Phase I and extension study of clofarabine plus cyclophosphamide in patients with relapsed/refractory acute lymphoblastic leukemia.
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).


CONCLUSIONS
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.
Division of Leukemia, Hackensack University Medical Center, Hackensack, NJ. Electronic address: sfaderl@hackensackumc.org.
Stefan
S
Faderl
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Kumudha
K
Balakrishnan
Department of Leukemia and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Deborah A
DA
Thomas
Department of Leukemia and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Farhad
F
Ravandi
Department of Leukemia and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Gautam
G
Borthakur
Department of Leukemia and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Jan
J
Burger
Department of Leukemia and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Alessandra
A
Ferrajoli
Department of Leukemia and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Jorge
J
Cortes
Department of Leukemia and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Susan
S
O'Brien
Department of Leukemia and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Tapan
T
Kadia
Department of Leukemia and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Jennie
J
Feliu
Department of Leukemia and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
William
W
Plunkett
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Varsha
V
Gandhi
Department of Leukemia and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Hagop M
HM
Kantarjian
D000227:Adenine Nucleotides / Q000008:administration & dosage; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000008:administration & dosage; D000077866:Clofarabine; D003520:Cyclophosphamide / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D012008:Recurrence; D016896:Treatment Outcome; D055815:Young Adult
D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D000077866:Clofarabine; D003520:Cyclophosphamide
ALL; Clofarabine; Salvage chemotherapy