title: A phase 1 clinical-laboratory study of clofarabine followed by cyclophosphamide for adults with refractory acute leukemias.
abstract: Clofarabine has shown impressive response rates in patients with acute leukemias. In vitro investigations with clofarabine in combination with cyclophosphamide in primary cells have demonstrated synergistic cytotoxicity and inhibition of DNA repair. Based on these clinical and laboratory observations, we designed a mechanism-based combination protocol with clofarabine and cyclophosphamide for patients with relapsed acute leukemias. Eighteen patients were treated with cyclophosphamide (200 mg/m(2)) alone on day 0 and with clofarabine plus cyclophosphamide on day 1. Clinical responses, toxicity, DNA damage measured as H2AX phosphorylation, and accumulation of clofarabine triphosphate (TP) were analyzed. At dose level 1 (20 mg/m(2) clofarabine + cyclophosphamide, 6 patients) and dose level 0 (10 mg/m(2) clofarabine + cyclophosphamide, 12 patients) overall response rates were 50% and 30%, respectively, with responses in 4 (67%) of 6 patients with refractory acute lymphoblastic leukemia. Dose-limiting toxicity occurred at dose level 1 with prolonged marrow aplasia. Four (22%) patients died from prolonged aplasia (1), fungal pneumonia (1), or multiorgan failure (2). In 12 of 13 patient samples, increased DNA damage (gammaH2AX) was observed with clofarabine and cyclophosphamide compared with cyclophosphamide alone. In conclusion, pharmacodynamic end points along with clinical results suggest usefulness of this combination strategy, whereas toxicity data suggest reduction in chemotherapeutic intensity. This clinical trial is registered with the National Cancer Institute's PDQ at www.clinicaltrials.gov as no. JHOC-J0561.
authors.affiliation: Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231-1000, USA. jkarp2@jhmi.edu
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Ricklis
authors.forename: Kumudha
authors.initials: K
authors.lastname: Balakrishnan
authors.forename: Janet
authors.initials: J
authors.lastname: Briel
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Greer
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDevitt
authors.forename: Hetty
authors.initials: H
authors.lastname: Carraway
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Levis
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
mesh_terms: D000208:Acute Disease; D000227:Adenine Nucleotides / Q000008:administration & dosage; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism / Q000627:therapeutic use*; D017209:Apoptosis; D001087:Arabinonucleosides / Q000008:administration & dosage; D000077866:Clofarabine; D003520:Cyclophosphamide / Q000008:administration & dosage; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000209:etiology* / Q000473:pathology; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000227:Adenine Nucleotides; D001087:Arabinonucleosides; C468783:H2AX protein, human; D006657:Histones; D000077866:Clofarabine; D003520:Cyclophosphamide