have adopted haploidentical stem cell transplants with umbilical cord blood infusion to enhance immune reconstitution and prevent GVHD for hematological malignancies.6 However, very little is known about its use for CCALD patients. This is the first report of a CCALD patient who successfully received a haploidentical stem cell transplant combined with an unrelated umbilical cord blood unit.
2
H. Jiang et al. / Pediatric Neurology xxx (2015) 1e3
Patient Description The patient was diagnosed with CCALD at the age of 5 years based on the accumulation of very long chain fatty acids. His older brother also had been diagnosed with CCALD and his regression occurred rapidly; he received HSCT treatment at an advanced stage of disease and died 1 year after transplantation. The patient initially presented with hyperpigmentation without neurological dysfunction. Plasma very long chain fatty acids and adrenocorticotrophic hormone levels were high (Table). Brain magnetic resonance imaging (MRI) showed massive high-intensity lesions bilaterally on fluid-attenuated inversion recovery T2-weighted images that only involved the splenium of corpus callosum. He was screened for an ABCD1 mutation; a deletion mutation of c.1415_16delAG was found. The patient was diagnosed with CCALD and prepped for HSCT treatment. Four months later, his brain MRI showed further cerebral involvement with a 7 Loes score. Because no full HLA-matched donor was readily available, a haploidentical stem cell transplant with infusion of unrelated umbilical cord blood was scheduled. The stem cell transplantation protocol detail is described in the supplemental file. On the first day of transplantation, the patient underwent a transplantation total containing 11.50 108 nucleated cells/kg and 5.68 105 CD34þ cells/kg, including cord cells consisting of 4.3 107 nucleated cells/ kg and. 1.3 105 CD34þ cells/kg. The engraftment of neutrophils occurred on day 11 for 3 consecutive days when the absolute neutrophil count was >0.5 109/L. Platelet engraftment occurred on days 17 for 7 consecutive days when the platelet count was >20 109/L. Complete persistent haploidentical chimerism (>95%) was observed on day 28. On day 9, he developed a grade 3 acute GVHD affecting the stomach, which was controlled by methylprednisolone (2 mg/kg). Ganciclovir was administered for the treatment of positive cytomegalovirus antigenemia at day 17. Six months after transplantation, the patient was normal with no indication of neurological damage. Brain MRI showed progressive deterioration. The level of very long chain fatty acids and adrenocorticotrophic hormone decreased (Table), and chimerism analysis showed >95% donor type. One year after transplantation, the brain MRI showed extending cerebral involvement (Figure). Chimerism analysis showed 85% donor type. He appeared to be reacting slowly with gait instability and poor sight, although his intelligence remained normal.
Discussion
CCALD is characterized by rapid progression to a vegetative state or death within 1-2 years (31%-35%), with a peak incidence at 4-7 years of age. The common initial manifestations are hyperactivity, visual disturbances, ataxia, poor handwriting, and worsening school performance.7 HSCT is the established therapeutic approach when the disease is in the early stages, a technique that was first demonstrated by Aubourg et al. in 1990.8 Several studies have supported that HSCT benefits patients with mild cerebral involvement.9,10 In addition, Moser and colleagues demonstrated in a
cohort of 89 patients that Lorenzo’s oil blunts the progress of adrenoleukodystrophy, but only if it is begun before the onset of either MRI changes or neurological manifestations.11 Thus, regardless of the therapy employed, early diagnosis and early therapy may be more effective. In recent years, a validated tandem mass spectrometry method has been developed to identify presymptomatic Xlinked adrenoleukodystrophy in newborn blood spots. This method offers tremendous potential for the identification of this genetic abnormality at birth, which is useful for early diagnosis.12 Early and effective therapy is crucial. It is wellknown that to acquire an available fully HLA-matched donor, the recipients usually have to wait up to 4 months.7 CCALD patients may experience rapid progression of the disease and lose the chance for HSCT therapy. A haploidentical family donor is considered a good option