ASH 2014

New cytarabine combinations could overcome toxicities in AML treatment

Dr Farhad Ravandi - MD Anderson Cancer Center, Houston, USA

Relapsed acute myeloid leukaemia is a dismal situation with a very dismal prognosis. There is no standard therapy for patients with relapsed AML that is FDA approved. By default physicians use cytarabine based regimens and many of the trials that have been conducted have used high doses of cytarabine as the standard of treatment. This is why we randomised patients to receive either high dose cytarabine or cytarabine plus vosaroxin.

Can you tell me about vosaroxin? What is it and what does it do?

Vosaroxin is a new quinolone derivative; it’s a first in class anti-cancer quinolone derivative so it’s related to commonly used antibiotics, ciprofloxacin and other quniolones in terms of its structure. But it has been shown to be active, highly active, in cell lines and primary AML patient samples and has also been shown to be synergistic with cytarabine, again in preclinical studies.

And interestingly potentially less cardiotoxic?

The interesting features of the drug are that it is not a  P-glycoprotein substrate so it does not get extruded from the cells and it does not work based on the p53 mechanism. Also it has limited reproduction of reactive oxygen species which reduces its potential for cardiotoxicity. It is a topoisomerase II inhibitor and this is why it is commonly compared with anthracyclines and other topo II inhibitors and we all know that those agents are associated with significant cardiotoxicity. As such, these characteristics make the drug an interesting drug for AML and particularly relapsed AML.

And it’s a big study – over 700 patients.

711 patients randomised and two arms of the study.

The primary endpoint?

The primary endpoint was overall survival; the secondary endpoints were complete response rate as well as toxicity and event free survival, the number of patients who went on to have a transplant etc.

Now response rate is pretty crucial in a study in this category of patients. What were your results?

The complete response rate was 30.1% for the vosaroxin arm as opposed to 16.3% for the control arm which was a highly statistically significant advantage for the treatment arm.

Now, did you break that down in terms of the age of the patients?

The response rate was very equivalent in both younger and older patients, I don’t have the exact numbers.

So what did you find overall in the study?

Overall this is an effective regimen producing high response rates which does translate to an improved overall survival and is not associated with higher early toxicity and early mortality.

Now it did have an impact on allogenic transplantation, didn’t it?

There were a bigger proportion of patients who achieved CR on the vosaroxin arm and underwent an allogeneic transplant. However, overall the two arms of the study were equivalent in terms of proportion of patients who underwent allogeneic transplant. Obviously patients who were younger had a higher rate of post-treatment allogeneic transplant which was about 45% for both arms of the study. In the older patients it was about 20%, which is what is expected.

So what are the most important findings that you would draw attention to, coming out of this?

Again, the most important finding is that the combination is associated with a higher CR rate and a highly significant survival advantage in patients over the age of 60.

What do you think could be the clinical implications?

I believe, based on the fact that there is no standard for therapy of relapsed AML, that this study has clearly demonstrated that the combination of cytarabine and vosaroxin is superior to cytarabine alone and should be the new standard in older patients with relapsed AML.

And that would be your conclusions, basically, would it?

That is my conclusion.

Bottom line message for doctors to take home?

A combination of vosaroxin and cytarabine should be the new standard in relapsed patients with AML who are over the age of 60.