BACKGROUND: 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/m(2) intravenously daily × 3 days and cyclophosphamide 200 mg/m(2) 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.
BACKGROUND: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/m(2) intravenously daily × 3 days and cyclophosphamide 200 mg/m(2) 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.
Authors: W B Parker; S C Shaddix; C H Chang; E L White; L M Rose; R W Brockman; A T Shortnacy; J A Montgomery; J A Secrist; L L Bennett Journal: Cancer Res Date: 1991-05-01 Impact factor: 12.701
Authors: Judith E Karp; Rebecca M Ricklis; Kumudha Balakrishnan; Janet Briel; Jacqueline Greer; Steven D Gore; B Douglas Smith; Michael A McDevitt; Hetty Carraway; Mark J Levis; Varsha Gandhi Journal: Blood Date: 2007-06-11 Impact factor: 22.113
Authors: Varsha Gandhi; Hagop Kantarjian; Stefan Faderl; Peter Bonate; Min Du; Mary Ayres; Mary Beth Rios; Michael J Keating; William Plunkett Journal: Clin Cancer Res Date: 2003-12-15 Impact factor: 12.531
Authors: Hagop Kantarjian; Varsha Gandhi; Jorge Cortes; Srdan Verstovsek; Min Du; Guillermo Garcia-Manero; Francis Giles; Stefan Faderl; Susan O'Brien; Sima Jeha; Jan Davis; Zeev Shaked; Adam Craig; Michael Keating; William Plunkett; Emil J Freireich Journal: Blood Date: 2003-06-05 Impact factor: 22.113
Authors: Anita W Rijneveld; Bronno van der Holt; Okke de Weerdt; Bart J Biemond; Arjen A van de Loosdrecht; Lotte E van der Wagen; Mar Bellido; Michel van Gelder; Walter J F M van der Velden; Dominik Selleslag; Daniëlle van Lammeren-Venema; Constantijn J M Halkes; Rob Fijnheer; Violaine Havelange; Geerte L van Sluis; Marie-Cecile Legdeur; Dries Deeren; Alain Gadisseur; Harm A M Sinnige; Dimitri A Breems; Aurélie Jaspers; Ollivier Legrand; Wim E Terpstra; Rinske S Boersma; Dominiek Mazure; Agnes Triffet; Lidwine W Tick; Karolien Beel; Johan A Maertens; H Berna Beverloo; Marleen Bakkus; Christa H E Homburg; Valerie de Haas; Vincent H J van der Velden; Jan J Cornelissen Journal: Blood Adv Date: 2022-02-22