ASH 2015

Exciting new immunosuppressive therapy treatment for aplastic anaemia

Dr Danielle Townsley - George Washington University School of Medicine, Washington, USA

You’re looking at this drug called eltrombopag and you’re adding it, you’ve been adding it, to standard immunosuppression for this very difficult condition, aplastic anaemia. Can you tell me what was the big thing that you were trying to focus on here? Why were you using this new approach?

Essentially the reason that we used eltrombopag is because we noted at the NIH in earlier trials which we had used the drug as a single agent for patients with refractory severe aplastic anaemia. These are patients who had failed multiple rounds of therapy with immunosuppression and remain transfusion dependent. We treated them with eltrombopag as a single agent and got very surprising results – basically 40% of those patients responded with blood count recovery and not just the platelets but the white cells and the red cells. That was a very ground-breaking result to find and it was really logical at that point to consider using eltrombopag for new onset severe aplastic anaemia in combination with the standard treatment for severe aplastic anaemia which is ATG and cyclosporine.

The normal approach, the normal use of eltrombopag would be what? In which situations?

The drug was actually developed to treat immune thrombocytopenia, ITP, and the drug was noted to have the ability to stimulate the production of platelets. It’s a thrombopoietin receptor agonist and that was really what it was designed for. It was FDA approved for the treatment of ITP originally so it was actually very surprising to learn that the drug was capable of not only improving platelet counts but red cells and white cell counts. We think that this is because the thrombopoietin receptors are also on stem cells and hematopoietic stem progenitors.

So it has a broad action which some people might not have been expecting.

No, nobody was really expecting that per se. But in hindsight it is quite logical that maybe that would occur.

Lots of things are logical in hindsight but nevertheless very remarkable. So you decided to use it in aplastic anaemia, what actually triggered your decision to try it?

Really it was based upon the surprising results in refractory severe aplastic anaemia and we really were only trying it in that setting in the hopes that maybe patients would improve their platelet count and come off platelet transfusions.

Right, so you’re trying to boost the platelets and you wave… you found you were getting another benefit as well?

Yes, and then additionally the idea was that the drug might actually be more helpful early on in disease, the idea being that maybe eltrombopag was capable of actually expanding the stem cell pool in patients early on. If you can expand the stem cell pool in these patients, the haematopoietic stem cell pool, you might actually boost response rates, boost count recovery and prevent clonal progression.

That’s what might be, what did you do and what did you find?

What we did is we actually are presenting data of 92 patients, which is actually a very large study for a very rare disease. What we did is we gave all of these patients standard immunosuppression with horse ATG for four days, cyclosporine for six months and then we added in three consecutively enrolling cohorts, consecutive and sequentially enrolling cohorts, we added eltrombopag. In the first cohort we gave it for about six months but starting at day 14 after ATG was delivered; in the second cohort we gave it for an abbreviated period for three months and the third cohort we gave it immediately on day 1 out to six months. What we found was overall the response rate was around 86% overall and this compares quite favourably, more than 20% higher, compared to ATG and cyclosporine alone in our historic trials. Then our complete response rate was around 37% and what we noticed was in the most recent cohort, cohort 3, where eltrombopag is actually delivered on day 1 the overall response rate is 95% and the complete response rate is 60%.

What about the potential impact on overall survival?

We will have to see but right now the current survival on the study is 99%; we’ve had one death only in these 92 patients that are enrolled. Obviously a longer follow-up period is going to be required to really fully assess that but this is already a very good result.

What should doctors be thinking about changing in their approach to aplastic anaemia in the light of what you’ve now discovered?

We will have to see. I think it’s going to be difficult to not consider using this drug in some way but it’s really going to be up to the FDA to decide whether or not the data as it is, or soon to be, should make this part of the relabelling for the drug and part of the standard. It will really be up to the FDA to decide that.

Would you use it off-label?

I can’t say, I can’t really attest to that because, to be honest, at the NIH we don’t do anything other than clinical trials.

So what’s the bottom line message for doctors to take note of right now then, do you think?

So one of the things that we’re going to be aggressively doing is making sure that patients get evaluated quickly and treated quickly and for us, moving forward at the NIH, what we’ll be doing is doing more thorough genomics screening from both germline mutations for somatically acquired mutations that are seen in MDS AML. For us, moving forward, we think it’s really characterising quickly the genomic architecture of these patients moving forward is going to be very, very important to determine their risk.