ASH 2015

Tosedostat for elderly acute myeloid leukaemia

Dr Giuseppe Visani - Ospedale S. Salvatore, Pesaro, Italy

You’re looking at a drug, tosedostat, you’re looking at it in the setting of elderly acute myeloid leukaemia. Can you tell me what it was you were trying to investigate here?

Elderly acute myeloid leukaemia is an unmet medical need for therapy as patients frequently are resistant to intensive chemotherapy or get side effects and their survival is very short.

Could you tell me something about tosedostat, what it is and how it works?

Tosedostat is an aminopeptidase inhibitor; aminopeptidase are enzymes that work all over the cycle of the cell and are linked to many important functions. Here we coupled tosedostat with low dose Ara-C that is a recognised drug for acute leukaemias.

So what did you do in the study?

We studied 33 patients according to Fleming’s method for numbers and we administered tosedostat for 240 days continuously and up to eight cycles of low dose Ara-C. We observed a complete remission rate of more than 45% so really significantly higher in comparison to the 25% that was the favourable result of the study in our statistical method.

Now that was in patients de novo, treated for the first time. Some of them might have had myelodysplastic syndrome.

They were de novo or secondary after myelodysplastic syndrome. More than 30% had adverse karyotype so it was a very poor prognosis series, that is.

How much did the complete remission rate improve?

It improved more than 20% in comparison to the normal 20-25% reached with this. But more, we have still six patients in CR after more than 500 days and that is very important for this series of very poor prognosis patients.

Do you feel there could be a signal on overall survival?

Up to now overall survival is seven months and so this is quite good but in line with good overall survivals for these kinds of studies. But more, we studied these patients with gene expression and system and this is another point that will give interesting results.

So what is it in the gene expression? Which factors are you looking for that predict CR?

We studied leukemic cells. Up to now 15 patients are available and others are in study. Out of these 15 patients that were CR versus no response we analysed with a Transcriptome 2.0 Array that covers more than 285,000 genes. We found a gene set of 212 genes differentially expressed in CR patients who attained response in comparison to the others. This is important because if we are able to validate in the future this we will find probably a small gene set useful as a companion tool for therapy.

So you could have prediction by a manageable number of gene variants could you?

Yes, the hope is if this works to get a small set of genes instead of 212 that it is now.

So you’ve got proof of principle at the moment with 212 but you’re hoping to get that down.

Yes, that’s true. We are just validating it now but we have not the final results of the validation. We should later make a reduced gene set.

Clearly it’s interesting that your drug works and that it’s improved complete remissions. It’s also interesting that you’ve got some genetic information. What should doctors be thinking about this right at the moment? It’s early days, of course, but interesting data.

Well it is a quite manageable drug and this is important because we use the low dose Ara-C to debulk the disease and later tosedostat, even some times at lower doses than the starting dose, was well tolerated for longer periods of time. So it could become even a maintenance drug after intensive therapies, not only for the elderly, in my opinion even for frail younger patients.

Could there be other aminopeptidase inhibitors that could do similar things, do you think?

This is possible but up to now in my knowledge it is the most energetic aminopeptidase inhibitor we know, or most tested in the clinics.

So what’s the bottom line message coming out of this clinically then?

That is that tosedostat is very promising and probably will be associated not only with this low dose Ara-C but possibly with other drugs such as decitabine or the other citadines in acute myeloid leukaemias and that we hope to find a small gene set for a companion tool in therapy.