Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias.
Clofarabine (2-chloro-2'-fluoro-deoxy-9-beta-D-arabinofuranosyladenine) is a second-generation nucleoside analog with activity in acute leukemias. As clofarabine is a potent inhibitor of ribonucleotide reductase (RnR), we hypothesized that clofarabine will modulate ara-c triphosphate accumulation and increase the antileukemic activity of cytarabine (ara-C). We conducted a phase 1-2 study of clofarabine plus ara-C in 32 patients with relapsed acute leukemia (25 acute myeloid leukemia [AML], 2 acute lymphoblastic leukemia [ALL]), 4 high-risk myelodysplastic syndrome (MDS), and 1 blast-phase chronic myeloid leukemia (CML).(1) Clofarabine was given as a 1-hour intravenous infusion for 5 days (days 2 through 6) followed 4 hours later by ara-C at 1 g/m(2) per day as a 2-hour intravenous infusion for 5 days (days 1 through 5). The phase 2 dose of clofarabine was 40 mg/m(2) per day for 5 days. Among all patients, 7 (22%) achieved complete remission (CR), and 5 (16%) achieved CR with incomplete platelet recovery (CRp), for an overall response rate of 38%. No responses occurred in 3 patients with ALL and CML. One patient (3%) died during induction. Adverse events were mainly less than or equal to grade 2, including transient liver test abnormalities, nausea/vomiting, diarrhea, skin rashes, mucositis, and palmoplantar erythrodysesthesias. Plasma clofarabine levels generated clofarabine triphosphate accumulation, which resulted in an increase in ara-CTP in the leukemic blasts. The combination of clofarabine with ara-C is safe and active. Cellular pharmacology data support the biochemical modulation strategy.
Department of Leukemia, Box 428, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. sfaderl@mdanderson.org
Stefan
S
Faderl
Varsha
V
Gandhi
Susan
S
O'Brien
Peter
P
Bonate
Jorge
J
Cortes
Elihu
E
Estey
Miloslav
M
Beran
William
W
Wierda
Guillermo
G
Garcia-Manero
Alessandra
A
Ferrajoli
Zeev
Z
Estrov
Francis J
FJ
Giles
Min
M
Du
Monica
M
Kwari
Michael
M
Keating
William
W
Plunkett
Hagop
H
Kantarjian
D000208:Acute Disease; D000227:Adenine Nucleotides; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D001087:Arabinonucleosides / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D000077866:Clofarabine; D003561:Cytarabine / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007621:Karyotyping; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D016896:Treatment Outcome
D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D003561:Cytarabine; D000077866:Clofarabine