because of its immediate acquisition. However, haploidentical stem cell transplants have some limitations.5 Bautista pioneered the myeloablative cord stem cell transplant with third-party donor support to accelerate lymphocyte recovery and reduce the risk of graft failure.13 Recent data have shown that haploidentical stem cell transplants with support from cord blood, which contains a subset of regulatory T-cell and mesenchymal stromal cells, could significantly reduce the incidences of severe acute GVHD in the treatment of hematological malignancies.6,14 In this boy, we used haploidentical transplantation with a coinfusion of cord blood to treat CCALD. After transplantation, there was rapid and sustained neutrophil and platelet engraftment, without severe acute GVHD; he showed neurological stability for 6 months. However, 1 year after transplantation, he developed further progression of neurological symptoms, with impairment of cognition, behavior, and vision. We speculated that there were two reasons for this clinical outcome. First, the patient had been in a “slow cerebral disease” stage before transplantation. Shapiro et al. considered that these patients would enter into the advanced cerebral disease stage during or after the HSCT procedure.10 Second, chimerism analysis for the patient showed 85% blood leukocytes derived from the donor, with 15% from the recipient. Schoenberger et al. first provided new insight into the mechanisms of the beneficial effect of HSCT; healthy donor cells reach neurons and assist affected cells in metabolic function by cellecell contact. Posttransplant mixed chimerism may influence the ability of donor cells to establish contact with organ-specific cells of the recipient. Nevertheless, very little is understood about the cellecell contact contributions on the beneficial
TABLE. Plasma Levels of VLCFAs and Adrenocorticotrophic Hormone Before and After Transplantation
VLCFAs
Normal range Pretransplantation Posttransplantation 3 months 6 months 1 year
Adrenocorticotrophic Hormone (pmol/L)
C26:0/C22:0
C24:0/C22:0
C26:0 (mmol/L)
C24:0 (mmol/L)
<0.013 0.075
<1.04 1.96
<0.89 3.7
<94.29 96.02
0-10.2 133
0.039 0.036 0.037
1.24 1.81 1.67
3.76 2.28 2.3
120.02 114.10 103.8
<1.11 <1.11 25.30
Abbreviation: VLCFAs ¼ Very long chain fatty acids
H. Jiang et al. / Pediatric Neurology xxx (2015) 1e3
3
FIGURE. Brain magnetic resonance imaging (MRI) scans before and after transplantation. Pretransplantation: (A) The initial MRI showed white matter high-intensity lesions on fluid-attenuated inversion recovery T2-weighted images involving the splenium of corpus callosum. (B) Four months passed, the white matter affected the trigone of the lateral ventricles and the splenium of corpus callosum. Posttransplantation: (C) By 3 months, the white matter involvement was similar to (B). (D) By 6 months, cerebral damage of the trigone of lateral ventricles and the splenium of corpus callosum were extending gradually. (E) By 1 year, the white signal involved in the midbrain, pons, cerebral peduncle, and splenium of corpus callosum. (F) By 1 year and 4 months, the white matter had extended to genu of corpus callosum.
effect of HSCT.15 Animal models are required to confirm this novel finding. In conclusion, we suggest that a haploidentical stem cell transplant combined with umbilical cord blood may be a favorable choice for patients who lack a full HLA-matched donor and need immediate treatment. It is critical to monitor posttransplant chimerism and carry out antirejection therapy timely. Further studies are needed to assess the long-term clinical outcome.
References 1. Engelen M, Kemp S, de Visser M, et al. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 2012;7:51-64. 2. Miller WP, Rothman SM, Nascene D, et al. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood. 2011;118:1971-1978. 3. Ballen KK, Koreth J, Chen YB, et al. Selection of optimal alternative graft source: mismatched unrelated donor, umbilical cord blood, or haploidentical transplant. Blood. 2012;119:1972-1980. 4. Yabe H, Inoue H, Matsumoto M, et al. Unmanipulated HLAhaploidentical bone marrow transplantation for the treatment of fatal, nonmalignant diseases in children and adolescents. Int J Hematol. 2004;80:78-82. 5. Barrett J, Gluckman E, Handgretinger R, et al. Point-counterpoint: haploidentical family donors versus cord blood transplantation. Biol Blood Marrow Transplant. 2011;17:S89-S93.
