Expert Highlights Current State of Severe Aplastic Anemia

Carlos Manuel de Castro III, MD

Eltrombopag (Promacta) has emerged as an effective addition to the treatment repertoire of severe aplastic anemia (SAA); however, obstacles still exist in terms of diagnosis and the subsequent risk of clonal disease, said Carlos Manuel de Castro III, MD.

Traditionally, the treatment of these patients required a decision between bone marrow transplant and immunosuppressive therapy. After showing promise in the relapsed/refractory setting, eltrombopag in combination with anti-thymocyte globulin (ATG) and cyclosporine is now the upfront standard of care, added de Castro, a professor of medicine at Duke University School of Medicine.

In November 2018, the FDA approved eltrombopag in combination with standard immunosuppressive therapy to include newly diagnosed adult and pediatric patients aged 2 years and older with SAA. This upfront approval is the most recent indication for the oral thrombopoietin receptor agonist, which was previously approved for patients with SAA who had an insufficient response to standard therapy.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, de Castro highlighted current treatment approaches for SAA and some of the unmet needs that still exist.

OncLive: Could you discuss the current treatment paradigm of SAA?

De Castro: SAA is one of the things that causes bone marrow failure. Patients present with cytopenias, which can be life-threatening in the severe cases. Traditionally, this has been thought of being related to an immune disorder where the T cells are attacking the bone marrow and depleting the stem cells. The current therapies involve a decision of whether the patient should undergo immunosuppressive therapy designed to fight those T cells or whether they should undergo bone marrow transplant. That is based on a lot of factors, including age, comorbidities, and whether there is a match available. The newer therapy that we've added to immunosuppressive therapy is eltrombopag.

What makes a patient eligible or ineligible for bone marrow transplant?

In general, the decision of whether or not to go on with a bone marrow transplant is based primarily on age, in part because immunosuppressive therapy is so effective. We don't want to take the risk of bone marrow transplant unless it is needed. The reason age plays a factor is that there is a risk of developing a clonal disease, either myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). If you take a young patient with a long life ahead of them, obviously that risk goes up with time. A transplant takes care of that risk, whereas immunosuppressive therapy does not.

What challenges still exist with immunosuppressive therapy?

With immunosuppressive therapy, [the biggest challenge] is still the risk of relapse, which we see in about 10% to 20% of patients. The risk, again, of developing a clonal disorder like leukemia is seen in about 10% of patients.

What data led to the FDA approval of eltrombopag?

Eltrombopag was first studied by our colleagues at the National Institute of Health. They used the drug first in patients with relapsed/refractory aplastic anemia who were not candidates for transplant and needed an effective treatment. Eltrombopag is a thrombopoietin receptor agonist. In the small patient population that was initially treated, they found that eltrombopag not only stimulated platelet recovery, but also seemed to improve other side effects like cytopenia and neutropenia. When they looked at the bone marrow of these patients, they saw recovery of cellularity there, suggesting that it was stimulating an earlier cell and had some response rate there.

[Researchers] then went on and asked "Hey, if it works so well in the refractory setting, should we try it upfront?" Therefore, they added eltrombopag in with ATG and cyclosporine. Compared with historical responses, the response rates seemed to get better, as did the complete response rates. That led to the eventual FDA approval.

What are some diagnostic challenges with these patients?

The biggest diagnostic challenge we have is distinguishing aplastic anemia from what we call hypocellular MDS, which is a true clonal disorder. We are finding that similar mutations exist in both disorders, so we still have this diagnostic dilemma of who has MDS and who has SAA. The problem is that when you take a bone marrow sample, you are looking at patients with very low cellularity. There aren't enough cells to say if there is dysplasia there or if it is just aplastic anemia. There are certainly cases where a patient has been [not received proper treatment because of this]. It has led to the knowledge that even patients with MDS can respond to immunosuppressive therapy in some cases. It has been used not too uncommonly in patients with hypocellular MDS, with reasonable success rates and transfusion independence.

What ongoing trials are you particularly excited about?

Right now, there isn't a whole lot going on in the aplastic anemia world. We're all looking to understand what the mutations mean and which patients harbor them. Is there a risk for developing MDS or AML [because of these mutations?] That is where we stand right now. These are the common mutations we see with MDS, so anything from BCOR to ASXL1.

We're also finding these in patients with aplastic anemia, which has led us to basically ask, “What does this means?” There is a depletion of stem cells, and as those stem cells have to divide more and more, there is a higher chance of them getting mutations. That's where the inherent risk of developing clonal disease lies. Whether these mutations exist before the aplastic anemia comes around is still unclear, and we are working on that.