A Phase I Trial of High-Dose Clofarabine, Etoposide, and Cyclophosphamide: A Novel Preparative Regimen Prior to Autologous Peripheral Blood Stem Cell (PBSC) Transplantation in Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma.

Abstract 3402

Poster Board III-290

Clofarabine (Clo) is a second-generation purine nucleoside antimetabolite, which unlike other purine nucleoside analogues, has a higher resistance to the action of adenosine deaminase and improved affinity for the activating phosphorylating enzyme deoxycytidine kinase, contributing to more potent activity against neoplastic cells. Recently, Clo was shown to have significant single agent activity in patients with relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL), but resulted in prolonged myelosuppression (Blum et al. Leuk Lymphoma 2009, 50: 349-56), suggesting that it may be a useful agent in high-dose therapy with stem cell support. We conducted a phase I trial to determine the maximum tolerated dose (MTD) of Clo in combination with high-dose Etoposide and Cyclophosphamide followed by autologous stem cell rescue in patients with relapsed or refractory NHL. Patients received Clo at 30-70 mg/m²/day on days -6 to -2 in successive cohorts, in combination with Etoposide 60 mg/kg day -8, and Cyclophosphamide 100 mg/kg days -6. G-CSF-mobilized autologous PBSC were infused on day 0. Patients were eligible if aged 18-70 years, had primary refractory or relapsed and refractory diffuse large cell lymphoma (DLCL), mantle cell lymphoma (MCL), or follicular lymphoma (FL), had Karnofsky performance status ≥70%, and adequate organ function. Toxicity was scored using the Common Terminology Criteria for Adverse events, version 3.0. Dose limiting toxicity (DLT) was defined as any grade 3-4 non-hematologic toxicity that did not resolve to grade 2 or less by day 30.

Fifteen patients were treated at 5 Clo dose levels, 30 (n=3), 40 (n=3), 50 (n=3), 60 (n=3), and 70 (n=3) mg/m²/day. Seven males and 8 females of median age 55 (32-67) years, with DLCL (n=8), MCL (n=3), and FL (n=4) were treated. At transplant, NHL was primary refractory (n=2), in first resistant relapse (n=7), and in second or third relapsed (n=6). Median number of lines of treatment failed before transplant was 3 (2-6). Median CD34+ count infused was 1.9 (0.9-3.7) x10⁶/kg. The median time to neutrophils >0.5×10⁹/l was 10 (9-13) days, and to platelets >20×10⁹/l was 16 (10-33) days. Only 1 patient treated at the 30 mg/m² dose level and infused with 0.9×10⁶ CD34+cell/kg failed to achieve platelets > 20×10⁹/l. No DLT was observed. Grades 3-4 non-hematological toxicity included neutropenic fever (n=9), vomiting (n=2), diarrhea (n=2), mucositis (n=1), and hemorrhagic cystitis (n=1); all toxicities resolved by day 30. Only grade 1-2 elevation of transaminases (AST/ALT) occurred; 2 of 3 patients at 30 mg/m², 3 of 3 at 40 mg/m², 2 of 3 at 50 mg/m², 1 of 3 at 60 mg/m², 2 of 3 patients at 70 mg/m² dose levels. AST/ALT peaked at day -1 to +1 and returned to baseline in all patients by day 10, with no long-term sequelae. There was no correlation between clofarabine dose and peak AST/ALT. No treatment related deaths occurred. Fourteen of the 15 patients (93%) achieved a response; complete response (CR) or CR unconfirmed (CRu) in 12, and partial response in 2 patients. Only patient treated at the 30 mg/m² dose level failed to respond. Four patients had progression of disease or relapse at 30 to 135 days after transplant. With a median follow-up of 199 days to date, the 1-year progression-free survival is 72% ± 12%, and the 1-year overall survival is 93% ± 6%. Clo at doses as high as 70 mg/m²/day x 5 days in combination with high-dose Etoposide (60 mg/kg) and Cyclophosphamide (100 mg/kg) are well tolerated, and showed promising efficacy in very-high risk NHL patients. The MTD has not been reached. We recommend the dose of Clo 70 mg/m²/day x 5 days in combination with high-dose Etoposide and Cyclophosphamide for Phase II testing as a preparative regimen in NHL patients undergoing autologous PBSC transplantation.