Dose-escalation trial of cladribine using five daily intravenous infusions in patients with advanced hematologic malignancies

Purpose: The optimal dose and schedule for cladribine (SCdA) therapy of malignant hematologic diseases have not been determined. This dose-escalation study was designed to assess toxicity when SCdA is given using five daily 1-hour intravenous infusions. Patients and Methods: Forty-two adults with advances hematologic malignancies were treated in one of nine cohorts, starting at 2.5 mg/m(2)/d for 5 days. Plasma drug concentrations 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 received 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 common in the higher 2CdA dose cohorts. Logistic regression analysis suggested that severe hematologic toxicity was associated with pretreatment platelet count and performance status (PS). Good-risk patients were identified 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 120,000/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 (PRs) were observed in eight patients. Conclusion: 2CdA can be administered using five daily 1-hour infusions at 21.5 mg/m(2)/d without dose-limiting nonhematologic toxicity. Unlike continuous intravenous infusions, neurotoxicity was not observed using this schedule. Further dose escalation may be possible in good PS patients with adequate platelet counts. (C) 1996 by American Society of Clinical Oncology.