EHA 2015

Chemoresistance and residual disease promoted by DNMT3A R882 in AML

Dr Olga Guryanova - Memorial Sloan Kettering Cancer Center, New York, USA

You’re looking at a mutation, a very special mutation, that apparently impacts whether a patient with acute myeloid leukaemia will actually become resistant to chemotherapy. Very interesting. What put you on to this and why was this a big issue?

Initially this  mutation was identified a couple of years ago and it also came up in a large clinical trial that was run by the ECOG, it’s a big Eastern Co-operative Oncology Group in the United States and the clinical trial was called E1900. It’s a clinical trial that evaluated response to two different doses of standard chemotherapy in a large cohort of AML patients, 398 patients. The clinical trial was actually the first positive clinical trial in AML in a really, really long time that evaluated the responses of patients to standard dose which is 45mg/m2 and the double dose, the 90mg/m2 of daunorubicin. The clinical trial also tried to correlate the response to chemotherapy to any mutational data.

Because in fact patients do very well, they respond very well to chemotherapy but then they fail.

Yes. So initially the vast majority of patients do respond to chemotherapy, however, in a lot of patients what we see happens is a very small number of leukaemic cells still persist despite chemotherapy, so they’re able to survive the chemo. They persist and then later on it’s believed that these persisting cells give rise to the relapse. So here, as a follow-up to the initial clinical trial we wanted to look if presence of certain mutations would correlate with this minimal residual disease because now we know that the presence of minimal residual disease actually predicts the relapse and it predicts adverse outcome.

That there is, in fact, capacity for the disease to rebound. But could you tell me about this mutation, DNMT3A R882?

Yes. DNMT3A, first of all it’s one of the genes that is recurrently mutated in AML. In fact it’s the third most commonly mutated gene in AML so it must be pretty important. It is mutated in roughly 30% of patients. However, the interesting thing is that the mutation, this particular mutation, is present in… it hits a very particular amino acid. It’s a point mutation and it’s present… half of all DNMT3A mutations are this particular amino acid. So there must be something very specific going on and that’s why we were so interested because, first, it’s a very common mutation but also it, according to clinical data, correlates with bad prognosis and it correlates with adverse response to chemotherapy.

Now, I hear that this mutation makes very good stem cells.

Yes, actually recent data that was first reported at ASH last year, three different groups found this mutation in elderly individuals without any haematological malignancies but in elderly people with so-called clonal hematopoiesis. It means that with age the function of many stem cells decreases, however, it looks like the presence of this mutation actually makes very good stem cells that persist and out-compete normal cells.

So it seems actually, then, that this is potentially a very good mutation to have but it can be very bad if you have AML.

Yes, actually this mutation recently last year it was reported at ASH, this mutation has been identified to be present in elderly individuals without any haematological malignancies but with so-called clonal hematopoiesis which means that this mutation makes very good stem cells. However, these individuals are also predisposed to develop leukaemia later on; they have roughly a fifty-fold increased risk. However, the overall risk is still so low that testing healthy individuals for this mutation is not recommended. But it means that these cells are more resistant to stress and chemotherapy is actually stress. So it means that in AML once the cells have this mutation it would require a much higher dose of chemotherapy to get them cleared out.

You’ve discovered some things that this mutation, knowledge about it, does enlighten you about as far as therapy is concerned. Are there others? Could it help you find new ways forward?

That’s exactly what we’re working on right now. So now that we know what this mutation does and how it decreases the sensitivity of cells to chemotherapy, so there are two separate avenues that we can pursue. One of them is actually increasing the dose of chemotherapy because patients with these mutations are the only group that benefit from increased daunorubicin. All the other patients with all the other mutations, they only get increased toxicity and no benefit. Now we know mechanistically on a molecular level why it is so. So this mutation prevents the cells from detecting the mutation and because the cells are unable to detect it it means that DNA breaks are not being repaired properly. We think that if we try to target some orthogonal mechanisms of DNA repair we can actually potentiate the effects of chemotherapy. However, we’re still working on that, we don’t have an answer ready for you.

So I’m wondering what the take home is for busy cancer doctors. Provisionally, what’s the potential clinical application of this knowledge?

The potential clinical application of this knowledge is whether the patient would receive standard dose chemotherapy daunorubicin or double dose chemotherapy daunorubicin. Multiple genetic testing panels are now being developed in different institutions and potentially the presence of this mutation can guide the clinical decision for doctors.