title: Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia.
abstract: In a phase 2 study, 62 patients with relapsed and refractory acute myeloid leukemia (AML; n = 31), myelodysplastic syndrome (MDS; n = 8), chronic myeloid leukemia in blastic phase (CMLBP; n = 11), and acute lymphocytic leukemia (ALL; n = 12) received 40 mg/m2 clofarabine intravenously over 1 hour daily for 5 days, every 3 to 6 weeks. Twenty patients (32%) achieved complete response (CR), 1 had a partial response (PR), and 9 (15%) achieved CR but without platelet recovery (CRp), for an overall response rate of 48%. In AML, responses were noted in 2 (18%) of 11 patients in first salvage with short first CR (</= 12 months), in 7 (87%) of 8 patients with longer first CR, and in 8 (67%) of 12 patients in second or subsequent salvage. Responses were observed in 4 of 8 patients with high-risk MDS (50%), in 7 (64%) of 11 with CML-BP, and in 2 (17%) of 12 with ALL. Severe reversible liver dysfunction was noted in 15% to 25%. After the first clofarabine infusion, responders accumulated more clofarabine triphosphate in blasts compared with nonresponders (median 18 vs 10 microM; P =.03). This increased only in responders (median, 1.8-fold; P =.008) after the second clofarabine infusion. In summary, clofarabine is active in acute leukemias and MDS; cellular pharmacokinetics may have prognostic significance.
authors.affiliation: Department of Leukemia, Anderson Cancer Center, Houston, TX, USA. hkantarj@mdanderson.org
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.forename: Min
authors.initials: M
authors.lastname: Du
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Sima
authors.initials: S
authors.lastname: Jeha
authors.forename: Jan
authors.initials: J
authors.lastname: Davis
authors.forename: Zeev
authors.initials: Z
authors.lastname: Shaked
authors.forename: Adam
authors.initials: A
authors.lastname: Craig
authors.forename: Michael
authors.initials: M
authors.lastname: Keating
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.forename: Emil J
authors.initials: EJ
authors.lastname: Freireich
mesh_terms: D000227:Adenine Nucleotides; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001087:Arabinonucleosides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000077866:Clofarabine; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000401:mortality; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality; D011379:Prognosis; D012008:Recurrence; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D000077866:Clofarabine