Frontline Eltrombopag for Severe Aplastic Anemia - Episode 1

Frontline Shift for Severe Aplastic Anemia After Eltrombopag FDA Approval


Phillip Scheinberg, MD: Eltrombopag was recently approved in the frontline for severe aplastic anemia in combination with immunosuppressive therapy. So what’s important to delineate here is that historically, immunosuppressive therapies have been developed to treat severe aplastic anemia when transplant was not an option. So it’s an alternative to stem cell transplantation with equal rates of long-term survival.

Immunosuppressive therapy in the form of horse ATG [antithymocyte globulin] cyclosporine has been the most well-studied regimen in Europe, Asia, and the United States for decades. Now, several attempts have been made to improve outcomes of horse ATG, including adding more immunosuppression like mycophenolate, sirolimus, rabbit ATG, alemtuzumab, and cyclophosphamide. Many of these therapies actually worked in the sense that they never improved their response rate or their survival.

In 2010, there was a trial that was developed to add eltrombopag to immunosuppressive therapy, which started in 2012 asking the question “Could a growth factor that was shown to be active in aplastic anemia earlier in refractory patients have activity in the up-front setting?” That is, in combination with a standard horse ATG cyclosporine regimen. That was a study that was conducted from 2012 to 2017. It was published in the New England Journal of Medicine in 2017, showing remarkable rates of overall response rate, in the order of 90%, 95%, and complete response rates in the order of 40% to 50%. And in some patients, actually, the response rate complete was up to 50% to 60%. So these are [unheard-of] numbers with immunosuppression alone. So this is what prompted the enthusiasm for this regimen: decreasing the pool of patients who were refractory to initial immunosuppressive therapy.

Historically, the response rate for immunosuppressive therapy is in the order of 60% to 70% and complete, like 10%. So having people 40% to 50% responding complete response actually looks like you’re really changing the natural history of the disease. And this is what was submitted to the FDA last year and this year, and this is what led to the approval of the combination of eltrombopag to standard horse ATG cyclosporine in frontline treatment for severe aplastic anemia.

So the standard regimen of severe aplastic anemia in terms of immunosuppressive therapy is ATG plus cyclosporine. Now, in the United States and some parts of the world, the preferred treatment is with horse ATG cyclosporine because it gives better results compared with all the other therapies like rabbit ATG cyclosporine. Now, rabbit ATG cyclosporine is given in many parts of the world because horse ATG is not available. The frontline regimen involves a combination of ATG plus cyclosporine, preferably horse ATG cyclosporine, which is the regimen that has been associated with higher overall response rates and long-term survival. In fact, there have been studies comparing horse versus rabbit ATG, and results from most prospective studies show that there is a benefit toward the horse ATG regimen, which is interestingly a less potent immunosuppressant regimen, which was unexpected given that more potent regimens were investigated, but they did not yield better results, so the standard is horse ATG cyclosporine.

Now, what’s probably going to change with the approval of eltrombopag is that given the higher overall response rates and complete response rates—and decreasing that pool of patients who actually are refractory to frontline therapy—I anticipate that most will end up incorporating eltrombopag to horse ATG cyclosporine like it was in the application for the FDA and the recent approval. So before it was just IST, or immunosuppressive therapy. I suspect that now with this data, the combination will be commonly applied.

Transcript Edited for Clarity