ASH 2014

Tyrosine kinase inhibitor in combination with chemo shows benefit in acute myeloid leukaemia

Dr Christoph Röllig - University Hospital Dresden, Dresden, Germany

In our study we added sorafenib, which is a tyrosine kinase inhibitor, to standard chemotherapy for younger patients aged 18-60 years to standard chemotherapy and as a maintenance treatment for twelve months. This was a placebo controlled randomised trial and we looked at event free survival, relapse free survival and overall survival.

What’s happened in the past when sorafenib has been added to AML therapy?

There has been a randomised trial in elderly patients and this trial showed no beneficial anti-leukemic effect, however, an increase in morbidity because these patients did not tolerate the side effects in addition to chemotherapy.

So what was your rationale, in view of that slightly dangerous background, for using it in younger patients?

First of all we do think, and it comes out from scientific data, that the biology of AML in younger patients seems to be different from elderly patients. On top, younger patients normally tolerate these additional treatments better than elderly patients because they have less comorbidities and so on. Therefore we thought this might still be a good thing to set up.

So tell me about the protocol.

Yes. At the initial diagnosis of AML patients aged 18-60 years with newly diagnosed AML were randomised to receive two cycles of induction chemotherapy, three cycles of consolidation and then one year of maintenance. One arm of the patients, half of them, received sorafenib in addition to the chemotherapy, which is a tablet, the other half received a placebo tablet. We looked at primary treatment failure, at relapse and at overall survival in these patients and we present the data from a 36 month follow-up.

And the primary objectives were event free survival?

Exactly, a prolongation of event free survival. The hypothesis was prolongation from 9 to 13.5 months and we can actually see a prolongation from 9 to 21 months, which is quite a dramatic increase in event free survival time.

And secondary endpoints and what about the potential for overall survival improvement?

An important secondary endpoint was relapse free survival, that showed a clear benefit as well with 56% of patients being relapse free and alive after three years, compared with 38% in the placebo arm. At this point we don’t see a clear overall survival benefit for sorafenib patients which means relapse free survival, event free survival show a clear significant difference and benefit, however, we don’t see an overall survival advantage at this point.

So could you summarise the importance of what you’ve found so far?

In general this is the first randomised data confirming the efficacy of a tyrosine kinase inhibitor in AML, that is the main outcome. Because all the other data we have are either from early phases, from case reports or from non-randomised trials. Therefore, I think the main message is the kinase inhibitors are still agents valuable to pursue for the treatment of AML.

Although I think there are some question marks about just how they’re doing this?

Exactly, that’s an excellent question because we don’t see differences in FLT3 ITD positive patients who are considered the best target patients for this drug. We see also in non-mutated patients an effect and we can just speculate that inhibition of other kinases are responsible for this beneficial effect but we cannot at this point say what exactly is the target or is it multiple target inhibition that does the job.

Sorafenib is widely available, what are the clinical implications?

The clinical implications are that we do think a confirmatory trial would be desirable in order to establish this drug as a standard treatment. On top of it, sorafenib is not approved and it is an expensive drug so I don’t think from our data at this point it will make sorafenib a standard treatment option in AML.

What are your recommendations to doctors about how they should view these data, especially the fact that it’s a very big study in younger patients with AML?

The results are a signal that it is valuable to keep on including patients into clinical trials, particularly with tyrosine kinase inhibitors, but I’m not in the position to recommend an off-label use of sorafenib. I also do think that on the basis of our data it is not a standard to use this drug in AML.

But if you were to sum up the essence of what you found in just five or ten seconds, how would you do that?

I would say tyrosine kinase inhibitors are efficacious and have a future for the treatment of AML.