Hexamethylene bisacetamide in myelodysplastic syndrome: effect of five-day exposure to maximal therapeutic concentrations.
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.
Rowinsky
E K
EK
Johns Hopkins Oncology Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205.
Conley
B A
BA
Jones
R J
RJ
Spivak
J L
JL
Auerbach
M
M
Donehower
R C
RC
D000081:Acetamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D000328:Adult; D000368:Aged; D000465:Algorithms; D002455:Cell Division / Q000187:drug effects; D003864:Depression, Chemical; D004334:Drug Administration Schedule; D005260:Female; D006397:Hematinics / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate; D013921:Thrombocytopenia / Q000139:chemically induced
D000081:Acetamides; D006397:Hematinics; C014026:hexamethylene bisacetamide