CHICAGO—The combination of amonafide + cytarabine does not provide a complete response (CR) benefit over treatment with daunorubicin + cytarabine in patients with secondary acute myeloid leukemia (sAML), according to a presentation at the American Society of Clinical Oncology’s 2011 Annual Meeting.  Amonafide L-malate (AS1413) is a topoisomerase II inhibitor and DNA intercalator that evades multidrug resistance mechanisms.

Secondary AML , which can evolve from myelodysplastic syndrome or as a result from exposure to chemotherapy or radiotherapy given to treat another type of cancer, responds poorly to current therapies and is often multidrug resistant. Responses with the current standard induction therapy of an anthracycline (such as daunorubicin) + cytarabine have been disappointing.

R.M. Stone, MD, from Dana Farber Cancer Institute, Boston, MA, and colleagues wanted to assess the efficacy and safety of amonafide + cytarabine compared with standard remission induction therapy of daunorubicin + cytarabine in newly diagnosed secondary AML. The randomized, open-label, Phase 3 ACCEDE trial is one of the largest ever conducted in this subgroup of AML patients.  Of 564 patients initially screened, 433 newly diagnosed sAML patients aged ≥18 years (median age 64 years) were randomized to receive cytarabine 200mg/m2 continuous IV infusion daily on Days 1–7 + either amonafide 600mg/m2 IV over 4 hours daily on Days 1–5 (n=216) or daunorubicin 45mg/m2 IV over 30 minutes daily on Days 1–3 ( n=217). A second course was administered if Day 14 marrow showed residual AML.

The primary endpoint was complete response (CR) rate (± hematopoietic recovery). The CR rate was confirmed at least 30 days following the first CR marrow, or after the first post CR course. The planned sample size of 420 patients provided 89% power to detect a 15% difference at the P=0.05 level (two-tailed) between anticipated CR rates. The results showed that disease etiology, cytogenetics and age were balanced between both arms.

The rates of CRwere 46% in amonafide arm and 45% in daunorubicin arm. When looking at WBC count, patients with WBC ≥20 x 109 cells/L (n=79) demonstrated a 21% and 29% CR rate for amonafide and daunorubicin, respectively, compared with 51% and 48%, respectively, for patients with a WBC count <20 x 109 cells/L 9n=354). Stratification of patients by favorable (n=9), intermediate (n=146), unfavorable (n=173), or unknown (n=105) cytogenetic risk for the amonafide arm showed CR rates of 100%, 53%, 41%, and 43%, respectively, compared with 88%, 54%, 32%, and 46% (P=0.001 for overall CR rate by cytogenetic category).  Thirty-day mortality was 20.4% in the amonafide arm and 12.4% in the daunorubicin arm. Serious adverse events were balanced between the two arms, and no event occurred in >6% of patients in either arm. Subgroup analyses are ongoing.

Dr. Stone et al stated that  the combination of amonafide + cytarabine does not provide a CR benefit over daunorubicin + cytarabine in sAML patients, and that these patients should be considered for clinical trials or specific therapies based on molecular profiles.