Clofarabine is a second-generation deoxyadenosine analog with activity in adult AML. To improve single agent activity, various combinations of clofarabine are being studied. In two dose-finding phase I studies, we have previously established the MTD and DLT of the CI and CIA combinations in AML salvage (

Blood 2006; 108: 51a
). Here we report the outcome of a subsequent adaptively (Bayesian) randomized phase 2 study comparing the two anthracycline-containing combinations CI and CIA with CA. Eligible were patients (pts) for first salvage therapy with first relapse or primary refractory AML. Drug doses and schedules were as follows: CI - clofarabine 22.5 mg/m2 iv d 1–5 and idarubicin 10 mg/m2 iv d 1–3; CIA – clofarabine 22.5 mg/m2 iv d 1–5, idarubicin 6 mg/m2 iv d 1–3, cytarabine 0.75 g/m2 d 1–5; CA - clofarabine 40 mg/m2 iv d 1–5 and cytarabine 1g/m2 iv d 1–5. Up to 2 induction and 4 consolidation cycles were allowed. Eighty-five patients were enrolled of whom 80 are evaluable. Pretreatment characteristics were similar with respect to median age (CI 57 yrs [range 25–73], CIA 56 [21–81], CA 55 [39–73]), proportion of pts with secondary AML (CI 33%, CIA 28%, CA 29%), proportion of pts with primary refractory disease (CI 31%, CIA 50%, CA 41%), prior median CR duration (CI 6 mos [1–108], CIA 6 [1–18], CA 10 [2–27]), prior exposure to at least intermediate doses of cytarabine (CI 78%, CIA 63%, CA 65%), and proportion of pts with FLT3/ITD abnormalities (CI 25%, CIA 17%, CA 18%). Thirty-three pts received CI, 31 CIA, and 16 CA. Overall, 31 (39%) pts responded (28% CR, 9% CRp). No difference in response was observed according to treatment arm (CI - CR 27%, CRp 12%; CIA - CR 29%, CRp 13%; CA - CR 25%, CRp 6%). Median CR duration was 6.4 mos (0.2–18) with CI, and not reached (1–12+) with CIA and CA (0.3–24) (p=0.07). Overall survival was 5.5 mos (0.3–25.5+) for CI, 5.1 mos (0.4– 13.4+) for CIA, and 5.1 mos (0.4–27+) for CA (p=0.94). Adverse events were comparable to the preceding phase 1 studies and as have been described with clofarabine in the past. Induction deaths occurred in 6% (CI), 16% (CIA), and 25% (CA), respectively (p>.05), and were due to myelosuppression-associated infectious complications. In summary, the response rate of the clofarabine combinations in AML salvage is 39% (CR+CRp). Response duration and overall survival are not significantly different between the treatment arms.

Topics:
clofarabine, cytarabine, idarubicin, leukemia, myelocytic, acute, salvage therapy, brachial plexus neuritis, c-reactive protein, cyclic amp receptor protein, epley maneuver, adverse event

Disclosures: Faderl:Genzyme: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Ravandi:Genzyme: Research Funding. Kantarjian:Genzyme: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Clofarabine in adult AML.

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2008, The American Society of Hematology
2008
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