PURPOSE: Richter's syndrome (RS) and fludarabine-refractory chronic lymphocytic leukemia (CLL) are associated with poor clinical outcomes. We conducted a phase I-II trial of oxaliplatin, fludarabine, cytarabine, and rituximab (OFAR) in these diseases. PATIENTS AND METHODS: The OFAR regimen consisted of increasing doses of oxaliplatin (17.5, 20, or 25 mg/m(2)/d) on days 1 to 4 (phase I), fludarabine 30 mg/m(2) on days 2 to 3, cytarabine 1 g/m(2) on days 2 to 3, rituximab 375 mg/m(2) on day 3 of cycle 1 and day 1 of subsequent cycles, and pegfilgrastim 6 mg on day 6, every 4 weeks for a maximum of six courses. Dose-limiting toxicity (DLT) was defined as any nonhematologic, treatment-related toxicity >/= grade 3. RESULTS: Fifty patients were treated (20 patients had RS, and 30 had CLL). The highest tolerated oxaliplatin dose was 25 mg/m(2), which was the highest dose tested. DLT was not observed. Pharmacodynamic analyses demonstrated enhanced leukemia cell killing by oxaliplatin in the presence of fludarabine and cytarabine. The overall response rates were 50% in RS and 33% in fludarabine-refractory CLL. The overall response rate in 14 patients with age >/= 70 years was 50%. Responses were achieved in seven (35%) of 20 patients with 17p deletion, two (29%) of seven patients with 11q deletion, all four patients with trisomy 12, and two (40%) of five patients with 13q deletion. The median response duration was 10 months. Toxicities were mainly hematologic; prolonged myelosuppression was not observed. CONCLUSION: The OFAR regimen is highly active in RS and has activity in fludarabine-refractory patients with CLL. This regimen warrants further investigation in the treatment of these disorders.