Hematopoietic stem cell transplantation

Authors: Charles Peters, M.D., Virginie Bonnamain, Ph.D. and Stephan Kemp, Ph.D.

What is hematopoietic stem cell transplantation?

Hematopoietic stem cell transplantation (HSCT, or also called bone marrow transplantation), is a medical procedure that is used to treat patients suffering from (blood) cancer or certain types of severe genetic conditions (like ALD). In this procedure a patient receives healthy stem cells from a donor. The procedure is composed of 3 main steps:

What is a hematopoietic stem cell?

A stem cell is a type of cell that has the unique ability to give rise to specialized cell types in the body (like cardiac cells, skin cells, brain cells, etc.).
A hematopoietic stem cell is a stem cell that specifically gives rise to different blood cells, such as red blood cells, white blood cells and platelets. But also to all the immune cells. Hematopoietic stem cells are mainly located in the bone marrow, which is a spongy tissue found inside the large bones in the body, but a small number of these cells can also be found in the blood.
Prior to the collection of hematopoietic stem cells the donor is given a drug that results in an increase of the release of hematopoietic stem cells from the bone marrow to the blood. Hematopoietic stem cells can then be collected directly from the bloodstream. This avoids the more complex procedure of bone marrow aspiration.

There are two main types of hematopoietic stem cell transplantation: allogeneic and autologous.

In the case of an allogeneic hematopoietic stem cell transplantation, the hematopoietic stem cells come from a genetically similar or matched donor. This person can be a relative (ideally a brother or sister) or, when a suitable matched sibling is not available, a person unrelated to the patient. In certain conditions, umbilical cord blood may also be used as a source of hematopoietic stem cell.

In this allogeneic setting, 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’s immune system will attack and reject the donor cells.

In the case of an autologous hematopoietic stem cell transplantation, the patient’s own hematopoietic stem cells are collected before the conditioning procedure and transplanted back to the patient after for example correction by gene therapy.

Movie explaining the basics of a stem cell transplant


Produced by bluebird bio, Inc.

How does hematopoietic stem cell transplantation work?

The transplanted donor hematopoietic stem cells travel to the bone marrow where they settle and start to generate blood cells. Over a period of several weeks to months the stem cells engraft and have produced sufficient cells to replenish the “ablated” blood producing system of the patient. However, recovery of the immune system requires a prolonged period and during this time the transplanted patient is at risk for developing a variety of potentially life-threatening “opportunistic” infections.

Over the past 4 decades, hematopoietic stem cell transplantation 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 several leukodystrophies like ALD.

How does hematopoietic stem cell transplantation work for the treatment of cerebral ALD?

In the case of genetic disorders, allogeneic hematopoietic stem cell transplantation represents a form of “adoptive” gene therapy. The cells from the donor are capable of producing the enzyme/protein that is not functioning in the patient’s own cells. 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. However, allogeneic hematopoietic stem cell transplantation for cerebral ALD presents some challenges:

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 hematopoietic stem cell transplantation in the setting of donor-derived engraftment. However, the time required for a successful donor-derived hematopoietic stem cell transplantation to effectively halt the progression of cerebral ALD demyelination is measured in months, often 6 to 12.

Historical overview of the experience with allogeneic hematopoietic stem cell transplantation in the treatment of cerebral ALD

1982: First bone marrow transplant for childhood cerebral ALD is performed in a boy with advanced (i.e., very late) stage disease. The patient died 141 days after the transplant due to disease progression despite successful engraftment (the donor hematopoietic stem cells traveled to the bone marrow and successfully started producing blood cells) (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: Shapiro and colleagues described long-term results (i.e., 5-10 years) of allogeneic hematopoietic stem cell transplantation in 12 boys with cerebral ALD, showing prospects for achieving stability in demyelination and changes in neuropsychologic function (Shapiro et al., 2000).

2004: The international hematopoietic stem cell transplantation experience from 1982 to 1999 for childhood and adolescent cerebral ALD was compiled through a consortium of 43 hematopoietic stem cell transplantation centers (Peters et al., 2004). This was the first comprehensive report of the worldwide experience with HSCT for this disease and described the results of 126 patients.

2007: Mahmood and colleagues analyzed the likelihood of survival in boys with cerebral ALD who had not received hematopoietic stem cell transplantation (Mahmood et al., 2007). In a subgroup of these patients with early cerebral disease, they compared survival in those boys who underwent hematopoietic stem cell transplantation with those boys who did not. The 5-year survival probability of the non-transplanted group was significantly poorer than the 5-year survival of 95% in the transplanted group with early stage cerebral disease. The authors concluded that hematopoietic stem cell transplantation in the early and progressive stages of childhood cerebral ALD is beneficial. They recommended that hematopoietic stem cell transplantation should be offered to boys in the early stages of cerebral disease.

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

2015: Van Geel and colleagues investigated if patients with adrenoleukodystrophy that underwent hematopoietic stem cell transplantation for cerebral ALD in childhood would still develop the adult-onset spinal cord disease (adrenomyeloneuropathy, AMN) in adulthood. This retrospective observational study found that three out of the five patients who underwent hematopoietic stem cell transplantation in childhood developed signs of myelopathy in adulthood. These data suggest that hematopoietic stem cell transplantation 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).

Experience with allogeneic hematopoietic stem cell transplantation for cerebral ALD and lessons learned

An important issue with respect to the future of therapy for cerebral ALD and specifically hematopoietic stem cell transplantation 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) with hematopoietic stem cell transplantation 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 hematopoietic stem cell transplantation 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.

The generally excellent to outstanding survival and functional outcomes observed after hematopoietic stem cell transplantation in boys with early stage cerebral disease (i.e., MRI severity score <9 and particularly ≤3) laid the foundation to implement newborn screening for adrenoleukodystrophy (see Newborn Screening). Furthermore, it would be highly beneficial and of extreme importance to identify marker(s) that predict which boys with adrenoleukodystrophy are destined to develop cerebral ALD and therefore will require hematopoietic stem cell transplantation.

It is important to note that currently there is no indication for use of hematopoietic stem cell transplantation in adult male or female patients with the spinal cord form, either with or without symptoms.

While significant advances have been made in reducing the risks associated with hematopoietic stem cell transplantation 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 hematopoietic stem cell transplantation may be considered in selected cases (e.g., unavailability of a suitably matched donor of blood stem cells).

Last modified | 2019-06-07