Hepsulfam is a bisulfamic
ester which is similar in structure to
busulfan and is believed to act as a bifunctional
alkylator inducing both
DNA-
DNA and
DNA-
protein crosslinks. Prior studies in patients with refractory solid
tumors have identified the dose-limiting toxicity of
hepsulfam to be cumulative myelosuppression resulting in prolonged
leukopenia and
thrombocytopenia. This phase I trial was designed to determine the maximally tolerated dose of
hepsulfam administered intravenously in patients with refractory
leukemias and other advanced
hematologic malignancies.
Hepsulfam was administered as a 30-min or 2-h
intravenous infusion to 21 patients with advanced
leukemia or
multiple myeloma. All patients had been extensively treated and had progressive disease. Cycles were repeated every 5 weeks. Cohorts of patients were treated at 360, 480, 640, and 800 mg/m2. The dose-limiting toxicity of intravenous
hepsulfam was severe
encephalopathy. The single patient treated at 800 mg/m2 became
comatose within 48 h and required 3 weeks for his mental status to return to baseline. There were, however, no irreversible neurological sequelae. Several patients treated at 640 mg/m2 had clinical evidence of toxic deliriums and slowing of alpha rhythm waves on electroencephalograms indicative of a gray-matter
encephalopathy. When
hepsulfam was infused over 30 min, patients complained of uncomfortable parasthesias, but when the
drug was administered over 2 h, these acute symptoms were less common. Myelosuppression was observed in most patients. Among those patients who had some suppression of their
leukemia, peripheral blood counts recovered to pretreatment levels after 3-5 weeks. Apart from CNS toxicity, non-hematologic toxicity was minimal. Pharmacokinetic studies demonstrated rapid clearance of
hepsulfam so that the
drug was not reliably detected in the plasma after 24 h. The recommended phase II dose of
hepsulfam as a single 2-h
intravenous infusion is 480 mg/m2, but this dose provided relatively little clinical benefit for patients with refractory
leukemia. The dose-limiting toxicity is CNS toxicity with increasingly severe
encephalopathy at doses > or = 640 mg/m2. It would be reasonable to investigate further dose escalation of
hepsulfam in a divided dose schedule to minimize the peak concentrations which may be related to the
encephalopathy. EEG monitoring is recommended for early detection of slowing of alpha rhythm waves. Hematopoietic stem cell support will probably be required at total doses exceeding 800 mg/m2.