Maintenance therapy with azacitidine and valproic acid after allogeneic stem cell transplant in patients with high-risk myelodysplastic syndrome and acute myelogenous leukemia.

6578 Background: Relapse is a major cause of death after allogeneic stem cell transplant (allo-SCT) in patients with high-risk myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Chemotherapy maintenance to prevent relapse has had limited success to date, with a phase 3 hypomethylating agent (HMA) study showing no improvement in relapse rate or survival (Oran et al.). A subgroup analysis, however, showed that high-risk patients may indeed benefit (Pasvolsky et al.). We tested a combination of an HMA [azacitidine (AZA)] and a histone deacetylase (HDAC) inhibitor [valproic acid (VPA)] as a novel maintenance following allo-SCT for high-risk AML and MDS patients based on previously reported in vitro synergism between these agents. Methods: This investigator-initiated, single-center, phase II trial included only patients with high-risk MDS and AML who were enrolled following day+40 of allo-SCT to receive AZA and VPA for 4, 28 day cycles. Exclusions included no grade 3-4 acute GVHD, active infection, low risk AML in CR1, a neutrophil count < 1500/µl, or platelets < 50 000/µl. Risk was assessed via DRI at time of transplant. AZA was administered at 40 mg/m2 daily for 5 days SQ with daily oral VPA starting at 15 mg/kg and dose-adjusted to achieve a trough level of bound VPA of 100 µg/mL. Tacrolimus and methotrexate were used as GVHD prophylaxis. The primary endpoints were 1-year relapse rate, overall (OS), and progression-free (PFS) survival. Results: Fifty patients were enrolled. The median age was 52 with 28 (56%) male. The median hematopoietic cell transplantation-specific comorbidity index was 2. Graft types: 21 (42%) matched related, 21 (42%) matched unrelated, and 8 (12%) cord blood. Thirty grafts were from peripheral blood and 12 marrow. Myeloablative conditioning was used in 36 (72%) and reduced intensity conditioning in 14 (28%). At time of transplant for AML patients, 21 (46%) were in CR1, 5 (11%) in CR2, 2 (4%) in CRi, and 18 (39%) were relapsed/refractory. Four had high grade MDS. Baseline DRI: 42 (84%) were very high risk or high risk and 8 (16%) were intermediate risk. Eight (16%) patients did not receive all four cycles: 5 (10%) due to progression of disease, 1 (2%) due to acute GVHD, 1 each (2%) due to fatigue and cytopenias. One-year PFS and OS were 80% and 86% and 5-year PFS and OS were 47% and 61%, respectively. The one-year relapse rate was 18%. Most toxicities were grade I or II: fatigue, cytopenias, and acute kidney injury. Conclusions: The co-administration of AZA and VPA as a short-term maintenance strategy following allo-SCT in patients with high risk MDS and AML is safe and feasible. 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. Clinical trial information: NCT02124174 .