Patients with newly diagnosed severe aplastic anemia (sAA) are treated with drugs that suppress the immune system, antithymocyte globulin (ATG) plus cyclosporine (CsA), or an allogeneic hematopoietic stem cell transplantation (Allo-HSCT). An Allo-HSCT is a type of bone marrow transplant that uses stem cells taken from another person, known as the donor source or source of the graft. The donor can be the patient’s brother or sister. This is called a “matched sibling or related donor”. If a patient does not have a matched sibling or related donor, an unrelated individual that shares important genetic similarities with the patient can be the donor. This is called a “matched unrelated donor.”
The stem cell transplant treatment remains the only potential curative option for patients with sAA. The patient’s age and type of stem cell donor present at the time of diagnosis are important factors to consider when deciding whether or not to proceed with an Allo-HSCT at the onset of disease.
In this journal article, Dr. Mary Eapen from the Medical College of Wisconsin discusses the latest data supporting the use of Allo-HSCT in patients with sAA.
A matched sibling Allo-HSCT is the best treatment option for newly diagnosed severe AA patients who are younger than 40 years of age. This recommendation results from good clinical data showing that the risk of dying after an Allo-HSCT increases with age.
To illustrate this, a study conducted by the Center for International Blood and Marrow Transplant Research, (CIBMTR), showed that the risk of dying from a matched sibling Allo-HSCT was higher in sAA patients who were 20 years of age and older as compared to those who were younger than 20 years. Within the group of patients who were older than 20 years, those who were greater than 40 years had a higher risk of dying compared to those who were between the age of 20 and 40 years. The reasons for decreased survival in older patients may be related to higher numbers of bone marrow transplant-related complications such as acute graft versus host disease (aGVHD) and chronic GVHD which occurs more often in older patients.
Other factors that may lead to lower survival rates include lower performance of normal activities after transplant, longer time to transplant from the original time of diagnosis (more than3 months), prior exposure to immunosuppressive therapies or androgens, and the use of peripheral blood stems cells as the source of the graft rather than bone marrow stem cells.
Unrelated donor Allo-HSCT is an alternative treatment option for patients with sAA. The biggest challenge with this treatment approach is the high risk of graft failure and the limited number of available, suitable, matched unrelated donors. The selection of the donor is critical in the success of the transplant. Patients who have an 8/8 HLA match have the best chance of survival while a single mismatch at either the allele or antigen level is associated with a greater likelihood of dying from the transplant due to grade 2-4 acute GVHD. In a study involving 118 children and adolescents with aplastic anemia, transplanted between 1989-2003, using bone marrow graft from unrelated adult donors, the risk of dying was lower with HLA-matched transplants as compared to mismatched transplants.
Umbilical cord blood (UCB) can also be used as a source of stem cells in patients who do not have a suitable matched, adult, unrelated donor. Some clinical data taken from the Eurocord and the Japan Cord Blood Bank Network suggest survival probabilities of about 40%. The results are not as positive as those seen with matched sibling and matched unrelated donor transplants. This is due to HLA matching disparities, the need for a large number of UCB cell dose, and the fact that most patients have been previously treated and failed multiple courses of immunosuppressive therapies.
To maximize the success of the transplant, physicians will administer drugs that will help prepare the patient’s bone marrow to receive the transplant. This is called “the conditioning regimen”. In aplastic anemia, the type of conditioning regimen given will depend on the type of donor to be used. Patients with sAA who have a matched sibling donor will receive cyclophosphamide (CTX) and ATG. For patients who have a matched unrelated donor, the preparation is more difficult because of higher rates of graft failure, the toxicity of the regimen needed, and the possibility of GVHD, (even with an 8/8 HLA-matched donor). Traditionally higher doses of total body irradiation (TBI) have been used to prevent graft failure. However, this treatment was associated with a higher number of acute toxicities as well as future secondary cancers. Currently, a lower radiation dose combined with CTX and ATG is being administered which has resulted in low rates of graft failure (5%), and a good 5 year survival of 55%.