Hematopoietic stem cell transplantation

April 15th, 2016 |

Charles Peters, M.D. and Stephan Kemp, Ph.D.

This section of the website will focus primarily on childhood-onset cerebral ALD which has a typical age of onset of 7 years. In addition, adrenal insufficiency (i.e., Addison’s disease) is observed in 90% of these affected boys.

MRI of age-matched control and CCALD patientThe predominant pattern of demyelination seen by brain MRI is posterior (i.e., in the parieto-occipital lobes) in 80-85% of cases. Frontal lobe and pyramidal tract involvement are also seen in 10-15% and approximately 5% of cases, respectively. Neurologic deterioration occurs in all boys. Neurologic deficits can include vision impairment, cortical blindness, hearing, auditory processing problems, aphasia (speech problems), apraxia (loss of the ability to execute or carry out learned purposeful movements), swallowing difficulty, gait and motor difficulties, fine motor deficits, bowel and/or bladder dysfunction, seizures. Disability, dementia and death can occur within a few months to several years from the onset of clinical symptoms. Complete evaluation of a boy with cerebral disease often includes: neurologic examination, neuropsychological evaluation, and MRI of the brain with and without contrast (gadolinium) with an MRI severity score determination (referred to as the Loes score) (Loes et al. (1994).

In contrast, adult-onset AMN symptoms typically first appear in men after the age of 20-25 years. AMN is an axonopathy with spinal cord atrophy usually involving the lower extremities. Progressive long tract signs develop when it progresses to the upper extremities. The majority of women with ALD (i.e., carriers for the ALD mutation) develop similar signs and symptoms later in their lives (please see Females with ALD for more details).

While there are a variety of treatments that have been investigated in cerebral ALD e.g., Lorenzo’s oil, low-fat diet, statins, immunosuppression, antioxidant agents, etc. this section will focus exclusively on hematopoietic stem cell transplantation (HSCT).

Experience with HSCT for cerebral ALD and lessons learned


Successful use of HSCT dates to 1969. Following intensive chemotherapy with or without radiation, suitably matched (HLA typed) blood (i.e., hematopoietic) stem cells from bone marrow, peripheral blood or umbilical cord blood are infused intravenously. In the setting of an allogeneic transplant (i.e., from a related or unrelated donor rather than autologous), measures must be taken to minimize or eliminate a potentially fatal complication in which donor-derived immune cells attack cells and tissues of the recipient. This reaction is termed graft-versus-host disease (GVHD). In addition, sufficient suppression of the recipient’s immune system function must be achieved to reduce the likelihood that the recipient will be capable of rejecting the donor cells. Over a period of several weeks to months, donor blood stem cells, after homing to the bone marrow, engraft and produce sufficient blood cells to replenish the “ablated” host blood producing system. By this time, the recipient has usually become red blood cell and platelet transfusion-independent. However, recovery of the immune system, which is intended to be donor-derived, requires a prolonged period and during this time the recipient is at risk for developing a variety of potentially life-threatening “opportunistic” infections. Deaths, which occur after HSCT that are the result of transplant-related measures are attributed to transplant-related mortality (TRM).

Over the past 4 decades, HSCT has been successfully used to treat a wide variety of disorders including leukemia, lymphoma, malignant solid tumors, aplastic anemia and bone marrow failure conditions, immune deficiency disorders, hemoglobinopathies such as sickle cell anemia and thalassemia, as well as genetic disorders such as lysosomal storage disorders and leukodystrophies.

In the case of genetic disorders, HSCT represents a form of “adoptive” gene therapy whereby cells from the donor are capable of producing the enzyme/protein that the recipient is genetically incapable of making. In the case of cerebral ALD, this mechanism and/or correction of the immune-mediated destruction of myelin may be the reason for its effectiveness. It should be noted that, in patients with leukemia, the development of GVHD may be associated with a graft-versus-leukemia effect thereby reducing the likelihood of leukemic relapse. In boys with cerebral ALD, there is no comparable therapeutic benefit, which can be derived from the development of GVHD after HSCT; instead, GVHD has been associated with further progression or worsening of cerebral disease. In addition, for there to be sustained benefit and protection from the HSCT, boys with cerebral ALD must continue to have a significant degree of donor-derived cells present.

It should be noted that gadolinium enhancement noted on brain MRI in boys with cerebral ALD is associated with “active” demyelination. Disappearance of this enhancement has been observed as early as 1 month following HSCT in the setting of donor-derived engraftment. However, the time required for a successful donor-derived HSCT to effectively halt the progression of cerebral ALD demyelination is measured in months, often 6 to 12.

Evaluations of boys with cerebral ALD undergoing HSCT usually include neurological examinations, neuropsychological testing which includes full scale intelligence quotient (FSIQ), verbal IQ (VIQ) and performance IQ (PIQ) as well as MRI of the brain with gadolinium contrast. These evaluations are essential to the assessment of the feasibility of HSCT and the likelihood that the recipient will benefit from it. A system of documenting neurologic deficits is routinely used. It has been noted that the performance IQ (PIQ) of neuropsychological testing is particularly sensitive to deficits in visual processing which are typically observed in boys with a posterior pattern of demyelination. Finally, a detailed demerit scoring (0-34 points) developed by Dr. Loes aids in determining the extent of myelin injury in brain (e.g., very early stage = MRI score 1-3; early stage = MRI score 4-8; late stage = MRI score 9-13; very late stage = MRI score greater than 13).

