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.