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Therapeutic and neurotoxic effects of 2-chlorodeoxyadenosine in adults with
acute myeloid leukemia
L Vahdat, ET Wong, MJ Wile, M Rosenblum, KM Foley and RP Warrell
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York,
NY 10021.
Despite expectations that 2-chlorodeoxyadenosine (2-CdA) would prove active
primarily in lymphoproliferative diseases, early reports suggested
unexpected high activity of this drug in heavily pretreated children with
acute myeloblastic leukemia (AML) at a maximally tolerated dose of 8.9
mg/m2/day for 5 days. In view of these findings, we conducted an escalating
dose trial of 2-CdA in adult patients with relapsed or resistant AML.
Thirty-six patients who had received extensive prior therapy were treated
at 9 dose levels of 2-CdA at daily doses ranging from 5 to 21 mg/m2 for 5
days. 2-CdA eliminated leukemic blasts from the peripheral blood in 32 of
36 cases; however, bone marrow hypoplasia was seen only at daily dose
levels > or = 15 mg/m2. We observed a total of 3 complete remissions: 1
at the 15 mg/m2/d dose level and 2 at the 21 mg/m2/d dose level; these
responses persisted for 3, 2, and 3 months, respectively. Although
prolonged myelosuppression would have been dose-limiting at 21 mg/m2/d for
5 days, the most important adverse effect was the development of a
sensorimotor peripheral neuropathy. This reaction, whose onset was
substantially delayed after completion of drug treatment, was observed in 2
of 5 patients at the 19 mg/m2/d level and in 4 of 4 evaluable patients at
the 21 mg/m2/d level. Pathologically, this process was characterized by
axonal degeneration and secondary demyelination. Other side effects
included reactivation of a posttransplant Epstein-Barr virus-related
lymphoma in 1 patient and tumor lysis syndrome. We conclude that the
maximally tolerable dose of 2-CdA in adult patients (17 mg/m2/d for 5 days)
in approximately twofold in excess of that previously reported in children
and that the limiting toxic effect is a degenerative neuropathic disorder.
We confirm that this drug has definite activity in AML, but the magnitude
of this effect needs to be determined in larger numbers of patients who
have received less extensive therapy. This agent deserves further
evaluation in patients with both AML and acute lymphoblastic leukemia at
these higher doses and perhaps as part of a preparative regimen for
patients undergoing bone marrow transplantation.
Volume 84,
Issue 10,
pp. 3429-3434,
11/15/1994
Copyright © 1994 by The American Society of Hematology
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