Inorganic
arsenic trioxide (
As(2)O(3)) induces a high proportion of complete remissions in relapsed patients with
acute promyelocytic leukemia (APL). Previously, we have shown that both
As(2)O(3 )and
melarsoprol, an organic arsenical used for the treatment of
trypanosomiasis, exhibit broad antileukemic activity against both chronic and acute myeloid and
lymphoid leukemia cell lines. Given the breadth of this activity, we initiated a clinical study to evaluate the pharmacokinetics, safety, and potential efficacy of
melarsoprol in patients with refractory or resistant
leukemia. Using the antitrypanosomal dose and schedule, patients received escalating intravenous doses daily for 3 days, repeated weekly for 3 weeks. Doses were 1 mg/kg on day 1, 2 mg/kg on day 2, and 3.6 mg/kg on day 3 and on all days thereafter, up to a maximum daily dose of 200 mg. Eight patients [6 AML (2 morphologic APL), 1 CML, 1 CLL] were treated. Mean peak plasma concentrations of the parent
drug were obtained immediately after injection, ranged from 1.2 microg/ml on day 1 to 2.4 microg/ml on day 3, were dose proportional, and decayed with a t(1/2) congruent with 15 min. A minor clinical response (regression of
splenomegaly and
lymphadenopathy) was observed in a patient with
chronic lymphocytic leukemia. Central nervous system (CNS) toxicity proved limiting on this dose and schedule. Three patients experienced generalized grand mal
seizures during the second week of
therapy. We concluded that this dose and schedule of
melarsoprol is associated with excessive CNS toxicity and that verification of the striking preclinical activity in patients with
leukemia will require developing an alternative dose and schedule.