Hexamethylene bisacetamide in myelodysplastic syndrome: Effect of five-day exposure to maximal therapeutic concentrations

Eric K. Rowinsky, Barbara A. Conley, Richard J. Jones, Jerry L. Spivak, Michael Auerbach, Ross C. Donehower

Research output: Contribution to journalArticle

Abstract

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 antiproliferative 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.

Original languageEnglish (US)
Pages (from-to)526-534
Number of pages9
JournalLeukemia
Volume6
Issue number6
StatePublished - Jun 1992

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ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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