6. Chen J, Wang RX, Chen F, et al. Combination of a haploidentical SCT with an unrelated cord blood unit: a single-arm prospective study. Bone Marrow Transplant. 2014;49:206-211. 7. Niu YF, Ni W, Wu ZY. ABCD1 mutations and phenotype distribution in Chinese patients with X-linked adrenoleukodystrophy. Gene. 2013;522:117-120. 8. Suzuki Y, Isogaki K, Teramoto T, et al. Bone marrow transplantation for the treatment of X-linked adrenoleukodystrophy. J Inherit Metab Dis. 2000;23:453-458. 9. Peters C, Charnas L, Tan Y, et al. Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood. 2004;104:881-888. 10. Shapiro E, Krivit W, Lockman L, et al. Long-term effect of bonemarrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. Lancet. 2000;356:713-718. 11. Moser HW, Raymond GV, Lu SE, et al. Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo’s oil. Arch Neurol. 2005;62:1073-1080. 12. Hubbard WC, Moser AB, Liu AC, et al. Newborn screening for X-linked adrenoleukodystrophy (X-ALD): validation of a combined liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Mol Genet Metab. 2009;97:212-220. 13. Bautista G, Cabrera JR, Regidor C, et al. Cord blood transplants supported by co-infusion of mobilized hematopoietic stem cells from a third-party donor. Bone Marrow Transplant. 2009;43: 365-373. 14. Daopei Lu, Tong Wu, Zhiyong Gao, et al. Significantly reduce acute graft-versus-host disease in haploidentical stem cell transplantation by using cord blood as the third party cells. Blood (ASH Annual Meeting Abstracts). 2008;112:2211. 15. Moser HW, Mahmood A. New insights about hematopoietic stem cell transplantation in adrenoleukodystrophy. Arch Neurol. 2007;64: 631-632.
3.e1
H. Jiang et al. / Pediatric Neurology xxx (2015) 1e3
Appendix
The stem cell transplantation protocol was as follows: the haploidentical donor was the patient’s father. Human leukocyte antigen (HLA) high-resolution classification results of the patient and his father were confirmed by polymerase chain reaction sequenceebased typing, which are A2402/2402, B4801/4801, C1502/1502, DR1202/1501, DQ0301/0601(patient), and A1101/2402, B1512/4801, C0303/1502, DR1202/1501, DQ0301/0601(father), respectively. The cord blood unit was selected based on HLA typing and cell count, which came from the cord blood banks in Guangzhou Province in China and showed 5/6 matched HLA loci (recipient: A2402/2402, B4801/4801, and DR0405/1501). The treatment was started using a conditioning regimen consisting of Busulfex at 1.1 mg/kg/dose every 6 hours starting on days 9 to 6, cyclophosphamide at 50 mg/kg/day 4 days from days 5 to 2, and antithymocyte globulin at 10 mg/kg starting from days 4 to 2. For graft-versus-host disease prophylaxis, the patient was given cyclosporin A and short-term methotrexate.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Combination of a Haploidentical Stem Cell Transplant With Umbilical Cord Blood for Cerebral X-Linked Adrenoleukodystrophy Hua Jiang MD a,1, Min-yan Jiang MD b,1, Sha Liu MD a, Yan-na Cai PhD b, Cui-li Liang MD b, Li Liu MD b, * a
Department of Pediatric Hematology, Guangzhou Women and Children’s Medical Center, Guangzhou, China Department of Pediatric Endocrinology and Genetic Metabolism, Guangzhou Women and Children’s Medical Center, Guangzhou, China b
abstract BACKGROUND: Childhood cerebral X-linked adrenoleukodystrophy is a rapidly progressive neurodegenerative disorder that affects central nervous system myelin and the adrenal cortex. Hematopoietic stem cell transplantation is the best available curative therapy if performed during the early stages of disease. Only 30% of patients who might benefit from a hematopoietic stem cell transplant will have a full human leukocyte antigenematched donor, which is considered to be the best choice. PATIENT DESCRIPTION: We present a 5-year-old boy with cerebral X-linked adrenoleukodystrophy whose brain magnetic resonance imaging severity score was 7 and who needed an immediate transplantation without an available full human leukocyte antigenematched donor. We combined haploidentical and umbilical cord blood sources for transplantation and saw encouraging results. After transplantation, the patient showed neurological stability for 6 months and the level of very long chain fatty acids had decreased. By 1 year, the patient appeared to gradually develop cognition, motor, and visual disturbances resulting from possible mix chimerism. CONCLUSION: Transplantation of haploidentical stem cells combined with the infusion of umbilical cord blood is a novel approach for treating cerebral X-linked adrenoleukodystrophy. It is critical to monitor posttransplant chimerism and carry out antirejection therapy timely for a beneficial clinical outcome. Keywords: X-linked adrenoleukodystrophy, CCALD, haploidentical transplantation, ABCD1
Pediatr Neurol 2015; -: 1-3 Ó 2015 Elsevier Inc. All rights reserved. Introduction
X-linked adrenoleukodystrophy (MIM 300100) is the most common peroxisomal disease, with an estimated birth incidence of 1 in 17,000 newborns (male and female).1 X-linked adrenoleukodystrophy affects the nervous system, adrenal cortex, and testis as a result of inactivating mutations in the ABCD1 gene located on the X chromosome. Childhood cerebral adrenoleukodystrophy (CCALD) is rapidly progressive and devastating, accounting for >50% of
Article History: Received January 21, 2015; Accepted in final form May 1, 2015 * Communications should be addressed to: Dr. Liu; Department of Endocrinology and Metabolism; Guangzhou Women and Children’s Medical Center; Guangzhou, China. E-mail address: [email protected] 1
HJ and M-YJ are the co-first authors.
