The efficacy of
hexamethylene bisacetamide (
HMBA), a potent polar-planar
solvent which is capable of differentiating
leukemias and solid
tumors in vitro at clinically achievable concentrations, was studied in 16 patients with severe
myelodysplastic syndromes (MDS). An adaptive control dosing algorithm was used to maintain
HMBA steady-state concentrations (Css) within a narrow therapeutic window (1-2 mM) for five days every four weeks. Despite achieving the target
HMBA Css during at least two courses in each of 15 patients,
HMBA did not produce clinically relevant improvements in blood cell counts nor in other functional indices. Instead,
HMBA induced
cytopenias in the majority of these patients, most of whom had preexisting
cytopenias and limited hematopoietic reserves. These disappointing results correlated with concurrent in vitro bone marrow studies from these patients in which both the
HMBA concentrations that were optimal for differentiation in vitro (2-5 mM) and the
HMBA Css that were achieved in this study (1-2 mM) substantially inhibited the growth of granulocyte-macrophage colony-forming units and erythroid burst-forming units. Although the mechanism responsible for the anti-proliferative effects of
HMBA on hematopoietic progenitors (cytotoxicity versus terminal differentiation) could not be determined, the induction of
cytopenias and lack of significant clinical improvements suggest that
HMBA is cytotoxic and will not be useful alone as a differentiating agent on this schedule of administration in the treatment of MDS.