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

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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 jco.ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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