0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.05.002
all cases. The only effective treatment to date has been allogeneic hematopoietic stem cell transplants (HSCT).2 Beneficial clinical results are obtained when HSCT is performed during the very early stages of CCALD. Hence, early diagnosis and emergent HSCT are crucial. However, it is time-consuming to find a full human leukocyte antigen (HLA)-matched donor. For patients that have no full HLAmatched donor, a haploidentical family donor is an attractive source.3,4 However, this therapeutic source has been limited by the risk of severe graft-versus-host disease (GVHD).5 To avoid this, several studies have adopted haploidentical stem cell transplants with umbilical cord blood infusion to enhance immune reconstitution and prevent GVHD for hematological malignancies.6 However, very little is known about its use for CCALD patients. This is the first report of a CCALD patient who successfully received a haploidentical stem cell transplant combined with an unrelated umbilical cord blood unit.
2
H. Jiang et al. / Pediatric Neurology xxx (2015) 1e3
Patient Description The patient was diagnosed with CCALD at the age of 5 years based on the accumulation of very long chain fatty acids. His older brother also had been diagnosed with CCALD and his regression occurred rapidly; he received HSCT treatment at an advanced stage of disease and died 1 year after transplantation. The patient initially presented with hyperpigmentation without neurological dysfunction. Plasma very long chain fatty acids and adrenocorticotrophic hormone levels were high (Table). Brain magnetic resonance imaging (MRI) showed massive high-intensity lesions bilaterally on fluid-attenuated inversion recovery T2-weighted images that only involved the splenium of corpus callosum. He was screened for an ABCD1 mutation; a deletion mutation of c.1415_16delAG was found. The patient was diagnosed with CCALD and prepped for HSCT treatment. Four months later, his brain MRI showed further cerebral involvement with a 7 Loes score. Because no full HLA-matched donor was readily available, a haploidentical stem cell transplant with infusion of unrelated umbilical cord blood was scheduled. The stem cell transplantation protocol detail is described in the supplemental file. On the first day of transplantation, the patient underwent a transplantation total containing 11.50 108 nucleated cells/kg and 5.68 105 CD34þ cells/kg, including cord cells consisting of 4.3 107 nucleated cells/ kg and. 1.3 105 CD34þ cells/kg. The engraftment of neutrophils occurred on day 11 for 3 consecutive days when the absolute neutrophil count was >0.5 109/L. Platelet engraftment occurred on days 17 for 7 consecutive days when the platelet count was >20 109/L. Complete persistent haploidentical chimerism (>95%) was observed on day 28. On day 9, he developed a grade 3 acute GVHD affecting the stomach, which was controlled by methylprednisolone (2 mg/kg). Ganciclovir was administered for the treatment of positive cytomegalovirus antigenemia at day 17. Six months after transplantation, the patient was normal with no indication of neurological damage. Brain MRI showed progressive deterioration. The level of very long chain fatty acids and adrenocorticotrophic hormone decreased (Table), and chimerism analysis showed >95% donor type. One year after transplantation, the brain MRI showed extending cerebral involvement (Figure). Chimerism analysis showed 85% donor type. He appeared to be reacting slowly with gait instability and poor sight, although his intelligence remained normal.
