Phase I-II clinical trial of oxaliplatin, fludarabine, cytarabine, and rituximab therapy in aggressive relapsed/refractory chronic lymphocytic leukemia or Richter syndrome

Background: To improve outcomes of patients with Richter syndrome (RS) and relapsed/refractory chronic lymphocytic leukemia (CLL), we modified the OFAR1 regimen (oxaliplatin and cytarabine doses of the oxaliplatin, fludarabine, cytarabine, and rituximab) for this phase I-II study (OFAR2). Patients and Methods: OFAR2 consisted of oxaliplatin at 30 mg/m² on days 1 to 4, fludarabine at 30 mg/m², cytarabine at 0.5 g/m², rituximab at 375 mg/m² on day 3, and pegfilgrastim at 6 mg on day 6. Fludarabine and cytarabine were given on days 2 and 3 (cohort 1), days 2 to 4 (cohort 2), or days 2 to 5 (cohort 3) every 4 weeks. Phase II followed the "3 + 3" design of phase I. Results: The 102 patients (CLL, 67; RS, 35) treated had heavily pretreated high-risk disease. Twelve patients were treated in phase I; cohort 2 was the phase II recommended dose. The most common toxicities were hematologic. Response rates (phase II) were 38.7% for RS (complete response [CR], 6.5%) and 50.8% for relapsed/refractory CLL (CR, 4.6%). The median survival durations were 6.6 (RS) and 20.6 (CLL) months. Among 9 patients who underwent allogeneic stem cell transplantation (SCT) as post-remission therapy, none has died (median follow-up, 15.9 months). Conclusion: OFAR2 had significant antileukemic activity in RS and relapsed/refractory CLL. Patients undergoing SCT as post-remission therapy had favorable outcomes.