Slides from presentations at ASH 2008 and transcribed comments from interviews with Gail J Roboz, MD (11/20/09), Steven D Gore, MD (10/8/09) and Allen SR Yang MD, PhD (7/30/09)

GAIL J ROBOZ, MD: The paper by Sekeres and colleagues is a Phase I study that is interesting. Two myelosuppressive drugs with cross-reacting toxicities, lenalidomide and azacitidine, were used in patients with high-risk myelodysplastic syndromes (MDS). The additive negative effect of the two drugs in combination was less than what the authors had anticipated. Patients were tolerant of the regimen. These preliminary results warrant additional studies.

The pathogenesis of MDS is multifaceted, and it seems logical to me to pursue combination therapies, because the number of changes that are going on in an MDS marrow, epigenetic, genetic and immune mediated, lend themselves to combinations. For example, we’re looking at lenalidomide in combination with cyclosporine. About a quarter of patients with low-risk disease who do not have a 5q deletion have responses with lenalidomide therapy.

DR LOVE: What do we know about the response rate to lenalidomide in patients with high-risk MDS?

DR ROBOZ: There are some scattered responses in high-risk disease, and it appears that patients with multiple karyotypic abnormalities beyond 5q and patients with particularly low platelet counts do not respond well. But for some patients, mostly those with isolated 5q disease, there are responses.

DR LOVE: Are there any other particular drug combinations that you believe make a lot of sense?

DR ROBOZ: I believe the scientific rationale is the strongest for combining HDAC inhibitors with a demethylating agent such as azacitidine or decitabine. The clinical results have been a little disappointing so far in that we have not seen responses as robust as we would have liked. This may be due to our not knowing yet the correct manner to combine these drugs.

The paper by Raffoux and colleagues is an early study that combines the HDAC inhibitor valproic acid with azacitidine and with the differentiating agent ATRA. This study is using drugs that make some sense scientifically to combine together and examining the outcomes. ATRA has a long history in MDS and acute myeloid leukemia (AML), though I believe in general that the data for the use of ATRA in MDS and in non-acute promyelocytic leukemia (non-APL)-AML are weak. From a scientific standpoint, however, it seems to make sense to try to force cells that are not maturing correctly to differentiate.

STEVEN D GORE, MD: The regimen that was examined by Raffoux was developed at the MD Anderson Cancer Center. It is one of several regimens that combine a DNA methyltransferase inhibitor such as azacitidine with a histone deacetylase (HDAC) inhibitor, valproic acid. In this particular regimen, they have also added ATRA in a type of triple approach in order to have the differentiating activity of ATRA after epigenetic modulation. The study demonstrated that the combined therapy using 5-azacitidine and valproic acid followed by retinoic acid therapy results in a 25 to 30 percent response rate in patients with high-risk acute myeloid leukemia or MDS. These results are worth continuing to pursue.

ALLEN SR YANG, MD, PHD: The study presented by Mikkael Sekeres and colleagues was a Phase I study examining the combined administration of azacitidine and lenalidomide to patients with higher-risk myelodysplastic syndromes (MDS). The study demonstrates that the two drugs can be administered safely in combination and that the main toxicity appears to be myelosuppression, as would be expected. The overall response rate was 72 percent. I believe that the combination of 5-azacitidine and lenalidomide is feasible. It would be very exciting to have a benefit demonstrated in a randomized clinical trial.

Dr Roboz is Associate Professor of Medicine and Director of the Leukemia Program at Weill Medical College of Cornell University at NewYork-Presbyterian Hospital in New York, New York.

Dr Gore is Professor of Oncology at Johns Hopkins University in Baltimore, Maryland.

Dr Yang is Assistant Professor of Medicine at the University of Southern California in Los Angeles, California.