TY - JOUR
T1 - Clinical study of an organic arsenical, melarsoprol, in patients with advanced leukemia
AU - Soignet, Steven L.
AU - Tong, William P.
AU - Hirschfeld, Steven
AU - Warrell, Raymund P.
N1 - Funding Information:
Presented in part at the Annual Meeting of the American Society of Hematology, San Diego, 8 December 1997 Supported in part by FD-R-001364 from the Orphan Products Division, Food and Drug Administration, and The Lymphoma Foundation. Steven Soignet is a Mortimer J. Lacher Fellow S.L. Soignet (& ) á R.P. Warrell, Jr. Developmental Chemotherapy, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, 1275 York Avenue, New York, NY 10021, USA e-mail: soignets@mskcc.org Tel. +1-212 639-8984; Fax +1-212 717-3272 W.P. Tong á R.P. Warrell, Jr. Leukemia Services, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, NY, USA
PY - 1999
Y1 - 1999
N2 - Inorganic arsenic trioxide (As2O3) induces a high proportion of complete remissions in relapsed patients with acute promyelocytic leukemia (APL). Previously, we have shown that both As2O3 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 melarsoproI 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 μg/ml on day 1 to 2.4 μg/ml on day 3, were dose proportional, and decayed with a t(1/2β) ≃ 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.
AB - Inorganic arsenic trioxide (As2O3) induces a high proportion of complete remissions in relapsed patients with acute promyelocytic leukemia (APL). Previously, we have shown that both As2O3 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 melarsoproI 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 μg/ml on day 1 to 2.4 μg/ml on day 3, were dose proportional, and decayed with a t(1/2β) ≃ 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.
KW - Advanced leukemia
KW - AsO
KW - Inorganic arsenic trioxide
KW - Melarsoprol
KW - Organic arsenical
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U2 - 10.1007/s002800050998
DO - 10.1007/s002800050998
M3 - Article
C2 - 10501916
AN - SCOPUS:0032831858
SN - 0344-5704
VL - 44
SP - 417
EP - 421
JO - Cancer chemotherapy and pharmacology
JF - Cancer chemotherapy and pharmacology
IS - 5
ER -