I will change to acquired anaemia and anaemia in the elderly. Myelodysplastic syndromes are indeed diseases in the elderly with a risk of progression to acute myeloid leukaemia but this is more in what we call high risk MDS. Here we’re going to deal with low risk MDS where the problem is mainly anaemia which is, of course, of concern in those elderly people because if they are regularly transfused the problem is fatigue, quality of life, because the mean haemoglobin level is low in those patients. So we try to treat them by drugs improving the haemoglobin level and the first line of treatment is generally erythropoietic stimulating agents like EPO. But they unfortunately work only in about half of the patients for a median duration of about two years. So indeed in those patients there are limited treatment options, especially in Europe where some drugs, second line drugs, are not approved like hypomethylating agents. Higher telomerase activity and shorter telomeres predict for shorter overall survival in those patients.

So Imetelstat is a first in class telomerase inhibitor which targets cells with short telomere lengths and active telomerase and has shown clinical activity in myeloid malignancies, particularly myeloproliferative neoplasms.

So we’re here with patients who are low risk, which is IPSS low and intermediate 1, who are refractory to ESAs or who have a very high EPO level, baseline EPO level, which predicts a very low response to EPO and virtually almost all the patients had received EPO. Those patients had to be transfusion dependent and a high transfusion burden with at least four units every four weeks. They should not have 5q deletion because 5q deletion is a specific type that responds in particular to lenalidomide and they should not have received hypomethylating agents, HMA or lenalidomide, which are drugs which, by the way, are not approved in Europe in this situation.

The primary endpoint was based on the usual response criteria – transfusion independence during at least eight weeks Secondary endpoints – transfusion independence for at least 24 weeks’ duration etc. including survival and, of course, safety. We also analysed the telomerase and hTERT activity.

The patients, 38 patients were included, as expected elderly people. Two-thirds of them were low risk, one-third intermediate 1 and the transfusion requirement was very high indeed with a median of eight concentrates every eight weeks which is very high. Almost all of them, 90%, had received EPO and one-third had a high EPO level.

The results were 42% transfusion independence with a median duration, Kaplan-Meier because some of them have limited follow-up, of 85 weeks. 29% achieved the secondary endpoint of 24 week transfusion independence. HIE, which is the erythroid response which may include transfusion independence or an improvement in transfusion rate, was obtained in 68% of the patients. Now, in a subset of the patients, the patients with excess blasts, we could evaluate the PR or CR, an incomplete or partial response, and indeed it was achieved in a certain proportion of those patients who could be evaluable for this endpoint.

Transfusion independence, this is in green, in particular the patients who achieved a 24 week transfusion independence and many of them with the arrow are continuing to respond. As you can see, on the right curve, in the right part, all but one patient had a reduction in transfusion rate although not all of them fulfilled the criteria for 8 week or 24 week response.

What can be said also is that the drug was generally well tolerated. Initially with imetelstat there had been some concerns about liver toxicity which were not found. Mild liver toxicity was seen. Cytopenias, thrombocytopenia and/or neutropenia, was indeed seen in about 60% of the patients. They were reversible but significant. And interestingly patients with worse prognosis, although they remain low risk but with worse prognosis, such as abnormal karyotype like trisomy 8 or even worse karyotype, tended to respond better to imetelstat in terms of transfusion independence which suggests that the drug is promising for higher risk MDS.

So, in conclusion, we have an 8 week transfusion independence rate of 42% in those patients resistant to Epo and 29% transfusion independence rate at 24 weeks with a median duration in responders of about 20 months and a response rate of 68%. Indeed, the transfusion independence rate was seen in all subtypes and, even better, in intermediate risk patients. Telomerase levels and hTERT levels were more reduced in responders as compared to non-responders so it may be an interesting biomarker. As I said before, apart from cytopenia no new safety signal was identified so based on those results there will be a phase III study comparing imetelstat 2:1 versus placebo starting in the next few months worldwide, especially in Europe. Thank you.

Prof Anton Hagenbeek
Thank you very much, it’s a most interesting study. One of the first, I think, focussing on telomeres, right?

Dr Pierre Fenaux
Yes.

Prof Anton Hagenbeek
Do you have any other examples in haematology where this drug is active?

Dr Pierre Fenaux
Yes, it’s active in myeloproliferative neoplasms including primary myelofibrosis where some interesting results have been seen. So more higher risk myeloid disorders so that’s the reason why in high risk MDS and potentially even in AML it could be interesting, at least in combination.

Prof Anton Hagenbeek
Questions please. Yes, here?

Neil Osterweil
Neil Osterweil with Hematology News. How specific is this drug? In other words will it have an effect on other telomeres in other cells and, if so, what kind of later off-target effects might you see?

Dr Pierre Fenaux
I think it’s unclear. Even the mechanism of action of erythropoiesis isn’t clear. It’s been studied in particular by Ron Hoffman and colleagues on megakaryopoiesis but on erythropoiesis a lot has to be learnt, obviously.

Neil Osterweil
And then why originally was the study in erythropoiesis? What prompted it?

Dr Pierre Fenaux
Initially the study was all comers in low risk MDS and it was shown that those who responded were mainly those who just had received EPO which is real life and no del(5q) so that’s how. Based on the results of a small number of patients we increased the cohorts in that particular subset.

Neil Osterweil
Okay, thank you.

Prof Anton Hagenbeek
Further questions please. So could you elaborate a bit more on the effect, the side effect, on white blood cells, neutropenia and platelets? Were there patients that had febrile neutropenia, got fever, got infections? Patients that started to bleed, did they need further transfusions?

Dr Pierre Fenaux
No, there were very few episodes of infection, two to three. I think two patients were hospitalised for febrile neutropenia and very few required platelet transfusion. It’s all grade 3 but it’s significant.

Prof Anton Hagenbeek
And it’s also striking that you see a significant effect on the disease itself in terms of CRs. So are you also planning to combine this anti-telomere drug with other effective drugs in MDS?

Dr Pierre Fenaux
I think the first step would be to study high risk MDS as a single agent, of course, then to combine it, including with hypomethylating agents etc.

Prof Anton Hagenbeek
And you are talking about starting a phase III trial? How will that look like, what will be the control arm?

Dr Pierre Fenaux
Yes. It will be placebo because, as usual, transfusion independence being the primary endpoint we know that even in the placebo arm there are often some… so agencies have required a phase III study based on transfusion independence in low risk MDS.

Prof Anton Hagenbeek
Further questions? If not, thank you again, Pierre.

Dr Pierre Fenaux
Thank you.