Severe aplastic anemia is a rare condition in which the bone marrow produces too few red blood cells, white blood cell and platelets, putting you at increased risk of bleeding, infection and at risk for circulatory system collapse as oxygen stops being delivered to the cells. Matched sibling donor stem cell transplants are a potentially curative option for children with the potentially fatal condition and, while other treatments are available, the risk of treatment failure, clonal evolution and lack available well-matched donors may limit long term outcomes for children with severe aplastic anemia.
Catherine McGuinn, M.D., a pediatric hematologist-oncologist at NewYork-Presbyterian and Weill Cornell Medicine, was part of a group of experts that recently developed recommendations for the treatment of newly diagnosed severe aplastic anemia in children, drawing on available literature and expert consensus. The graded recommendations and a treatment algorithm were published in Pediatric Blood & Cancer.
Right now, transplant with an unrelated donor is not a universally accepted standard of care first-line option but as we get better at matching donors and decrease the morbidity associated with the transplant, it could move up.
— Dr. Catherine McGuinn
Below, Dr. McGuinn discusses the specific recommendations and the need to generate more evidence that specifically relates to the treatment of children with severe aplastic anemia.
Matched unrelated donor stem cell transplants are not currently a universal frontline treatment recommendation for severe aplastic anemia in children, but they could become a preferred option as donor matching, conditioning regimens and supportive care for transplant patients improves outcomes.
Weighing the Evidence
Severe aplastic anemia which is an immune mediated destruction of stem cell that results in bone marrow failure and low blood counts. Acquired Aplastic Anemia has multiple causes, from past infections to medications to toxic exposures and should be differentiated from underlying genetic predisposition, such as an inherited bone marrow failure syndrome for example dyskeratosis congenita or Fanconi Anemia. The challenge is that while we think this is an immune mediated process, there is not just one type of immune cell or pathway that we can target for effective treatment. Additionally there are not things we can measure that can predict how a patient will respond and how much therapy a patient will need. Instead, we have matched sibling donor stem cell transplants as a highly effective potentially curative option and then evolving evidence on what to do if a matched donor is not available.
I was one of a group of experts – pediatric hematologists, hematopoietic stem cell transplanters, and hematopathologists – who are part of working group of the North American Pediatric Aplastic Anemia Consortium (NAPAAC) that reviewed the latest available evidence for the management of the condition. We aimed to publish new guidelines and a treatment algorithm for children with severe aplastic anemia.
Treatment Options
For newly diagnosed patients without a matched sibling donor, the best current evidence supports immunosuppressive therapy with horse anti-thymocyte globulin (ATG) in combination with cyclosporine. For some patients, that is enough to be able to see an improvement in the cellularity of their bone marrow and for them to become transfusion independent. But others don’t respond well or initially respond and then lose their response as we taper off the cyclosporine and need to undergo a bone marrow transplant with a matched unrelated donor.
Right now, transplant with an unrelated donor is not a universally accepted standard of care first-line option. However, as we get better at matching donors, decreasing the toxicity of conditioning regimens, improving therapies for Graft Versus Host Disease (GVHD) and decreasing the morbidity associated with the transplant, it could move up. That’s an unanswered question in the field right now but one that clinical trials are addressing. My colleague, Monica Bhatia, M.D., director of the Pediatric Stem Cell Transplant Program at NewYork-Presbyterian and Columbia, is part of a randomized clinical trial called TransIT that is comparing immunosuppressive therapy and matched unrelated donor transplant in children and adolescents with severe aplastic anemia.
One of the challenges is that we’re getting trial data from adults that might not be relevant for pediatric patients.
— Dr. Catherine McGuinn
More Clinical Trials Needed
There are not enough clinical trials today to provide the data we need to answer critical questions about treating children with severe aplastic anemia. One of the additional challenges is that we’re getting trial data from adults that might not be relevant for pediatric patients. For instance, the addition of eltrombopag, a thrombopoietin receptor agonist, to immunosuppressive therapy has been effective for adult patients but the benefit is less clear in children. For that reason, the panel recommended against the routine addition of eltrombopag to immunosuppressive therapy in children. More studies are needed to help define a subgroup of pediatric patients who could potentially benefit from this therapy. Looking to the future, we also need more basic science research to try to pinpoint a therapeutic target that could offer new options to our patients. This data is essential to enable us to advance the treatment of severe aplastic anemia to provide the best possible outcomes for our patients.
