Currently, treatment options for patients with myelodysplastic syndromes (MDS) are limited. So far, the U.S. Food and Drug Administration has approved three drugs for the treatment of MDS: Revlimid (lenalidomide), Vidaza (azacitidine), and Dacogen (decitabine). In an effort to increase the treatment options for MDS patients, researchers are currently investigating various combination therapies involving the three currently approved drugs.

In this recent study, French researchers evaluated the efficacy of Vidaza in combination with valproic acid (Depakene), and tretinoin (all-trans retinoic acid, Vesanoid) in patients with high-risk MDS or acute myeloid leukemia (AML). 

Previous studies have demonstrated that Vidaza and valproic acid can be used together for the treatment of MDS (see related Beacon news).

Tretinoin, which is commonly used to treat acute promyelocytic leukemia, induces immature blood cells (called blasts) to mature and differentiate. The blasts would otherwise accumulate in the bone marrow, resulting in a lower number of healthy blood cells.

A total of 65 patients entered the study, with 34 of those patients receiving the six planned treatment cycles. The median patient age was 72 years. Ten patients had MDS, and 55 patients had AML (including 13 with relapsed/refractory cancer). Approximately half of the patients had chromosomal abnormalities associated with unfavorable prognoses for MDS and AML.

Of the patients that completed six treatment cycles, 38 percent achieved a complete response, and 6 percent achieved a partial response.  The researchers observed that patients who responded early to the treatment experienced a rapid recovery in platelet counts.

The median overall survival was 12.4 months for all patients and 19.6 months for patients who responded to treatment. Patients who had not received any treatment before lived significantly longer (18.1 months) compared to relapsing patients (2.9 months).

For the 34 patients who received all six treatment cycles, the overall survival was comparable for patients who responded to treatment and those who showed stable disease, which according to the study authors suggests that patient survival was not influenced by achieving a complete or partial response.

The most common side effects were confusion, fatigue, drowsiness, infection, constipation, nausea/vomiting, and bleeding. Fifteen patients died during the course of the study, with five causes of death due to disease progression.

For more information, please see the full study in the journal Oncotarget (PDF).

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).