2011 ASH Annual Meeting, December 10-13, San Diego, USA
Update and new perspectives in the management of MDS
Dr Mikkael Sekeres – Cleveland Clinic Taussig Institute, USA
We presented data on a phase II study that combined azacytidine with lenalidomide; we had previously published a phase I study in The Journal of Clinical Oncology combining the two regimens where we determined a go-forward dose, we ordinarily call that a maximum tolerated dose but actually it wasn’t maximum tolerated, it was the agreed upon go-forward dose based on adverse events which were rare in the dose level we determined and response rate. That go-forward dose was azacytidine at 75mg/m2 daily for five days and lenalidomide, 10mg daily for 21 days out of a 28 day cycle. In our phase II study we enrolled an additional eighteen patients using this regimen, the characteristics of these patients were similar to the phase I study, so a median age of 68 years old, most of them had de novo untreated disease, and when we gave the regimen together we had an overall response rate of 72% and a complete remission rate of 42%.
Can you explain these high response rates?
We were, frankly, pleasantly surprised when we presented the phase I data and found almost an identical response rate. What’s nice about the phase II study is it really supports the phase I data because the response rates were unchanged. We think that what’s happening is the lenalidomide is treating aspects of a patient’s disease that derive from when they had lower risk disease, so probably bone marrow microenvironment conditions, the presence of pro-apoptotic, pro-inflammatory cytokines and, in addition, patients with higher risk disease, when their disease has evolved, have genetic abnormalities, molecular abnormalities and methylation abnormalities that are best treated with the hypermethylating agent, the azacytidine. We think that this combination, therefore, is superior to the azacytidine monotherapy. We did publish, in addition to the phase I study, a report of three patients who received the combination therapy for a total of seven cycles, seven months, then went on to receive single agent azacytidine. They went into a complete remission after the combination therapy, continued in a complete remission on the single agent azacytidine, lost their response, so had relapse of their disease and then we were able to recover the complete remission by just adding back the lenalidomide. It’s a clinical proof of concept that there’s something about the combination therapy there that isn’t there when you’re just giving patients monotherapy.
What about the speed of response?
Anecdotally, people will talk about a bi-modal peak to responses with azacytidine monotherapy. You seem to see some responses early and then some responses that occur some time around five or six cycles of therapy. It appeared to us that our responses were occurring early, so some patients were having, for example, improvements in their platelet counts after only one treatment cycle but we were still seeing that second peak of responses where patients reached their best response some time between four and seven cycles of therapy.
How would this compare to azacytidine alone?
In the AZA-001 study, which is the survival study that was conducted in the European Union where patients were randomised to receiving azacytidine monotherapy versus conventional care regimens, either best supportive care, low dose cytarabine or 7+3 induction type chemotherapy, in that study the overall response rate was 35% for patients who receive azacytidine and they achieved a CR rate of 17%. In our study the overall response rate was 72%, so double that, and our CR rate was 42%, so we appear to have higher activity with the combination, compared to azacytidine monotherapy but it’s a non-comparative study. So the next step will be a North American inter-group study where we will be randomising patients to receiving azacytidine monotherapy, azacytidine plus lenalidomide combination or azacytidine plus vorinostat and we’ll be looking for a superior response rate in one of the combination arms compared to the azacytidine monotherapy.
What about toxicity?
When we conducted the phase I study we were very worried about hematologic toxicity because we were giving two potentially cytotoxic drugs. Again we were pleasantly surprised, we found that the average decrease in neutrophil count was about 35%, the average decrease in platelet count was about 20% in the phase II setting, so not very toxic. The adverse events that we saw are typical of a higher risk, older MDS population – we saw some infections, we saw some bleeding, we saw some unusual, atypical adverse events that may just have been because these are older folks with comorbidities who have myelodysplastic syndrome, but nothing that was an outlier compared to azacytidine monotherapy.
What are the potential implications?
The combination regimen is still being studied, it’s not officially approved by the US FDA but we are conducting the North American inter-group study, it’s a randomised phase II study. If it does show superior response rate for the combination of azacytidine and lenalidomide compared to azacytidine monotherapy, we will then go to a phase III study which presumably would be a registration study of the combination.