Combination of Oxaliplatin, Fludarabine, Cytarabine, and Rituximab in Richter’s Syndrome and Fludarabine-Refractory Chronic Lymphocytic Leukemia.
Authors: Tsimberidou Apostolia-Maria , Wierda William G. , O’Brien Susan , Plunkett William W. , Kipps Thomas J. , Brown Jennifer R. , Lerner Susan , Kantarjian Hagop , Keating Michael J. 
Published: October 2019

Abstract
Background: Richter’s syndrome (RS) and fludarabine-refractory chronic lymphocytic leukemia (CLL) are associated with poor prognosis. Oxaliplatin is a platinum compound that covalently binds DNA, inducing DNA intra- and inter-strand cross-links. Fludarabine and cytarabine act synergistically to inhibit excision repair of DNA cross-links. We conducted a phase 1–2 trial of oxaliplatin, fludarabine, cytarabine, and rituximab (OFAR) in patients with RS or fludarabine-refractory CLL. The objectives of this trial were to identify a safe, tolerated dose and any dose-limiting toxicities (DLT) of oxaliplatin, to assess pharmacodynamic endpoints (phase 1); and to assess the complete (CR) and partial remission (PR) rates for the OFAR regimen (phase 2).
Methods: The OFAR regimen consisted of increasing doses of oxaliplatin (17.5, 20, or 25 mg/m2/d), D1–4 (phase 1); fludarabine 30 mg/m2, D2–3; cytarabine 1 g/m2, D2–3; rituximab 375 mg/m2, D3; and pegfilgrastim 6 mg, D6, every 4 weeks for a maximum of 6 courses. Prophylaxis for PCP pneumonia and DNA virus were given. DLT was defined as any non-hematologic, treatment-related toxicity > grade (G) 3.
Results: From November 2004 to August 2006, 46 patients were enrolled, including 19 patients in phase 1. The tolerated oxaliplatin dose identified was 25 mg/m2. No DLT was observed. Pharmacodynamic analyses demonstrated enhanced leukemia cell killing by oxaliplatin in the presence of fludarabine and cytarabine. Thirty-seven patients are currently evaluable (14 RS, 23 fludarabine-refractory CLL). The median age of patients with RS was 69 yrs (range, 41–78) and of fludarabine-refractory CLL was 57 yrs (range, 34–77); the median number of prior therapies was 3 (range, 0–10), and 4 (range, 1–11), respectively. Among patients with fludarabine-refractory CLL, 16 (70%) had Rai stage 3–4. G3–4 septic episodes occurred in 2, pneumonia in 4, and CMV infection occurred in 2 patients. The median number of OFAR cycles was 2 (range, 1–6). RBC and platelet transfusions were required in 56% and 61% of cycles, respectively. Responses are shown in Table [insert].
Nine patients (1 RS) received allogeneic stem cell transplantation. Responses included 6 of 16 patients with 17p deletion, 1 of 5 evaluable patients with 11q deletion, 3 of 3 patients with trisomy 12, 1 of 4 patients with 13q deletion, and 2 of 7 others. With a median follow-up of 7 months, 6 of 14 with RS and 11 of 23 patients with fludarabine-refractory CLL have failed. The median failure-free survival has not been reached for RS and is 4 months for fludarabine-refractory CLL.
Conclusions: The OFAR regimen is highly active in RS and has activity in fludarabine-refractory patients with CLL. No DLT for oxaliplatin at 25 mg/m2 was noted. Hematologic toxicities did occur, but no prolonged myelosuppression was observed. The trial continues to accrue patients, with a target accrual of 40 patients on phase 2.
Oxaliplatin dose (mg/m2/d) 17.5 20 25 All doses RS Evaluable 2 5 5 12 CR 0 2 1 3 PR 0 2 2 4 Overall (%) 0 4 (80) 3 (60) 7 (58) Fludarabine-refractory CLL Evaluable 1 3 19 23 CR, nodular 0 0 1 1 PR 0 0 5 5 Overall (%) 0 0 6 (32) 6 (26) Total (%) 0 4 (50) 9 (38) 13 (37)