Therapeutic and neurotoxic effects of 2-chlorodeoxyadenosine in adults with acute myeloid leukemia Journal Article

Authors: Vahdat, L.; Wong, E. T.; Wile, M. J.; Rosenblum, M.; Foley, K. M.; Warrell, R. P. Jr
Article Title: Therapeutic and neurotoxic effects of 2-chlorodeoxyadenosine in adults with acute myeloid leukemia
Abstract: Despite expectations that 2-chlorodeoxyadenosine (2-CdA) would prove active primarily in lymphoproliferative diseases, early reports suggested unexpectedly 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 ≥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) is 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.
Keywords: immunohistochemistry; adolescent; adult; clinical article; aged; aged, 80 and over; acute granulocytic leukemia; gadolinium; neurotoxicity; nuclear magnetic resonance imaging; bone marrow suppression; nausea; peripheral neuropathy; protein; aciclovir; motor neurons; lymphoma; creatine kinase; lymphoproliferative disease; blood cell count; infusions, intravenous; axons; epstein barr virus; peripheral nervous system diseases; cladribine; leukemia remission; middle age; thyroxine; demyelination; nerve fiber degeneration; neural conduction; leukemia, myelocytic, acute; leukemia, myeloid, chronic; sural nerve; human; priority journal; article; headache and facial pain; support, u.s. gov't, p.h.s.
Journal Title: Blood
Volume: 84
Issue: 10
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 1994-11-15
Start Page: 3429
End Page: 3434
Language: English
PROVIDER: scopus
PUBMED: 7949097
Notes: Export Date: 14 January 2019 -- Article -- Source: Scopus