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, also called bone marrow transplantation) is a medical procedure used to treat patients with (blood) cancers or certain types of severe genetic diseases (such as ALD). In this procedure, a patient receives healthy stem cells from a donor. The procedure consists 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 (such as heart 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. It also gives rise to all immune cells. Hematopoietic stem cells are found primarily in the bone marrow, a spongy tissue found inside the large bones of the body, but a small number of these cells can also be found in the blood.
Before the collection of hematopoietic stem cells, the donor is given a drug that increases the release of hematopoietic stem cells from the bone marrow into 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 HSCT: allogeneic and autologous.

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

In this allogeneic setting, measures must be taken to minimize or eliminate a potentially fatal complication in which donor-derived immune cells attack the cells and tissues of the recipient. This reaction is known as 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 autologous hematopoietic stem cell transplantation, the patient’s own hematopoietic stem cells are harvested prior to conditioning and transplanted back into the patient after correction, for example by gene therapy.

How does hematopoietic stem cell transplantation work?

Transplanted donor hematopoietic stem cells travel to the bone marrow where they settle and begin to make blood cells. Over a period of several weeks to months, the stem cells engraft and have produced enough cells to replenish the patient’s “depleted” blood-producing system. However, the immune system takes a long time to recover, and during this time the transplanted patient is at risk for developing a variety of potentially life-threatening “opportunistic” infections.

Over the past four decades, hematopoietic stem cell transplantation has been successfully used to treat a wide variety of diseases, including leukemia, lymphoma, malignant solid tumors, aplastic anemia and bone marrow failure, immune deficiency disorders, hemoglobinopathies such as sickle cell anemia and thalassemia, and genetic disorders such as lysosomal storage disorders and various leukodystrophies such as ALD.

How does hematopoietic stem cell transplantation work to treat cerebral ALD?

For genetic disorders, allogeneic hematopoietic stem cell transplantation is a form of “adoptive” gene therapy. The donor’s cells 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 immune-mediated myelin destruction may be the reason for its efficacy. However, allogeneic hematopoietic stem cell transplantation for cerebral ALD presents several challenges:

It should be noted that the gadolinium enhancement seen 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 after hematopoietic stem cell transplantation in the setting of donor-derived engraftment. However, the time required for successful donor-derived hematopoietic stem cell transplantation to effectively halt the progression of cerebral demyelination in ALD is measured in months, often 6 to 12 months.

Historical review of the experience with allogeneic HSCT 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 migrated to the bone marrow and successfully began producing blood cells) (Moser et al., 1984).

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

2000: Shapiro and colleagues describe 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 neuropsychological function (Shapiro et al., 2000).

2004: The international experience with HSCT for childhood and adolescent cerebral ALD from 1982 to 1999  was compiled by 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 the outcomes 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 boys who received hematopoietic stem cell transplantation with those who did not. The 5-year survival of the non-transplanted group was significantly worse than the 5-year survival of 95% of the transplanted group with early stage cerebral disease. The authors concluded that hematopoietic stem cell transplantation is beneficial in the early and progressive stages of childhood cerebral ALD. They recommended that HSCT should be offered to boys in the early stages of cerebral disease.

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

2015: Van Geel and colleagues investigated whether patients with adrenoleukodystrophy who underwent hematopoietic stem cell transplantation for cerebral ALD in childhood would still develop adult-onset spinal cord disease (adrenomyeloneuropathy, AMN) in adulthood. This retrospective observational study found that three 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 need to be confirmed in independent studies. However, if true, this will have implications for the follow-up of patients transplanted in childhood who 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 regarding the future of therapy for cerebral ALD, and specifically hematopoietic stem cell transplantation, is the challenge of treating boys with advanced-stage disease. 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) further explore the use of N-acetyl cysteine; (3) evaluate the use of reduced intensity conditioning regimens for hematopoietic stem cell transplantation; (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 inflammatory demyelination, repair damaged myelin, and restore lost function.

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 especially ≤3) laid the foundation for the implementation of newborn screening for adrenoleukodystrophy (see Newborn Screening). In addition, it would be extremely beneficial and important to identify marker(s) that predict which boys with adrenoleukodystrophy are destined to develop cerebral ALD and therefore require hematopoietic stem cell transplantation.

While significant progress has been made in reducing the risks associated with hematopoietic stem cell transplantation, particularly from unrelated donors of bone marrow or umbilical cord blood, there is still a significant risk of transplant-related mortality as well as death from disease progression. With advances 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 matched blood stem cell donor).

Last modified | 2024-06-24