Frontline Eltrombopag for Severe Aplastic Anemia - Episode 5

Eltrombopag Trial and Treatment Discontinuation


Phillip Scheinberg, MD: That was a single-arm trial. The trial that led to the approval of eltrombopag in frontline aplastic anemia, alongside immunosuppressive therapy, was a single-arm trial that separated. There were 92 patients, with roughly 30 patients in each cohort. And the first cohort used eltrombopag starting on day 14 and gave eltrombopag for a total of 6 months alongside a horse ATG [antithymocyte globulin] cyclosporine. Now, the reason for this 2-week gap was that there was a concern that there could be toxicity by giving horse ATG cyclosporine and eltrombopag at the same time, especially liver toxicity. So there was this 2-week delay.

The association with eltrombopag and these regimens actually turned out to be pretty safe and tolerable. So for the next 30 patients, eltrombopag was continued starting on day 14, but the course was abbreviated to 3 months to try to decrease drug exposure and potential complications from that continued drug exposure. Some patients lost the response between 3 and 6 months. So for the last cohort, the eltrombopag duration was extended to 6 months, and because the concerns of toxicity between eltrombopag and the other agents minimized, it was then started on day 1. So now you’re having 150 mg starting on day 1 and giving it for 6 months. That group appeared to be the most auspicious group in terms of overall response rate, of about 90%, and complete, of 58%.

This led to the submission for approval, given that in about 100 patients, the overall in total response rate and complete was higher than anything we have seen in the past. So the long-term results of relapse and clonal evolution, which is a complication that’s been followed, are being gathered as we speak. But so far, there hasn’t been a safety signal regarding these late events. So this is a trial actually that was designed for and led to the approval of eltrombopag in association with horse ATG cyclosporine in the front line.

This continuation of eltrombopag is actually a very important question. We notice that some patients in the refractory protocol…actually were able to be taken off eltrombopag. This observation started out somewhat serendipitously in a patient who had to stop the drug for a reason, and his counts never dropped and kept going up and up and up off therapy, which raised the possibility that, wow, maybe patients don’t need to be on this therapy forever. Maybe we can try to stop it. So some criteria of robustness of response were developed based on hemoglobin greater than 10, neutrophil greater than 1000, and platelet count greater than 50 to see whether patients who achieve that level of response could then be tapered off very quickly. And indeed, many patients were able to tolerate discontinuation, meaning that they were tapered to off and their counts maybe fluctuated for a bit but didn’t drop significantly. And they were able to maintain hematopoiesis and blood counts on their own without the need for continued chronic oral therapy.

Now, some patients have actually shown relapse but responded again, the majority, to resumption to eltrombopag. So in the refractory experience, that has shown to be the case. Now, what’s even more interesting is that when you give eltrombopag from day 1 at 150 mg instead of doing a dose escalation as was done in the first pivotal trial of dose increments of 50 mg, 75 mg, 100 mg, 125 mg, 150 mg every 2 weeks, there was a follow-up cohort that just started 150 mg on day 1—for full-refractory patients—and gave it for 6 months. So the response rate overall there was about 49%. Some patients responded between 3 and 6, indicating that giving another 3 months, from 3 to 6, is actually beneficial for some patients, kind of establishing the duration of eltrombopag in the refractory setting.

But what’s even more interesting is that of the 19 responders of this 39-patient cohort, 18 had robust response. And of these 18, 13 tolerated discontinuation of eltrombopag without having to go back on it. And of the patients who relapsed, they responded going back on eltrombopag. So that’s about 70% of patients actually who had a robust response who were able to go off therapy. It’s real. It’s real, and it’s obviously beneficial to patients not having to be on chronic treatment.

Transcript Edited for Clarity