Frontline Eltrombopag for Severe Aplastic Anemia - Episode 3
Phillip Scheinberg, MD: In the relapse setting, we think that some of the autoimmunity that was involved in causing the disease in the first place actually is acting up again in the sense that it started. We control this autoimmune attack with the first round of immunosuppression. It gets controlled for a while, and eventually the autoreactive T cells do come back. So the rationale is, if they responded the first time around, we would then repeat that course of immunosuppression to again address the issue of autoreactive T cells attacking the bone marrow. And about 50% to 60% of patients do respond when you do repeat immunosuppression in the relapsed setting.
For the treatment resistance/refractoriness scenario, we have some hypotheses. When you do research, you have to think about possibilities, and the hypotheses that we think are plausible, and this is what actually formed the basis for developing large programs in terms of clinical protocols, were basically 2 things. One was that we were probably not addressing the immune pathophysiology of the autoimmunity. The disease caused idiopathic acquired aplastic anemia by an autoimmune insult to the bone marrow with several dysregulations of T cells and cytokines and proteins attacking the stem cells. When somebody did not respond, we thought that we were not getting rid of this autoimmune T-cell population in a sufficient way that eliminated them and allowed the bone marrow to recover.
So that’s why several protocols were designed with that in mind, to increase immunosuppression, giving more drugs, adding third drugs, like sirolimus and mycophenolate, or giving more potent drugs like alemtuzumab. But that didn’t pan out, so we started thinking that maybe there’s a different possibility, that maybe it’s not the autoimmunity that we haven’t controlled, but maybe there are just not enough stem cells, or stem cell reserve, for that patient to recover from, even after we control the autoimmune attack. Because, again, horse ATG [antithymocyte globulin], which is the best regimen, is really not that immunosuppressive. It’s not that potent of an immunosuppressant. So we moved gears and thought about stimulating the bone marrow.
Now, historically, giving drugs to stimulate the bone marrow was negative in aplastic anemia, so there was some hesitancy in terms of a TPO agonist, or a thrombopoietin receptor agonist, like eltrombopag to be effective. But it was very effective as a single agent in refractory patients, which gives some credence to the notion that by stimulating the bone marrow with a thrombopoietin receptor agonist, we can improve marrow function and counts can get better. Now, keep in mind that eltrombopag can also have some immunomodulatory effect, so there might be other mechanisms that are in play here helping the bone marrow to work in a healthier fashion.
Transcript Edited for Clarity