A Phase I Trial of High-Dose Clofarabine, Etoposide, and Cyclophosphamide and Autologous Peripheral Blood Stem Cell Transplantation in Patients with Primary Refractory and Relapsed and Refractory Non-Hodgkin Lymphoma

作者：Srivastava Shivani; Jones David; Wood Lisa L; Schwartz Jennifer E; Nelson Robert P Jr; Abonour Rafat; Secrest Angie; Cox Elizabeth; Baute Jay; Sullivan Cheryl; Kane Kathleen; Robertson Michael; Farag Sherif S^*

来源：Biology of Blood and Marrow Transplantation, 2011, 17(7): 987-994.

DOI：10.1016/j.bbmt.2010.10.016

• Autologous stem cell transplantation
• Clofarabine
• non-Hodgkins lymphoma

Clofarabine has significant single-agent activity in patients with indolent and aggressive non-Hodgkin lymphoma and synergizes with DNA-damaging drugs. Treatment, however, may be associated with severe and prolonged myelosuppression. We conducted a phase 1 trial to determine the maximum tolerated dose (MTD) of clofarabine in combination with high-dose etoposide and cyclophosphamide followed by autologous peripheral blood stem cell transplantation in patients with refractory non-Hodgkin lymphoma (NHL). Patients received clofarabine at 30-70 mg/m(2)/day on days 6 to 2 in successive cohorts, in combination with etoposide 60 mg/kg (day 8), and cyclophosphamide 100 mg/kg (day 6), followed by filgrastim-mobilized PBSC on day 0. Sixteen patients of median age 57 (range: 32-67) years with diffuse large B cell (n = 8), follicular (n = 5), or mantle cell (n = 3) lymphoma that was either primary refractory (n = 2) or relapsed and refractory (n = 14) were treated at 5 clofarabine dose levels: 30 (n = 3), 40 (n = 3), 50 (n = 3), 60 (n = 3), and 70 mg/m(2)/day (n = 4) in combination with etoposide and cyclophosphamide. All patients had grade 4 neutropenia and thrombocytopenia. Grade 3-4 nonhematologic toxicity was evenly distributed across all 5 dose levels, and included diarrhea (n = 3), mucositis (n = 1), nausea (n = 1), reversible elevation of alanine aminotranferease/aspartate aminotransferase (AST/ALT) (n = I) or bilirubin (n = 1), and hemorrhagic cystitis (n = 1); all resolved by day +30 following transplantation. The MTD was not reached. No treatment-related deaths occurred. At day +30, 13 patients achieved a complete remission (CR) or unconfirmed CR (CRU), and 2 patients achieved a partial response, for an overall response rate of 94%. After a median follow-up of 691 days, the 1-year progression-free survival (PFS) and overall survival (OS) were 63% (95% confidence interval [CI]: 43%-91%) and 68% (95% CI: 49%-96%), respectively. We recommend clofarabine 70 mg/m(2)/day x 5 days as a phase 11 dose in combination with high-dose etoposide and cyclophosphamide for further testing as a preparative regimen in NHL patients undergoing autologous PBSC transplantation.

• 出版日期2011-7