PHASE-I STUDY OF CLADRIBINE (2-CHLORODEOXYADENOSINE) IN LYMPHOID MALIGNANCIES

Cladribine (2-chlorodeoxyadenosine;) is a purine analogue with clinica l activity against hairy cell leukemia, chronic lymphocytic leukemia a nd indolent lymphoma. To clarify the toxicity profiles of cladribine, we conducted a phase I and pharmacological study of cladribine with a schedule of seven-day continuous intravenous infusion every 28 days up to a maximum of three cycles. We enrolled 10 previously-treated patie nts with various lymphoid malignancies. No dose-limiting toxicity (gra de 4 hematologic and/or grade 3 or more non-hematologic) was observed in the three patients who received 0.06 mg/kg/day (Level 1). Of the se ven patients who received 0.09 mg/kg/day (Level 2), one patient develo ped grade 4 hypoxemia and grade 4 thrombocytopenia, and another develo ped grade 4 neutropenia. Of the seven patients treated at Level 2, one with cutaneous T-cell lymphoma attained complete remission, and one w ith mantle cell lymphoma, one with chronic lymphocytic leukemia and on e with adult T-cell leukemia-lymphoma attained partial remission. A ph armacokinetic analysis of the seven patients without leukemic cells sh owed that their area under the concentration versus time curves of pla sma cladribine increased dose-dependently from 2661.3 +/- 300.4 nMxh a t Level 1 (n = 3) to 3411.3 +/- 341.0 nMxh at Level 2 (n = 4) (P = 0.0 34). We conclude that the recommended phase II dose of cladribine (0.0 9 mg/kg/day as a seven-day continuous i.v. infusion) in Caucasian pati ents can be safely administered to Japanese patients. The encouraging results prompted us to plan subsequent phase II studies of cladribine against adult T-cell leukemia-lymphoma, hairy cell leukemia and indole nt lymphoma.