The MDS Beacon™

A new study summarizes results from a review of previous published research into the treatment of myelodysplastic syndromes (MDS) patients with the hypomethylating agents Vidaza (azacitidine) and Dacogen (decitabine).  The study finds that treatment with the hypomethylating agents produces longer overall survival than conventional care.  This survival benefit, however, comes with a greater risk of serious treatment side effects.

Selected results from the new study, by a team from Tel Aviv University in Israel, were presented this summer at the European Hematology Association 14th Congress in Berlin, and were briefly discussed in a previous MDS Beacon news article.

After reviewing a large number of studies for potential inclusion in their analysis, the Israeli researchers found four relevant randomized controlled trials.  The four trials involved 952 predominantly high-risk MDS patients who received either Vidaza, Dacogen, or conventional treatment.

Vidaza and Dacogen are two examples of hypomethylating (or demethylating) agents that help decrease uncontrollable cell division, a characteristic of MDS that can be caused by methyl groups that are bound to DNA sequences, blocking the regulation of cellular growth.  The drugs remove the problematic methyl groups and allow the DNA sequences to function normally.

There were three types of conventional treatment included in the studies analyzed by the Israeli team: supportive care, low-dose chemotherapy, and intensive chemotherapy.

Supportive care is used to treat symptoms of MDS caused by low blood cell counts, but it does not cure MDS or prevent progression to acute myeloid leukemia (AML).  Stem cell transplantation is currently the only therapy able to generate complete recovery from MDS.  Supportive care includes blood transfusions and treatment with growth factors.

The low-dose chemotherapy in the studies was low-dose cytarabine (Cytosar-U).  The intensive chemotherapy was the “7+3” regimen involving standard dose cytarabine plus daunorubicin (Cerubidine).

The study evaluated overall survival, length of time to AML or death, complete or partial response, and severity of side effects.  A complete response, as measured by the 2000 International Working Group (IWG) criteria, is defined as having a blood count of more than 1,000 neutrophils per µL and more than 100,000 platelets per µL.

Results from the Israeli team’s systematic review indicate that hypomethylating agents as a group prolong overall survival and slow progression to AML compared to conventional care.  Patients receiving hypomethylating agents also were more than seven times likelier to achieve a complete response, and more than six times likelier to achieve a partial response, regardless of which drug was administered.  At the same time, although Vidaza and Dacogen increased blood counts (as reflected in the better response rates for the agents), they did not as a group decrease dependence on red blood cell transfusions.

Moreover, patients receiving hypomethylating agents had a 20 percent greater chance of serious side effects such as lowered white blood cell counts (neutropenia) and platelet counts (thrombocytopenia).  They also had a higher rate of treatment-related mortality than those receiving conventional care.

The study also examined whether the hypomethylating agents have better overall survival than each of the three specific kinds of conventional care covered by the analysis. The study finds such a benefit versus supportive care and low-dose chemotherapy, but not versus intensive chemotherapy.  The authors note, though, that the hypomethylating agents may still be a better option for patients due to their ease of administration and the adverse events common with intensive chemotherapy.

The Israeli researchers also compared the overall survival benefit of the individual hypomethylating agents versus conventional care.  This analysis favors Vidaza, finding evidence of a survival benefit for Vidaza but not for Dacogen.  Similarly, the study finds Vidaza more effective than Dacogen in lengthening the time to death or AML.

Despite the review’s findings, the authors note that the small number of clinical trials limits the emphasis that should be placed on the Dacogen vs. Vidaza comparisons.

Neither Celgene Corporation, the company that markets Vidaza, nor Eisai Inc., the company that markets Dacogen, responded to requests from The MDS Beacon for comment on the article by the Israeli researchers.  Eisai announced late last year that it will be sponsoring the first clinical trial to directly compare Vidaza against Dacogen.  The main goal of the study will be to compare the complete response rates of the two drugs.

Overall, the Israeli team concludes that hypomethylating agents should “have a major role in the treatment of [high risk] MDS.”

In comments to the MDS Beacon about the Israeli team’s article, Dr. Emmanuel Besa of Thomas Jefferson University in Philadelphia said he is uncertain whether the article really adds much beyond what is already available in the four individual studies analyzed in the paper.  Dr. Besa, an MDS specialist, took issue with the authors’ grouping of supportive care, low-dose chemotherapy, and intensive therapy into a single “conventional care” category of treatment, noting that the three treatments are very different from one another.

Likewise, Dr. Besa pointed out that both of the Dacogen clinical trials surveyed by the paper were halted before significant survival data could be collected.  In addition, one of the two Vidaza trials in the paper included a large number of patients who were treated with both Vidaza and supportive care.

For more information about the Israeli team’s study, please see the journal Haematologica (abstract; full article also available at no cost).