Hematopoietic Stem Cell Transplantation in Aplastic Anemia | Aplastic Anemia & MDS International Foundation Return to top.

Hematopoietic Stem Cell Transplantation in Aplastic Anemia

How do you currently think about the role of stem cell transplantation in aplastic anemia?

This is an exciting time for advances in stem cell transplantation, with marked improvements in outcomes for unrelated donor transplants. When considering treatments for newly diagnosed aplastic anemia, we explain to patients the short- term and long-term risks and benefits of the different treatment alternatives. For young patients, the risks of matched sibling donor transplantation are low and outcomes are excellent. Stem cell transplant is the only curative therapy for aplastic anemia, so if there is a matched sibling donor, that is the treatment of choice for young patients. This has low upfront and long-term risks for young people, so the pediatric and young adult populations are the best candidates.  

For young patients lacking an HLA-matched sibling donor, immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine has been considered the first-line therapy. Up to 80% of patients become transfusion-independent and attain adequate neutrophil counts, and a smaller number of patients attain normal blood counts. Limitations of IST have included refractory disease, relapse and long-term risk of developing myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).  Many patients treated with immunosuppressive therapy do not need transfusions, but continue to have low blood counts that impair their quality of life.

Recently, the outcomes of unrelated donor transplantation have markedly improved. Previously, there was a high risk of adverse outcomes with unrelated donor transplants. The preference was to use immunosuppressive therapy (IST) because the upfront risks were low. In the past, when unrelated donor transplantation was much riskier, it was only resorted to as a third-line therapy, depending on the status of the patient.

Now we have retrospective data from Europe, and from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), a non-randomized prospective study in patients failing immune suppression undergoing unrelated donor bone marrow transplantation (BMT). This shows equivalent survival rates in young patients with unrelated donor transplant compared to matched sibling transplants. There appeared to be a long-term benefit when comparing unrelated donor transplant to immunosuppressive therapy. However, it is important to keep in mind that these studies were non-randomized, small and with a limited duration of follow-up. An important aspect of these studies was that in addition to excellent survival, the risk of events such as relapse, refractory disease, or clonal progression that we see with IST, was not seen after transplantation.

For the pediatric population, where we expect many years of life post-treatment, these long term issues are critical to consider. Although we do not have long-term data specific to transplantation for aplastic anemia on these regimens, these agents have been used for transplants at these types of dosages for many years with lots of long-term data. Overall, in discussion with my transplant colleagues, concerns of long-term effects are low, but still need to be studied carefully.

Should IST be tried first?

It could be asked what the potential downside is for trying IST first before going to transplant and resorting to unrelated donor transplant only if there is failure, relapse, or poor response to IST. After all, unrelated donor transplants are still associated with risks such as engraftment failure and graft versus host disease (GVHD).

However, potential transplant risks may increase with delayed time to transplant, which is especially true with refractory disease. With prolonged neutropenia, the risk of infection, particularly fungal infections, increases transplant risk. With multiple transfusions, the risk of failure of engraftment may increase when a stem cell transplant is finally performed. Iron overload from frequent red cell transfusions over a long term can increase transplant risk. We have observed that the rate of iron overload can be surprisingly rapid in some aplastic anemia patients with refractory disease.

Also, remember that if aplastic anemia develops into MDS or AML, then outcomes aren’t as good. The survival is lower due to increased treatment-related toxicities as these conditions have to be treated more aggressively – especially for AML. Even for MDS, you can’t use the standard conditioning regimen that would be used for aplastic anemia. You now have to give more intensive therapy to eliminate pre-malignant clones, which is associated with higher toxicity. With MDS and AML, you now have to also deal with the risk of relapse of the malignant cells. Relapsed MDS or AML is much more challenging to cure. It all just becomes more complicated.

We currently need more data to inform the role of unrelated donor transplant as upfront therapy for young patients lacking a matched sibling donor. Based on this, the North American Pediatric Aplastic Anemia Consortium (NAPAAC) in collaboration with the Pediatric Blood and Marrow Transplant Consortium (PBMTC) has begun a randomized, prospective analysis of IST versus matched unrelated donor transplants in pediatric aplastic anemia for patients lacking a matched sibling donor.

How does the diagnosis of a genetic bone marrow failure disease affect treatment?

A small subset of patients with aplastic anemia have a genetic cause of their disease.  The identification of a genetic cause affects decisions about the course of treatment. Patients with genetic bone marrow failure disorders generally have poor, partial, or transient responses to IST, so a transplant is the preferred treatment. However, these patients often have increased sensitivity to the standard chemotherapy and radiation regimens that are routinely used for an unrelated donor transplant. This calls for an individually tailored therapy, depending on the underlying disorder, to avoid excessive toxicity.

Does the use of eltrombopag in treating aplastic anemia affect the decision to proceed to stem cell transplantation?

Eltrombopag has been one of the most exciting recent advances in non-transplant treatment for refractory aplastic anemia. Results of the NIH trial of upfront treatment with eltrombopag plus IST are eagerly awaited. What is not known is if eltrombopag affects the risk of secondary events such as relapse and clonal progression, especially in the pediatric population. These are concerns that still need to be studied and fully evaluated because at this stage we don’t know.

Are there any other factors to mention?

For unrelated donor transplants, it takes time to identify the donor and harvest the bone marrow, so there is a delay in starting treatment. IST can be started right away.  However, responses to IST are typically not seen until 3 to 6 months of treatment, while recovery of blood counts after transplant is typically much sooner, typically within 3 to 4 weeks of initiating transplant. Whether eltrombopag might change response rates to IST remains to be determined. An important consideration when deciding between IST versus transplant is how quickly an HLA-matched donor can be found and cleared for collection. Donor availability will inform the decision as to which patients could consider an unrelated donor transplant.

So although recent data with unrelated donor transplants for young patients with aplastic anemia are very encouraging, more studies are needed to determine whether outcomes are superior to those with IST and to identify the factors that guide treatment decisions for each patient.


Akiko Shimamura, MD

Position / Title: 
Director, Bone Marrow Failure and Myelodysplastic Syndrome Program
Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Primary Disease Area of Focus: 
  • aplastic anemia
  • myelodysplastic syndromes (MDS)
  • paroxysmal nocturnal hemoglobinuria (PNH)
  • pediatric
Other Disease Area(s) of Focus: 
Shwachman Diamond syndrome, Fanconi anemia, Dyskeratosis congenita/telomere biology disorders, Diamond Blackfan anemia, GATA2 disorders, SAMD9/SAMD9L, Congenital neutropenia disorders, RUNX1, ETV6, ANKRD26

Dr. Akiko Shimamura directs the Bone Marrow Failure and Myelodysplastic Syndrome Program of the Dana Farber/Boston Children’s Cancer and Blood Disorders Center. Her research focuses on translational studies spanning clinical through basic science investigations to understand the genetic and molecular basis of bone marrow failure, MDS, and leukemia predisposition with the goal of developing more effective and less toxic treatments. Dr. Shimamura had previously directed the Bone Marrow Failure Clinic at Boston Children’s Hospital and then at Seattle Children’s Hospital before returning to Boston Children’s Hospital in the fall of 2015.

Practice Location: 
Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
300 Longwood Avenue Karp 0821
Boston , MA 02115
Physician Status: 
  • accepting new patients
Share with addtoany.com.