ASH 2015

Combining treatment options for higher risk myelodysplastic syndromes and chronic myelomonocytic leukaemia

Dr Mikkael Sekeres - Cleveland Clinic Foundation, Cleveland, USA

You’re presenting here on two conditions, MDS and chronic myelomonocytic leukaemia, looking at two options for treating them. Can you tell me why you were investigating these conditions?

Sure, so higher risk myelodysplastic syndrome is a very serious disorder. People live, on average, less than a year and a half from the time that they are diagnosed. People who have higher risk myelodysplastic syndromes are distinct from those who have chronic myelomonocytic leukaemia. CMML, how we abbreviate it, is a combination of a myelodysplastic syndrome and a myeloproliferative neoplasm. So there are no drugs specifically FDA approved for chronic myelomonocytic leukaemia.

Now you’ve got azacitidine in both arms of your study, tell me about the rationale of the study.

Sure. The standard therapy for somebody who has higher risk MDS or CMML is to treat them with a drug like azacitidine. Azacitidine alone improves overall survival in patients with higher risk myelodysplastic syndromes. The overall response rate to azacitidine alone is approximately 35%. We did a couple of things: we added lenalidomide to azacitidine. People who have higher risk myelodysplastic syndromes have a couple of things going on. Some of the biology of the disease is targeted by azacitidine in being a hypomethylating agent; some of it can be targeted by lenalidomide in affecting the bone marrow environment.

OK, so there are theoretical reasons and practical reasons for adding that drug. You also, in the study you’re talking about here, added vorinostat, didn’t you?

Correct. Vorinostat is a histone deacetylase inhibitor that acts synergistically with azacitidine.

So you’re covering all your bases, basically, aren’t you there?

We’re trying to.

In theory. How did it work out in practice?

We gave these drugs to patients and we enrolled 277 patients across North America. This was the largest prospective study that has ever been conducted in myelodysplastic syndromes. We were able to enrol these patients within two years, that’s a very rapid accrual.

And the primary endpoint was what?

The primary endpoint was overall response rate, and recall it was approximately 35% for azacitidine monotherapy. We were looking to improve on that by 20%.

Did you?

We came close. So in patients who received azacitidine and lenalidomide the overall response rate was 49% versus 38% for the azacitidine monotherapy. For those who got azacitidine and vorinostat the response rate was actually less than those who got azacitidine monotherapy but there were no statistically significant differences between either combination arm and azacitidine monotherapy though it came close in patients who received azacitidine and lenalidomide with a p-value of 0.16.

Is there any signal on survival?

There was not a signal on overall survival though if you look at the absolute numbers, patients who got combination therapy seemed to live about 3 to 4 months more than those who got azacitidine monotherapy. It wasn’t statistically significantly different but the study wasn’t powered to find a difference on overall survival. So we saw a numerical improvement but not a statistical improvement.

Were there differences between the patients who had MDS as compared with those who had chronic myelomonocytic leukaemia?

Well an absolutely fascinating signal that emerged is that in those patients who had chronic myelomonocytic leukaemia the overall response rate was 68% compared to 29% in those who got azacitidine monotherapy. That is a full out 40% difference in overall response rate and that was statistically significantly different.

Very interesting. I have to ask you about subgroups and possible biomarkers to indicate susceptibility to this new regimen. Did you see any or any hints of any?

We saw some hints of things emerging but it was impossible to see any significant differences because of the small numbers of patients.

So what are the guidelines coming out of this for practical cancer doctors, do you think?

Another great question. One thing that we noticed is that patients who received combination therapies were significantly more likely to have their dose reduced not by protocol specifications but by a doctor just deciding to reduce that dose. So one thing we need to communicate to doctors is that when they’re treating patients with combinations of therapy in MDS they’ve got to stick to it, they’ve got to keep giving the right doses.

But were those dose reductions related to toxicities?

In some cases yes but in some cases no. The question I would ask is are they related to toxicities that are otherwise manageable? The answer is that most of these toxicities are actually manageable. We also found that those patients who had their lenalidomide dose reduced had a significantly worse overall survival. So there may be an association between those dose reductions and people not living as long.

Alright, it’s a slightly complex conclusion then, but could you sum this up by the take home messages in a sort of take home message for cancer doctors about treating this group of patients?

Absolutely. So the bottom line, the primary endpoint of the study was not met. The overall response rate was not improved in a statistically significant way for either combination therapy versus azacitidine for higher risk MDS. However, in patients who had chronic myelomonocytic leukaemia the overall response rate was significantly improved for patients who got the combination of azacitidine and lenalidomide compared to azacitidine alone. We’re going to have to pool data to look at other subgroups to find by cytogenetics to see if there are specific cytogenetic subgroups who benefit from combination therapy.