Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome

Abstract

Epigenetic mechanisms underlying tumorigenesis have recently received much attention as potential therapeutic targets of human cancer. We designed a pilot study to target DNA methylation and histone deacetylation through the sequential administration of 5-azacytidine followed by sodium phenylbutyrate (PB) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Ten evaluable patients (eight AML, two MDS) were treated with seven consecutive daily subcutaneous injections of 5-azacytidine at 75 mg/m 2 followed by 5 days of sodium PB given intravenously at a dose of 200 mg/kg. Five patients (50%) were able to achieve a beneficial clinical response (partial remission or stable disease). One patient with MDS proceeded to allogeneic stem cell transplantation and is alive without evidence of disease 39 months later. The combination regimen was well tolerated with common toxicities of injection site skin reaction (90% of the patients) from 5-azacytidine, and somnolence/fatigue from the sodium PB infusion (80% of the patients). Correlative laboratory studies demonstrated the consistent reacetylation of histone H4, although no relationship with the clinical response could be demonstrated. Results from this pilot study demonstrate that a combination approach targeting different mechanisms of transcriptional modulation is clinically feasible with acceptable toxicity and measurable biologic and clinical outcomes.

Myelodysplastic Syndromes: Review of Pathophysiology and Current Novel Treatment Approaches

“…A pilot study combining phenylbutyrate (HDI) with 5-azacitidine showed that both complete and partial remissions could be achieved in nearly half of the MDS and AML patients and showed a strong association between the clinical responses and changes in hypermethylation and expression of p15 [200]. The clinical responses were supported with findings from a second pilot study of the same combination [201]. Gore et al combined MS-275 (HDI) with 5-azacitidine (DMTI) in a follow-up pilot study recently presented in abstract form at ASH 2006 2 .…”

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

“…Cameron et al (1999) first reported the synergistic effect of DNMT inhibitors with HDAC inhibitors on global acetylation of histones H3 and H4. This was also detected in vivo in peripheral blood leukocytes from AML/MDS patients undergoing treatment with the DNMT inhibitor 5-azacytidine and the HDAC inhibitor sodium PB (Gore et al, 2006;Maslak et al, 2006), and with decitabine and VPA (Garcia-Manero et al, 2006;Blum et al, 2007).…”

Mechanistic insight into WEB-2170-induced apoptosis in human acute myelogenous leukemia cells: The crucial role of PTEN

“…This approach, however, is not effective on ATRA-resistant APL forms and other AML (non-APL) subtypes [3], which are refractory to ATRA-induced differentiation [4]. Therefore, the current treatment for the bulk of the other AML subtypes still consists of high-dose chemotherapy with potential lifethreatening toxicity and acquired drug resistance [5].Inhibitors of histone deacetylases [6] and DNA demethylating agents [7,8] 2009;37:1176-1185 [9], thus providing additional tools for cancer therapy [10]. Indeed, epigenetic modulators are functional to set up an environment permissive for cell differentiation and/or apoptosis, but may not always be sufficient themselves to trigger these processes without the cooperation of other proactive signals.…”