Discussion
CCALD is characterized by rapid progression to a vegetative state or death within 1-2 years (31%-35%), with a peak incidence at 4-7 years of age. The common initial manifestations are hyperactivity, visual disturbances, ataxia, poor handwriting, and worsening school performance.7 HSCT is the established therapeutic approach when the disease is in the early stages, a technique that was first demonstrated by Aubourg et al. in 1990.8 Several studies have supported that HSCT benefits patients with mild cerebral involvement.9,10 In addition, Moser and colleagues demonstrated in a
cohort of 89 patients that Lorenzo’s oil blunts the progress of adrenoleukodystrophy, but only if it is begun before the onset of either MRI changes or neurological manifestations.11 Thus, regardless of the therapy employed, early diagnosis and early therapy may be more effective. In recent years, a validated tandem mass spectrometry method has been developed to identify presymptomatic Xlinked adrenoleukodystrophy in newborn blood spots. This method offers tremendous potential for the identification of this genetic abnormality at birth, which is useful for early diagnosis.12 Early and effective therapy is crucial. It is wellknown that to acquire an available fully HLA-matched donor, the recipients usually have to wait up to 4 months.7 CCALD patients may experience rapid progression of the disease and lose the chance for HSCT therapy. A haploidentical family donor is considered a good option because of its immediate acquisition. However, haploidentical stem cell transplants have some limitations.5 Bautista pioneered the myeloablative cord stem cell transplant with third-party donor support to accelerate lymphocyte recovery and reduce the risk of graft failure.13 Recent data have shown that haploidentical stem cell transplants with support from cord blood, which contains a subset of regulatory T-cell and mesenchymal stromal cells, could significantly reduce the incidences of severe acute GVHD in the treatment of hematological malignancies.6,14 In this boy, we used haploidentical transplantation with a coinfusion of cord blood to treat CCALD. After transplantation, there was rapid and sustained neutrophil and platelet engraftment, without severe acute GVHD; he showed neurological stability for 6 months. However, 1 year after transplantation, he developed further progression of neurological symptoms, with impairment of cognition, behavior, and vision. We speculated that there were two reasons for this clinical outcome. First, the patient had been in a “slow cerebral disease” stage before transplantation. Shapiro et al. considered that these patients would enter into the advanced cerebral disease stage during or after the HSCT procedure.10 Second, chimerism analysis for the patient showed 85% blood leukocytes derived from the donor, with 15% from the recipient. Schoenberger et al. first provided new insight into the mechanisms of the beneficial effect of HSCT; healthy donor cells reach neurons and assist affected cells in metabolic function by cellecell contact. Posttransplant mixed chimerism may influence the ability of donor cells to establish contact with organ-specific cells of the recipient. Nevertheless, very little is understood about the cellecell contact contributions on the beneficial
TABLE. Plasma Levels of VLCFAs and Adrenocorticotrophic Hormone Before and After Transplantation
VLCFAs
Normal range Pretransplantation Posttransplantation 3 months 6 months 1 year
Adrenocorticotrophic Hormone (pmol/L)
C26:0/C22:0
C24:0/C22:0
C26:0 (mmol/L)
C24:0 (mmol/L)
<0.013 0.075
<1.04 1.96
<0.89 3.7
<94.29 96.02
0-10.2 133
0.039 0.036 0.037
1.24 1.81 1.67
3.76 2.28 2.3
120.02 114.10 103.8
<1.11 <1.11 25.30
Abbreviation: VLCFAs ¼ Very long chain fatty acids
H. Jiang et al. / Pediatric Neurology xxx (2015) 1e3
3
FIGURE. Brain magnetic resonance imaging (MRI) scans before and after transplantation. Pretransplantation: (A) The initial MRI showed white matter high-intensity lesions on fluid-attenuated inversion recovery T2-weighted images involving the splenium of corpus callosum. (B) Four months passed, the white matter affected the trigone of the lateral ventricles and the splenium of corpus callosum. Posttransplantation: (C) By 3 months, the white matter involvement was similar to (B). (D) By 6 months, cerebral damage of the trigone of lateral ventricles and the splenium of corpus callosum were extending gradually. (E) By 1 year, the white signal involved in the midbrain, pons, cerebral peduncle, and splenium of corpus callosum. (F) By 1 year and 4 months, the white matter had extended to genu of corpus callosum.
effect of HSCT.15 Animal models are required to confirm this novel finding. In conclusion, we suggest that a haploidentical stem cell transplant combined with umbilical cord blood may be a favorable choice for patients who lack a full HLA-matched donor and need immediate treatment. It is critical to monitor posttransplant chimerism and carry out antirejection therapy timely. Further studies are needed to assess the long-term clinical outcome.
