The MDS Beacon™

A combination therapy of Vidaza (azacitidine) and valproic acid (Depakene) may be more effective than Vidaza alone for the treatment of myelodysplastic syndromes (MDS), according to a Phase 2 study published in the journal Clinical Cancer Research.

Valproic acid is commonly used to reduce seizures in epilepsy patients and to treat bipolar disorder. It has recently become of interest as a possible treatment for blood- and bone marrow-related cancers like MDS.

Previous studies have shown that two classes of drugs, hypomethylating agents, which include Vidaza, and histone deacetylase inhibitors, which include valproic acid, used together can suppress cancer. This is done by inhibiting methylation of DNA, a process that at normal levels prevents genetic abnormalities but at higher levels can lead to MDS.

This Phase 2 study included 62 patients with either intermediate-2 or high-risk MDS and was conducted at several Italian hematology centers.

Valproic acid was given orally from the start of treatment to reach a desired plasma concentration of more than 50 μg/mL, at which point Vidaza was administered using standard dosing. Patients were allowed supportive care but not growth factors.

Additionally, tretinoin (all-trans retinoic acid, Vesanoid), a chemotherapy drug used to treat acute promyelocytic leukemia, was given in cases of little response, disease stability, or failure after four cycles of Vidaza and valproic acid.

The study evaluated response to treatment, transformation to acute myeloid leukemia (AML), survival, and side effects.

Forty-one patients completed four cycles of treatment, and 26 of those patients continued to complete the full eight cycles.

Of the patients that completed eight cycles of valproic acid and Vidaza, 31 percent achieved complete or partial remission. Hematologic improvement was reported in 15 percent, and the disease was stable in 39 percent. The Vidaza and valproic acid regimen also reduced the need for red blood cell transfusions.

However, the addition of tretinoin had no significant clinical benefit.

Patients’ prognostic factors had a significant impact on outcome. At 10 months, disease progression or transformation to AML was observed in 45 percent of high-risk patients compared to 10 percent of lower-risk Intermediate-2 patients. Likewise, survival was also negatively impacted by higher risk. Median survival was 8.9 months for high-risk patients and 18.7 months for Intermediate-2 patients.

Higher response rates were seen in patients who reached higher valproic acid concentrations in their blood, indicating that valproic acid enhances the efficacy of Vidaza.

The most common side effect was low blood cell counts. Twelve patients discontinued treatment due to infections, cardiovascular complications, and neurological toxicity. The mild neurological toxicity seen during treatment was most often linked to Vidaza, while toxicity linked to valproic acid was usually temporary and reversible, said Dr. Maria Teresa Voso of the Hematology Institute in Rome and principle investigator of the study.

“Side effects were mild, and I think that this combination is feasible in higher risk MDS patients,” said Voso.

According to Voso, the research group has plans for a randomized study involving a control group along with the combination therapy group.

For more information, please the study in Clinical Cancer Research (abstract).