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.
Faderl
Stefan
S
Department of Leukemia, Box 428, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. sfaderl@mdanderson.org
Gandhi
Varsha
V
O'Brien
Susan
S
Bonate
Peter
P
Cortes
Jorge
J
Estey
Elihu
E
Beran
Miloslav
M
Wierda
William
W
Garcia-Manero
Guillermo
G
Ferrajoli
Alessandra
A
Estrov
Zeev
Z
Giles
Francis J
FJ
Du
Min
M
Kwari
Monica
M
Keating
Michael
M
Plunkett
William
W
Kantarjian
Hagop
H
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