Frontline Eltrombopag for Severe Aplastic Anemia - Episode 2

Treatment Plan Criteria and Second-Line Options


Phillip Scheinberg, MD: The issue of what to choose for the patient who’s coming to see you, as a physician, with this diagnosis is an important and interesting one for the following reasons. Historically, age has been the discriminator for what we offer patients. So if you’re 40 years of age or younger and you have a histocompatible sibling donor, stem cell transplantation should be offered up front. Now, most people will not have a matched sibling donor. It’s only a 1-in-4 chance per sibling. The majority of people in the world don’t have an HLA [human leukocyte antigen]—matched sibling donor, so immunosuppressive therapy is for those patients who either are over the age of 40 or don’t have a matched sibling donor, which ends up being most patients with a diagnosis of this disease.

Now, we have done a lot of work and a lot of laboratories have added enormous amounts of contributions with the understanding of the biology of severe aplastic anemia in terms of genes, telomeres, and other risk factors. But they have not been consistently linked to outcomes across studies, especially the genomics data. It’s not that predictive in terms of outcomes. So they have not been incorporated into treatment algorithms, so today we’re still using just age and the availability of a donor in order to make those decisions. We’re hoping that in coming years, more information will be added to this decision making, but as of now, this is the current paradigm. This is what we’re doing in 2018.

In the refractory patients, not everybody responds to immunosuppressive therapy, so 60% to 70% of patients respond. That gives about 30% to 40% of patients who will not respond. Now, at 6 months you may end up having a situation where somebody has not responded, meaning that their counts have not improved; they’re still low. They still meet criteria for severe aplastic anemia, and they’re likely getting transfusions still. So these are unresponsive patients. Now, the options for these patients are actually very, very broad. There’s no randomized trial comparing all these treatment modalities, but you do have lots of options. If somebody is younger and they do have a matched unrelated donor, that will be an option to go to transplant—or if somebody is 20, 22, and they don’t have a matched sibling but they had a matched unrelated donor—so it’s important to look for these unrelated donors at the time you’re treating some of these younger patients with immunosuppressive therapy in case at 6 months, they turn out not to be responsive. So that might be an option.

Historically, we also had repeated immunosuppression, meaning that we gave a second round of immunosuppression. So if somebody got a horse ATG [antithymocyte globulin]—we have treated several patients with rabbit ATG as a second course, or alemtuzumab, or even repeating the same horse ATG—responses are variable. They’re between 30% and 40%. So a third of patients actually can respond a second time around if they had not responded the first time with similar immunosuppressive agents like a second course of therapy. Now, why do some patients respond the second time around and don’t respond the first time? It’s not entirely clear, but some of these responses the second time can be very robust. Patients go on to normal counts, transfusion independence, and go well for a long, long time. So this is something that has been done.

Continuing patients on cyclosporine is of limited benefit. It’s not something that we think is actually helpful, and it may add to toxicity long term. Androgens are interesting because androgens historically have been used in aplastic anemia, for not only aplastic anemia but also many diseases. In unselected patients, we don’t know the efficacy of androgens. We think it’s about a third, but we don’t know. Now, in patients with telomeropathy or telomerase gene mutations, or some disorder in the telomere system, we published 2 years ago that androgens can actually be quite effective. About 70% to 80% of patients have shown response to androgens in that setting.

Now, growth factor support, we think, is also of limited benefit. But what has come along in the last 7 years is eltrombopag, which was used initially for refractory patients, just as in the scenario that I just showed you, a 22-year-old who got ATG cyclosporine did not respond, doesn’t have a donor. Eltrombopag was investigated in that setting. About 40% to 50% of patients responded to a single-agent oral outpatient regimen like an eltrombopag. And some of the responses were multilineage, meaning that the hemoglobin went up and neutrophil counts went up, even though the study was designed to have the platelet count go up. That showed that we were probably stimulating some very primitive stem cell compartment by giving this agent, thrombopoietin receptor agonist.

Transcript Edited for Clarity