Historical overview of the experience with HSCT in the treatment of cerebral ALD

1982: First bone marrow transplant for childhood cerebral ALD performed in a boy with advanced (ie, very late) stage disease followed by death due to disease progression despite successful engraftment (Moser et al., 1984).

1990: Aubourg and colleagues in Paris described the first successful bone marrow transplant in a boy with very early stage cerebral disease (Aubourg et al., 1990).

2000: Long-term results (i.e., 5-10 years) of BMT in 12 boys. Shapiro and colleagues described the prospects for achieving stability in demyelination and changes in neuropsychologic function with a propensity for deterioration before ultimate stabilization in visual processing as reflected in the PIQ in boys with a posterior pattern of demyelination (Shapiro et al., 2000).

2004: The international HSCT experience from 1982-99 for childhood and adolescent cerebral ALD was compiled through a consortium of 43 HSCT centers (Peters et al., 2004). This was the first comprehensive report of the worldwide experience with HSCT for this disease and described 126 subjects of whom 94 were deemed to have complete data, which were suitable for detailed statistical analysis. The demographics and characteristics of the patients and their transplants are presented in Table 1 (adapted from Peters C et al Blood 2004).

Table 1: Characteristics of 94 boys with CCALD who underwent HSCT. Adapted from Peters et al. (2004).
Related donor, n=42 Unrelated donor, n=52 Total, n=94
Year of HSCT
1982-1995 29 (69%) 20 (38%) 49 (52%)
1996-1999 13 (31%) 32 (62%) 45 (48%)
Median age patient at HSCT
Years (range) 9 (5-16) 9 (5-19) 9 (5-19)
Reason for diagnosis
Family History 11 (26%) 17 (33%) 28 (30%)
ALD signs/symptoms 27 (64%) 31 (60%) 58 (62%)
Unknown 4 (10%) 4 (8%) 8 (9%)
Blood Stem Cells
bone marrow/umbilical cord blood 42 (100%)/0 (0%) 40 (77%)/12 (23%) 82 (87%)/12 (13%)
Chemo only 31 (74%) 17 (33%) 48 (51%)
Chemo + radiation 11 (26%) 35 (67%) 46 (49%)

The ALD-disability rating scale (ALD-DRS) was developed at the University of Minnesota to assess the functional level of a boy with cerebral ALD. It includes an assessment of the boy’s need for services that is distinct from neurologic and neuropsychological evaluations. The levels range from 0 to IV with increasing disability

Table 2: Adrenoleukodystrophy-Disability Rating Scale (ALD-DRS). Adapted from Peters et al. (2004).
Scale Level Description
0 No limitations or difficulties in learning or coordination due to ALD
I Mild learning or coordination difficulties due to ALD; patient does not require support or intervention
II Moderate learning or coordination difficulties due to ALD; patient requires support or intervention in some areas
III Severe learning or coordination difficulties due to ALD; patient requires support or intervention in many areas
IV Loss of cognitive abilities with disorientation due to ALD; patient requires constant supervision

Assessments of neurologic function with identification of neurologic deficits (NDS, i.e., vision, hearing, speech, gait) were performed before and after HSCT and are presented in Table 3. To assign an NDS for a boy with cerebral ALD, the number of neurologic deficits is summed (e.g., a boy with vision and gait problems, but without hearing or speech deficits, would have an NDS of 2; he would receive one point each for vision and gait and no points for either hearing or speech). Assessments of ALD-DRS were also performed before and after HSCT (see Table 3). This table illustrates that with advanced stage cerebral ALD, i.e., increasing NDS and/or ALD-DRS there is less likelihood that the neurologic and functional status of the boy will be stabilized at the pre-HSCT level following HSCT. Approximately 60% of boys with an NDS of 0 or an ALD-DRS of 0 were able to remain at this level following successful transplant.

Table 3: Neurologic deficit (NDS) and ALD-DRS scores before and after HSCT presented as percentage of patients who stabilized*. Adapted from Peters et al. (2004).
NDS Total Number of patients who stabilized after HSCT
0 32 18 (56%)
1 28 13 (46%)
2 21 7 (33%)
ALD-DRS Total Number of patients who stabilized after HSCT
0 13 8 (62%)
I 21 7 (33%)
II 36 12 (33%)
III 12 1 (8%)

* Stabilization is defined as maintaining the same NDS or ALD-DRS score or lower following HSCT when compared to the baseline/pre-HSCT score.

