By David P. Steensma, MD

2008-12-08

At the 2007 ASH annual meeting, the big news in myelodysplastic syndromes (MDS) treatment was the result of the multicenter AZA-001 trial, in which patients with higher-risk MDS randomized to receive the DNA methyltransferase inhibitor (DNMTI) azacitidine lived a median of nine months longer than those who received only conventional care. This year’s oral session on Myelodysplastic Syndromes: Clinical Studies: Genetic and Epigenetic Targets, to be held today at 7:00 a.m. (Room 304 South), will continue the theme of DNA methyltransferase inhibitors — the focus of six of the eight presentations.

Does decitabine, the other DNMTI currently available for treatment of MDS in the United States, also extend survival in higher-risk MDS, similarly to azacitidine? This question will be addressed this morning (7:00 a.m., Room 304 South) by Dr. Pierre Wijermans, from Den Haag in the Netherlands, who will discuss the results of the EORTC Leukemia and German MDS Groups’ 06011 trial, in which there was no survival difference between decitabine and supportive care in patients with MDS (abstract #226). Patients eligible for enrollment had either 11 percent to 30 percent marrow blasts or poor cytogenetics. “It is possible that study design differences accounted for these discordant results,” explained Dr. Wijermans. “Unlike AZA-001, in which patients were treated until disease progression and received a median of nine treatment cycles, patients in the 06011 study received a median of four cycles of decitabine, possibly not in the optimal schedule, and treatment was not continued beyond eight cycles. In addition, many patients in the control arm received intensive treatments subsequently.”

Dr. Lewis Silverman, of Mount Sinai School of Medicine in New York, who led the pivotal CALGB 9221 study that prompted FDA approval of azacitidine for MDS in 2004, will also emphasize the importance of the number of DNMTI treatment cycles in his presentation of updated data from AZA-001 (abstract #227). “We’ve previously shown that a complete response (CR) is not necessary to get a survival benefit with azacitidine in MDS. Further analysis of the AZA-001 study indicates that 48 percent of patients who had an initial response achieved a better response with continued treatment, at a median of four cycles later. These data support the value of maintenance therapy,” Dr. Silverman reported.

Because DNMTIs still fail to benefit many patients with MDS, a key question now is whether other drugs can be added to improve the quantity or quality of responses. The most logical candidates for combination therapy are the histone deacetylase (HDAC) inhibitors, due to their in vitro epigenetic synergism. Dr. Jean-Pierre Issa, of M. D. Anderson Cancer Center, will discuss data from a 76-patient randomized trial in which valproic acid, a relatively weak HDAC inhibitor, was added to decitabine, with only minimal benefit in terms of response, increased neurotoxicity, and no survival difference (abstract #228). Ongoing controlled trials such as the ECOG E1905 study, where all patients receive azacitidine and half also receive the more potent HDAC inhibitor entinostat (SNDX-275), should help clarify whether valproate was just too weak an agent to be effective, or whether HDAC inhibitors offer no additional benefit to DNMTIs generally.

Combinations of DNMTIs with non-HDAC inhibitors may also prove useful. A Bone Marrow Failure Disease Consortium study led by Cleveland Clinic’s Dr. Mikkael Sekeres successfully used lenalidomide and azacitidine together, with an encouraging preliminary 41 percent CR rate (abstract #221). In addition, Dr. Hagop Kantarjian from M. D. Anderson Cancer Center will discuss early results of an ongoing trial combining azacitidine plus the thrombopoietin agonist romiplostim (abstract #224); the 27 patients receiving combination therapy had higher platelet nadirs and lower platelet transfusion needs than 13 patients receiving azacitidine plus a placebo. We can expect to hear more about these and other DNMTI combinations in MDS at next year’s meeting. 

Dr. Steensma disclosed that he is an investigator on multicenter clinical trials involving azacitidine, decitabine, lenalidomide, entinostat, and other HDAC inhibitors.

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