No Improvement in Complete Remission Rate With Cytarabine Plus Amonafide L-Malate vs Daunorubicin in Secondary AML


Key Points

  • Cytarabine plus amonafide did not improve complete remission rates over standard daunorubicin plus cytarabine.
  • Induction death rates were higher with cytarabine-amonafide.

In a phase III trial reported in the Journal of Clinical Oncology, Stone et al found that the combination of cytarabine and amonafide L-malate, a DNA intercalator and non–ATP-dependent topoisomerase II inhibitor, did not improve complete remission rate compared with cytarabine plus daunorubicin as induction therapy in secondary acute myeloid leukemia (AML).

Study Details

In this open-label trial, 433 patients with previously untreated secondary AML from 150 centers worldwide were randomly assigned between January 2008 and August 2010 to receive cytarabine at 200 mg/m2 via continuous infusion on days 1 to 7 plus either amonafide at 600 mg/m2 intravenously over 4 hours on days 1 to 5 (n = 216) or daunorubicin at 45 mg/m2 intravenously over 30 minutes on days 1 to 3 (n = 217). The primary endpoint was complete remission rate.

Nearly half of the patients in each group were from North America. The amonafide-plus-cytarabine and daunorubicin-plus-cytarabine groups were generally balanced for age (median, 65 and 63 years, 64% and 62% ≥ 60 years), sex (50% and 58% male), type of secondary AML (antecedent myelodysplastic syndrome in 48% and 51%, therapy-related AML in 41% and 39%, both in 11% and 10%), white blood cell count ≤ 20,000/µL (82% and 81%), elevated lactate dehydrogenase (61% vs 59%), and unfavorable cytogenetics (41% vs 39%).

No Improvement

The complete remission rate was 46% in the amonafide-plus-cytarabine group vs 45% in the daunorubicin-plus-cytarabine group (P = .81). Median survival was 7.0 months (95% confidence interval [CI] = 5.1–9.0 months) vs 7.0 months  (95% CI = 5.6–9.1 months). The 30- and 60-day mortality rates were 19% vs 13% and 28% vs 21%.

Adverse events in the two groups were those typically observed with cytotoxic therapy in patients with AML. At 30, 45, and 60 days, the induction death rate in the amonafide-plus-cytarabine group exceeded the upper 95% confidence boundary in the daunorubicin-plus-cytarabine group, indicating that  amonafide-plus-cytarabine was more toxic than the standard regimen.

The investigators concluded: “Induction treatment with [amonafide plus cytarabine] did not improve the [complete remission] rate compared with [daunorubicin plus cytarabine] in patients with [secondary] AML.”

They noted: “On the basis of previous phase I and II clinical trial data and a mechanism of action including evasion of drug efflux, the induction regimen of [amonafide plus cytarabine] held the promise of being superior to standard [daunorubicin plus cytarabine] in patients with difficult-to-treat [secondary] AML. Our study demonstrated that the doses of amonafide used in the experimental arm plus cytarabine did not produce a higher [complete remission] rate than the use of standard therapy with [daunorubicin plus cytarabine]. Moreover, the amonafide-containing regimen was more toxic than standard induction, making it less likely that inadequate doses of amonafide were used in this study.”

Richard M. Stone, MD, of the Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by Antisoma. For full disclosures of the study authors, visit

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