ORLANDO (FRONTLINE MEDICAL NEWS) – Azacitadine and valproic acid can be safely coadministered as maintenance therapy after allogeneic stem cell transplantation in patients with high-risk acute myelogenous leukemia (AML), according to interim findings from an investigator-initiated phase II study.

One-year relapse-free and overall survival rates were about 80%, and no significant toxicities were reported in 28 such patients who began the treatment at least 40 days after transplant and were treated for 4 months, Patrick A. Hagen, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Patients had been followed for a median of 18.4 months at the time of the analysis, and median relapse-free and overall survival had not been reached. Nonrelapse mortality at 1 year was 4.2%, said Dr. Hagen of Loyola University Medical Center in Chicago.

“As we all know, relapse after allogeneic transplant for AML is a huge and ongoing problem. It’s the primary cause of death following transplant, and unfortunately it really hasn’t decreased over the past couple decades,” Dr. Hagen said, adding that relapse is of increasing concern for biologically high-risk patients and is a “pretty ripe area for improved methodologies or approaches.” The decision to pursue maintenance therapy after transplant is complicated: It’s a good opportunity to improve outcomes, but there are many challenges, including problems with drug interactions and myelosuppression, he said.

The study was undertaken based in part on previously reported findings of synergism of a demethylating agent and a histone dacetylase inhibitor in patients with AML, he said.

The maintenance therapy included up to four 28-day cycles of azacitadine at 40 mg/m2 daily on days 1-5, along with oral valproic acid daily throughout the cycle at a 15-mg/kg dose adjusted to achieve a 100-mcg/mL trough level of bound valproic acid as tolerated. Nineteen patients completed all four cycles of treatment.

“The regimen was pretty well tolerated. The vast majority of the toxicities were grade I/II – 70%. The only grade-4 toxicities were cytopenia related and did not lead to a delay in treatment,” he said.

No patients developed acute graft-versus-host disease after therapy, although 11 (39%) developed chronic GVHD, which was extensive in 8, Dr. Hagen said.

Study participants were adults with high-risk AML with no grade 3-4 acute GVHD. All had adequate organ function after allogeneic stem cell transplantation (allo-SCT) performed 40-60 days prior to the start of maintenance therapy. Those with active or uncontrolled infections, low-risk AML in first relapse, neutrophil counts below 1,500, and platelets below 50,000 were excluded, he said.

The patients’ median age was 44 years, they had a median of two prior chemotherapy regimens, and their median Sorror Comorbidity Index was 2.5. Cytogenetics were mostly intermediate and adverse; only one patient had favorable cytogenetics.

Graft type was mixed, with most patients having matched unrelated donors. Conditioning regimens also were mixed, although they “skewed toward myeloablative,” he said. GVHD prophylaxis was standard for the institution and included tacrolimus and methotrexate.

The promising 1-year overall survival and relapse rate without significant dose-limiting toxicities warrants further evaluation in a phase III trial, Dr. Hagen concluded.

He reported having no disclosures.