THERAPEUTIC AND NEUROTOXIC EFFECTS OF 2-CHLORODEOXYADENOSINE IN ADULTS WITH ACUTE MYELOID-LEUKEMIA

Despite expectations that 2-chlorodeoxyadenosine (2-CdA) would prove a ctive primarily in lymphoproliferative diseases, early reports suggest ed unexpectedly high activity of this drug in heavily pretreated child ren with acute myeloblastic leukemia (AML) at a maximally tolerated do se of 8.9 mg/m(2)/day for 5 days. In view of these findings, we conduc ted 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/m(2) for 5 days. 2-CdA eliminated leukemic blasts fro m the peripheral blood in 32 of 36 cases; however, bone marrow hypopla sia was seen only at daily dose levels greater than or equal to 15 mg/ m(2). We observed a total of 3 complete remissions: 1 at the 15 mg/m(2 )/d dose level and 2 at the 21 mg/m(2)/d dose level; these responses p ersisted for 3, 2, and 3 months, respectively. Although prolonged myel osuppression would have been dose-limiting at 21 mg/m(2)/d for 5 days, the most important adverse effect was the development of a sensorimot or peripheral neuropathy. This reaction, whose onset was substantially delayed after completion of drug treatment, was observed in 2 of 5 pa tients at the 19 mg/m(2)/d level and in 4 of 4 evaluable patients at t he 21 mg/m(2)/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 m aximally tolerable dose of 2-CdA in adult patients (17 mg/ m(2)/d for 5 days) is approximately twofold in excess of that previously reported in children and that the limiting toxic effect is a degenerative neur opathic disorder. We confirm that this drug has definite activity in A ML, but the magnitude of this effect needs to be determined in larger numbers of patients who have received less extensive therapy. This age nt deserves further evaluation in patients with both AML and acute lym phoblastic leukemia at these higher doses and perhaps as part of a pre parative regimen for patients undergoing bone marrow transplantion. (C ) 1994 by The American Society of Hematology.