Phase I and Extension Study of Clofarabine Plus聽Cyclophosphamide in Patients With聽Relapsed/Refractory Acute Lymphoblastic聽Leukemia

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• 作者：Stefan Faderl¹ ; ^{sfaderl@hackensackumc.org" class="auth_mail} ; Kumudha Balakrishnan² ; Deborah A. Thomas³ ; Farhad Ravandi³ ; Gautam Borthakur³ ; Jan Burger³ ; Alessandra Ferrajoli³ ; Jorge Cortes³ ; Susan O'Brien³ ; Tapan Kadia³ ; Jennie Feliu³ ; William Plunkett³ ; Varsha Gandhi² ; Hagop M. Kantarjian³
• 关键词：ALL ; Clofarabine ; Salvage chemotherapy
• 刊名：Clinical Lymphoma Myeloma and Leukemia
• 出版年：June 2014
• 年：2014
• 卷：14
• 期：3
• 页码：231-238
• 全文大小：701 K

文摘

Clofarabine is a nucleoside analogue with activity in children with acute lymphoblastic leukemia (ALL). Based on the hypothesis that clofarabine inhibits DNA repair after exposure to DNA-damaging agents, we designed a phase I and extension study to evaluate the combination of clofarabine and cyclophosphamide in adult patients with relapsed/refractory ALL.

Methods

The continual reassessment method (CRM) was used to define the maximum tolerated dose (MTD).

Results

Fifty patients with a median age of 30 years (range, 21-72 years) were enrolled, 30 of whom were part of the phase I group. Clofarabine 40 mg/m² intravenously daily × 3 days and cyclophosphamide 200 mg/m² intravenously every 12 hours × 3 days were established as the MTDs. Dose limiting toxicity (DLT) included diarrhea, transaminase elevations, and skin rashes. The response rate of the whole study group was 14%, including 10% of patients who achieved complete remission (CR) or CR without platelet recovery (CRp). Three responses occurred in patients with primary refractory disease. Early mortality (< 30 days) was 6%. The median duration of response was 69 days (range, 5-315 days). Median overall survival was about 3 months. Compared with day 1 (cyclophosphamide alone), H2AX phosphorylation was increased on day 2 when clofarabine and cyclophosphamide were administered as a couplet (n = 8).

Conclusion

The combination of clofarabine plus cyclophosphamide at the doses used in this study in a group of heavily pretreated patients with ALL is only moderately effective. Other doses, alternative schedules, or a more favorable patient population may achieve better results.