HMA-HDAC Combination Safe and Feasible in Patients With AML and MDS After HSCT

The hypomethylating agent (HMA) azacitidine in combination with the histone deacetylase (HDAC) inhibitor valproic acid is a safe and feasible maintenance regimen for patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) following allogeneic hematopoietic stem cell transplant (HSCT), according to a study presented at the 2025 American Society of Clinical Oncology Annual Meeting.

Results of the investigator-initiated, single-center, phase 2 trial were presented by Timothy O’Connor, MD, of the Loyola University Medical Center.

At least 40 days after allogeneic HSCT, 55 patients (median age, 52 years) received subcutaneous azacitidine at 40 mg/m² daily for 5 days. Daily oral valproic acid was administered at a starting dose of 15 mg/kg and adjusted to achieve a trough level of bound valproic acid of 100 µg/mL.

Graft-versus-host-disease (GVHD) prophylaxis included tacrolimus and methotrexate. Twenty-one (42%) patients had matched related donors, 21 (42%) had matched unrelated donors, and 8 (12%) had cord blood donors. Thirty grafts were from peripheral blood, and 12 were from bone marrow. Patients with grades 3 or 4 acute GVHD were excluded from the study.

The primary endpoints were 1-year relapse rate, overall survival (OS), and progression-free survival (PFS). The 1-year relapse rate was 18%, the one-year PFS and OS rates were 80% and 86%, respectively, and the five-year PFS and OS rates were 47% and 61%, respectively. Toxicities were mostly grades 1 or 2 and included fatigue, cytopenias, and acute kidney injury.

“The co-administration of [azacitidine and valproic acid] as a short-term maintenance strategy following [allogeneic HSCT] in patients with high-risk MDS and AML is safe and feasible,” wrote Dr. O’Connor and colleagues. “While a comparative trial is warranted, the use of this HMA+HDAC regimen seems to validate prior data that HMA-based maintenance may improve the outcomes of high-risk MDS and AML patients.”