We conducted the North American Intergroup myelodysplastic syndrome studies in higher risk MDS patients. We enrolled 282 patients and randomised them to one of three arms. They either received azacitidine alone as monotherapy, azacitidine combined with lenalidomide or azacitidine combined with vorinostat. We chose those two comparator arms because the initial single arm phase II data from them showed very high response rates, higher than we would have expected from azacitidine alone.

Now which patients in particular were you looking at? Which sorts of patients?

We were focussing specifically on patients who had either higher risk myelodysplastic syndromes, we defined that as patients who had excess blasts, 5% blasts or greater, or who had higher risk scores on the IPSS, International Prognostic Scoring System, and we enrolled patients who had chronic myelomonocytic leukaemia, CMML.

So standard therapy at the moment would be azacitidine so why did you choose the other two agents?

Standard therapy is azacitidine as a single agent. We added agents to it because single arm phase II studies showed a higher response rate for the combination. We added vorinostat to azacitidine because it’s a histone deacetylase inhibitor - it makes the azacitidine work better. We added lenalidomide to the azacitidine because they have different mechanisms of action and therefore may have better activity in higher risk myelodysplastic syndromes.

Could you tell me about the study protocol and what you did?

Sure. We enrolled 282 patients, they were randomised to one of these three arms and we followed them for a response over time.

What happened?

We found that their response rates for patients who received azacitidine alone was 37%; azacitidine and lenalidomide was 39% and azacitidine and vorinostat was 24%. So actually there was no difference in overall response rate for one arm versus the other arms. There were, however, signals in subgroups. The actual response in patients with chronic myelomonocytic leukaemia was higher in the azacitidine and lenalidomide arm compared to azacitidine monotherapy. We also looked at disease free survival. What we found is that although patients in the azacitidine and vorinostat arm weren’t as likely to respond as those patients in the azacitidine arm, if they did respond it appeared that they had a borderline better disease free survival than those patients receiving just azacitidine.

What sort of additional toxicities did you get with the extra agents?

It’s a great question. Actually we didn’t see a lot of excess toxicities in the combination arms. The rate of suppression of blood counts was similar across all three arms. We did find a higher rate of rash in patients who received lenalidomide with azacitidine and a higher rate of GI toxicities in patients who received vorinostat with azacitidine.

You were looking at combination therapy, it must have been a little bit of a disappointment not to find a clear winner. Do you have any ideas why this happened?

It’s a great question. So why is it that we didn’t see the robust results we saw in single arm phase II studies translate to a randomised phase II study? Well, one reason could be because the combination arms were stopped prematurely. We actually found that patients were stopped on combination arms earlier than they were on the azacitidine monotherapy. In addition, we found a significantly higher rate of non-protocol defined dose reductions in the combination arms compared to the monotherapy so patients may not have received enough of the therapy. Yet if they did and if they did respond they seemed to have a deeper response.

So what are your feelings about the prospects for recommending combination therapy for patients with high risk MDS?

I think combination therapies are a potential future way to improve response and improve outcome… let me start that over. I think combination therapies still have a bright future in higher risk MDS. One of the tricks in giving two drugs to patients with MDS is that these patients are older and their toxicities have to be managed more carefully and we have to be careful not to dose reduce them and not to take them prematurely off of these agents until they’ve had a chance to respond.

There is an issue, though, isn’t there, of frailty; if you’re adding additional agents that could be a negative factor.

Absolutely. So I monitor my older patients closer than I might somebody who is younger. I might see them more frequently in clinic. I might check their blood counts more frequently but I don’t discriminate against them because of their age. I don’t dose reduce just because they’re old.

What about progression to AML, what was happening there?

We did not see any signal of a higher rate of AML progression in patients on any arm but we’re still collecting longer term data, we’re still collecting overall survival data and event free survival data.

What do you think, then, are the clinical implications for busy cancer doctors coming out of this?

Right now the standard therapy for patients with higher risk MDS is still either azacitidine monotherapy or decitabine monotherapy. We’re still exploring combination regimens; we’re hoping that one of these combination regimens will improve survival in patients with higher risk MDS.

So, for the busy doctor with a patient that he or she has just diagnosed with MDS, what’s the very brief message that you’d like people to remember right now?

A patient who is diagnosed with higher risk MDS should receive azacitidine monotherapy or decitabine monotherapy. In the future we’ll be able to define sub-groups who benefit from combination therapy and we’ll make sure that we’re giving these drugs in a way that patients can tolerate.

But is there anything coming down the highway in terms of targeted therapies, for instance, for MDS?

There has been a lot of excitement about the IDH inhibitors, particularly in acute myeloid leukaemia. Well, acute myeloid leukaemia isn’t the only cancer that has IDH expression, MDS does as well. I think that those compounds have potential for MDS.

And putting that in focus for doctors, what would you say right now?

We are increasingly defining diseases like myelodysplastic syndromes by their genetic underpinnings, their molecular profile. As we identify these molecular lesions we’re going to increasingly identify drugs that treat those molecular lesions and the IDH inhibitors may be that class of drugs.