Results of neuropsychological function and ALD-DRS scores after HSCT according to baseline PIQ 80 are presented (Table 4). As baseline PIQ less than 80 has been previously noted to predict poorer outcomes after HSCT. The authors separated patients into 2 groups: baseline PIQ ≥80 and PIQ <80. Patients with a baseline PIQ less than 80 were significantly more impaired in both neuropsychological functions measured by PIQ and on the ALD-disability rating scale after HSCT.

Table 4: Neuropsychological function (performance IQ, PIQ) and ALD-DRS after HSCT according to baseline PIQ. Adapted from Peters et al. (2004).
PIQ <80 PIQ ≥80
Median PIQ (range) 45 (45-63) 78.5 (45-122.5)
Observations 6 26
Median ALD-DRS (range) IV (I-IV) II (0-IV)
Observations 28 36

Comparisons of neuropsychological function (verbal IQ, VIQ and PIQ) according to MRI pattern of demyelination (posterior vs frontal lobes or pyramidal tracts) are presented (Table 5). All survivors were compared with those who died on the basis of baseline neuropsychological testing. Although no difference was found in baseline median VIQ scores (survivors, 98 vs deceased patients, 92), the median baseline PIQ score was significantly lower in patients who died (survivors, 94.5 vs deceased patients, 77.5). Patients with a posterior pattern of demyelination demonstrated a greater mean loss of PIQ points (i.e., -21.6) than patients with a frontal pattern of demyelination (i.e., 0.4 PIQ points).

Table 5: Neuropsychologic outcomes (verbal IQ, VIQ; performance IQ, PIQ) according to the pattern of demyelination on MRI. Adapted from Peters et al. (2004).
Posterior Frontal/Pyramidal Total No data after HSCT due to death
Baseline 99 89 98 92 P= not significant
Post HSCT 79 80.5
Change -13.7 -6.4 12.1
Baseline 96 92 94.5 77.5 P < 0.01
Post HSCT 64 93 73
Change -21.6 0.4 -16.8 P = 0.03

The (Peters et al., 2004) report documents that the cumulative incidence of transplant-related mortality (TRM) at 3 years was 14%. In addition to providing related and unrelated donor HSCT Kaplan-Meier probabilities of survival, this report also described for the first time the excellent survival outcomes which could be achieved in boys transplanted for early stages of cerebral disease defined as 0 or 1 neurologic deficit and MRI severity score <9 (92% survival at 5 years vs. 45% for all others)

Survival BMT versus non-BMT

2007: Mahmood and colleagues analyzed the likelihood of survival in childhood cerebral ALD patients who had not received HSCT (Mahmood et al., 2007). In a subgroup of these patients with early cerebral disease, they compared survival in those who underwent HSCT with those who did not (Figure).

1997-2011: Numerous reports from single institutions describing their HSCT experience, the use of reduced intensity conditioning, and umbilical cord blood as a source of blood stem cells.

2011: Miller and colleagues from the University of Minnesota recently published the largest single center HSCT experience for childhood cerebral ALD (Miller et al. 2011).

2015: Van Geel and colleagues investigated if patients with ALD that underwent HSCT for cerebral ALD in childhood still develop AMN in adulthood. This retrospective observational study found that three out of the five patients who underwent HSCT in childhood developed signs of myelopathy (AMN) in adulthood. These data suggest that HSCT for cerebral ALD in childhood does not appear to prevent the onset of myelopathy and peripheral neuropathy in adulthood. These findings will have to be confirmed in independent studies. But if true, this will have consequences for follow-up of patients that were transplanted in childhood and are now becoming adults (Van Geel et al. 2015).

New directions and implications for the use of HSCT

An important issue with respect to the future of therapy for cerebral ALD and specifically HSCT is the challenge of treating boys with advanced stage disease. In order to more effectively treat boys with advanced stage cerebral disease (i.e., MRI severity score ≥9) prior to HSCT it is imperative to address the following issues: (1) develop a method to accurately assess cerebral disease velocity; (2) explore further the use of N-acetyl cysteine; (3) evaluate the use of reduced intensity HSCT conditioning regimens, (4) investigate combination therapies including alternative or complementary stem cells such as neural stem cells; (5) develop and implement more effective ways to rapidly halt the inflammatory demyelination, repair damaged myelin, and restore lost functionality.

In light of the generally excellent to outstanding survival and functional outcomes observed after HSCT in boys with early stage cerebral disease (i.e., MRI severity score <9 and particularly ≤3), it would be highly advantageous to develop and implement newborn screening for ALD. Furthermore, it would be highly beneficial and of extreme importance to identify marker(s) that predict which boys with ALD are destined to develop childhood cerebral disease and therefore will require HSCT.

It is important to note that currently there is no indication for use of HSCT in men with AMN or for women with ALD either with or without symptoms.

While significant advances have been made in reducing the risks associated with HSCT particularly those from unrelated donors of bone marrow or umbilical cord blood, there is still significant risk of transplant-related mortality as well as death due to disease progression. With the advances made in gene therapy (See the Gene Therapy for ALD page) an alternative to HSCT may be considered in selected cases (e.g., unavailability of a suitably matched donor of blood stem cells).

Disease-related lessons, which have been learned over the past 3 decades

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