References 1. Engelen M, Kemp S, de Visser M, et al. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 2012;7:51-64. 2. Miller WP, Rothman SM, Nascene D, et al. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood. 2011;118:1971-1978. 3. Ballen KK, Koreth J, Chen YB, et al. Selection of optimal alternative graft source: mismatched unrelated donor, umbilical cord blood, or haploidentical transplant. Blood. 2012;119:1972-1980. 4. Yabe H, Inoue H, Matsumoto M, et al. Unmanipulated HLAhaploidentical bone marrow transplantation for the treatment of fatal, nonmalignant diseases in children and adolescents. Int J Hematol. 2004;80:78-82. 5. Barrett J, Gluckman E, Handgretinger R, et al. Point-counterpoint: haploidentical family donors versus cord blood transplantation. Biol Blood Marrow Transplant. 2011;17:S89-S93.
6. Chen J, Wang RX, Chen F, et al. Combination of a haploidentical SCT with an unrelated cord blood unit: a single-arm prospective study. Bone Marrow Transplant. 2014;49:206-211. 7. Niu YF, Ni W, Wu ZY. ABCD1 mutations and phenotype distribution in Chinese patients with X-linked adrenoleukodystrophy. Gene. 2013;522:117-120. 8. Suzuki Y, Isogaki K, Teramoto T, et al. Bone marrow transplantation for the treatment of X-linked adrenoleukodystrophy. J Inherit Metab Dis. 2000;23:453-458. 9. Peters C, Charnas L, Tan Y, et al. Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood. 2004;104:881-888. 10. Shapiro E, Krivit W, Lockman L, et al. Long-term effect of bonemarrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. Lancet. 2000;356:713-718. 11. Moser HW, Raymond GV, Lu SE, et al. Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo’s oil. Arch Neurol. 2005;62:1073-1080. 12. Hubbard WC, Moser AB, Liu AC, et al. Newborn screening for X-linked adrenoleukodystrophy (X-ALD): validation of a combined liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Mol Genet Metab. 2009;97:212-220. 13. Bautista G, Cabrera JR, Regidor C, et al. Cord blood transplants supported by co-infusion of mobilized hematopoietic stem cells from a third-party donor. Bone Marrow Transplant. 2009;43: 365-373. 14. Daopei Lu, Tong Wu, Zhiyong Gao, et al. Significantly reduce acute graft-versus-host disease in haploidentical stem cell transplantation by using cord blood as the third party cells. Blood (ASH Annual Meeting Abstracts). 2008;112:2211. 15. Moser HW, Mahmood A. New insights about hematopoietic stem cell transplantation in adrenoleukodystrophy. Arch Neurol. 2007;64: 631-632.
3.e1
H. Jiang et al. / Pediatric Neurology xxx (2015) 1e3
Appendix
The stem cell transplantation protocol was as follows: the haploidentical donor was the patient’s father. Human leukocyte antigen (HLA) high-resolution classification results of the patient and his father were confirmed by polymerase chain reaction sequenceebased typing, which are A2402/2402, B4801/4801, C1502/1502, DR1202/1501, DQ0301/0601(patient), and A1101/2402, B1512/4801, C0303/1502, DR1202/1501, DQ0301/0601(father), respectively. The cord blood unit was selected based on HLA typing and cell count, which came from the cord blood banks in Guangzhou Province in China and showed 5/6 matched HLA loci (recipient: A2402/2402, B4801/4801, and DR0405/1501). The treatment was started using a conditioning regimen consisting of Busulfex at 1.1 mg/kg/dose every 6 hours starting on days 9 to 6, cyclophosphamide at 50 mg/kg/day 4 days from days 5 to 2, and antithymocyte globulin at 10 mg/kg starting from days 4 to 2. For graft-versus-host disease prophylaxis, the patient was given cyclosporin A and short-term methotrexate.