New line of therapy for acute myeloid leukaemia

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Published: 18 Dec 2013
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Dr David Taussig - Barts Cancer Institute, London, UK

Dr Taussig talks to ecancertv at ASH 2013 about his study "Arginine Deprivation With Pegylated Arginine Deiminase Induces Death Of Acute Myeloid Leukaemia Cells In Vivo".

Malignant cells require amino acids for a wide range of core functions. Amino acid deprivation using enzymatic degradation has been used to induce remission in acute lymphoblastic leukaemia for decades. Amino acid deprivation may also benefit patients with acute myeloid leukaemia (AML). We have previously shown that AML cells lack of argininosuccinate synthetase 1(ASS1), a key enzyme in the pathway that produces arginine. Here we tested the effect of an arginine depleting agent, pegylated arginine deiminase (ADI-PEG 20) on primary AML cells in a xenograft model of AML.

The experiments showed that arginine deprivation by ADI-PEG 20 can decrease the leukaemic burden in mice transplanted with primary AML cells. The combination of ADI with cytarabine had a greater effect than cytarabine alone in half the experiments. These results provide the rationale to test ADI-PEG 20 with cytarabine in clinical trials.

I think it’s important to look at the context. Acute myeloid leukaemia is a disease where we’ve had no new drugs since the 1970s so what we’ve done in our preclinical model is provide evidence that an approach to acute myeloid leukaemia by depriving a critical amino acid called arginine might, either as single agent or with conventional chemotherapy, increase the response rates and hopefully improve survival by doing so. So it’s potentially exciting, obviously we’ve only tested this in the lab but I think we’ve used the best model available because we’ve tested the drug against primary cells i.e. directly from patients that we’ve transplanted into mice and the primary cells grow in the mice rather nicely and then once the leukaemia is fully established in the bone marrow we then treat. So it’s very similar to what happens with the patients and we’re testing against human cells which I think is critical and we’re doing it against established disease. We’re not treating the cells in a test tube and then transplanting them, the leukaemia is fully established when the treatment starts.

If this targeted approach works which category of patient would you go to first?

There are two areas which are very difficult in acute myeloid leukaemia. One is relapsed or refractory disease in younger patients and the second area which is very difficult is in older patients and the survival is dreadful in those over the age of 65. So I see this potentially being used for the older patients with low dose cytarabine which is one of the current standard of care options available. I would hope that we can improve remission rates, keep patients out of hospital longer and make them live longer as well. But I also think there is the relapsed refractory situation for younger patients is also in need of improvement; the ten year survivals are really very poor for patients with relapsed refractory disease and I should state that the types of leukaemia we studied were all poor risk so we didn’t go for any of the easy ones where we’d cure with standard chemotherapy. Out of the six samples, two had poor risk cytogenetics and the other four had poor risk molecular lesions so we’ve gone for the hardest nuts to crack.

I think it’s ready for an early phase clinical study now, yes.

How much difference do you think this sort of targeted technique could make?

It’s difficult to predict. One has to be cautious that lots of drugs have been tried in the last forty years and none of them have stood the test of time. So this is a difficult disease to treat but I’m optimistic. I’m optimistic that it will help some patients, yes.

How does it fit in with allogeneic transplantation?

For the younger relapsed refractory patients, I would see it as a bridge to transplant; I don’t believe that it would be sufficient in and of itself to cure these highly refractory diseases. In the older patients I would see it really to improve the palliation; I think it’s too much to ask of this drug to completely eliminate these highly aggressive diseases.