DOSE-ESCALATION TRIAL OF CLADRIBINE USING 5 DAILY INTRAVENOUS INFUSIONS IN PATIENTS WITH ADVANCED HEMATOLOGIC MALIGNANCIES

Purpose: The optimal dose and schedule for cladribine (SCdA) therapy o f malignant hematologic diseases have not been determined. This dose-e scalation study was designed to assess toxicity when SCdA is given usi ng five daily 1-hour intravenous infusions. Patients and Methods: Fort y-two adults with advances hematologic malignancies were treated in on e of nine cohorts, starting at 2.5 mg/m(2)/d for 5 days. Plasma drug c oncentrations were measured by high-performance liquid chromatography. Responses were assessed by bone marrow biopsy on day 15 of the first course and by clinical measurements after each course. Patients receiv ed one to four courses each. Results: Nonhematologic toxicity was mild , and dose-limiting nonhematologic toxicity was not observed, even at the highest dose level of 21,5 mg/m(2)/d. In particular, neurotoxicity was not observed. The maximum-tolerated dose (MTD) was not identified . However, pro longed cytopenias and severe infections were more commo n in the higher 2CdA dose cohorts. Logistic regression analysis sugges ted that severe hematologic toxicity was associated with pretreatment platelet count and performance status (PS). Good-risk patients were id entified as having a PS of 0 and platelet count greater than or equal to 80,000/mu L, PS of 1 and platelet count greater than or equal to 12 0,000/mu L, or PS of 2 and platelet count greater than or equal to 160 ,000/mu L. Sustained complete responses (CRs) and partial responses (P Rs) were observed in eight patients. Conclusion: 2CdA can be administe red using five daily 1-hour infusions at 21.5 mg/m(2)/d without dose-l imiting nonhematologic toxicity. Unlike continuous intravenous infusio ns, neurotoxicity was not observed using this schedule. Further dose e scalation may be possible in good PS patients with adequate platelet c ounts. (C) 1996 by American Society of Clinical Oncology.