Hexamethylene bisacetamide in myelodysplastic syndrome and acute myelogenous leukemia: a phase II clinical trial with a differentiation- inducing agent

Abstract

Hexamethylene bisacetamide (HMBA) is a potent inducer of differentiation of a number of transformed cell lines in vitro. We report results of a phase II clinical trial in 41 patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) to whom HMBA was administered by continuous infusion for 10 days and repeated after an interval of 18 to 75 days. HMBA induced a complete remission (CR) in three patients and a partial remission (PR) in six patients. The median duration of CR was 6.8 months (range 1.3 to 16 months) and 3.7 months for PR (range 1 to 7 months). No significant difference was observed between responders and nonresponders with respect to the mean HMBA plasma levels, which were 0.86 +/- 0.04 mmol/L and 0.87 +/- 0.12 mmol/L, respectively. In certain patients morphologic and chromosome analyses provided evidence that HMBA induced differentiation of transformed hematopoietic precursors. The most prominent toxicity was thrombocytopenia, generally reversible on cessation of administration of HMBA.

Notch-1 inhibits apoptosis in murine erythroleukemia cells and is necessary for differentiation induced by hybrid polar compounds

“…Among these, hybrid polar compounds can induce differentiation in transformed cells derived from many tissues of all embryonic lineages [Marks et al, 1996]. The prototype of this class, hexamethylene bisacetamide (HMBA) has been extensively characterized in vitro [Marks et al, 1996] and has been clinically tested in patients with hematopoietic malignancies [Andreef et al, 1992]. The mechanism of action of HMBA has been studied extensively in murine erythroleukemia (MEL) cell lines.…”

Induction of Differentiation and Apoptosis— A Possible Strategy in the Treatment of Adult Acute Myelogenous Leukemia

“…Hexamethylene bisacetamide (HMBA) is classified as a hybrid polar compound, and this agent can induce differentiation and apoptosis in malignant cells [63][64][65]. HMBA is not suitable for clinical therapy due to dose-limiting toxicity [64], but the second generation of hybrid polar compounds seems to include agents that are much more potent inducers, and in contrast to HMBA these new agents are also potent inhibitors of HDAC activity [65].…”

Differentiation Therapy of Myelodysplastic Syndromes: Fact or Fiction?

“…None of the patients had a reduction in transfusion requirements, but in 3/16 there was a reduction of blasts, even if accompanied, as in all other cases, by leucopenia and thrombocytopenia ( Rowinsky et al , 1992 ). The second phase II trial ( Andreef et al , 1992 ) was based on the 10 d course at 4‐week intervals. A total of 41 patients were included in the study; 24 MDS (six RA, two RARS, 10 RAEB, four RAEB‐T, two CMML) and 17 AML.…”