Combination of topotecan with cytarabine or etoposide in patients with refractory or relapsed acute myeloid leukemia: Results of a randomized phase I/II study

Norbert Vey, Hagop Kantarjian, Miloslav Beran, Susan O'Brien, Jorge Cortes, Charles Koller, Elihu Estey

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29 Scopus citations


The topoisomerase I inhibitor topotecan has shown activity in acute myeloid leukemia (AML) and myelodysplastic syndromes. The present study was designed to assess whether topotecan with cytosine arabinoside (ara-C) or with etoposide (VP-16) should be studied in phase II trials in patients with refractory or relapsed AML. Patients with refractory or relapsed AML were assigned to one of 3 strata defined by expected CR rates of 7%, 20% and 40%, then randomly assigned to receive topotecan (d1-5) and ara-C (1 g/m2 over 2 hours; d1-5), topotecan (d1-5) followed by VP-16 (250 mg/m2 twice daily, d6-7), or VP-16 (250 mg/m2 twice daily d1-2) followed by topotecan (d3-d7). A dose-finding phase was conducted in the poorest stratum of each arm (topotecan starting dose: 1.0 mg/m2/day x 5). A Bayesian pre-phase II selection design was used to assess whether the CR rate with a given arm was sufficient to merit investigation in phase II. Thirty-seven patients, median age 58 years, were treated. Their median first CR duration was 28 weeks and 24% were primary refractory. Grade 3-4 mucositis occurred in the initial patients in the topotecan→VP-16, but not in the topotecan + ara-C or VP-16→topotecan arms. Consequently, in subsequent patients, the topotecan dose was lower in the topotecan→VP-16 than in the other 2 arms (1.0 vs 1.25 mg/m2 daily x 5) and the VP-16 dose was lower in the topotecan→VP-16 arm (200 vs 250 mg/m2 twice daily x 2). One CR occurred (topotecan→VP-16 arm), and the treatment arms were terminated after 10, 15, and 12 patients were treated on the topotecan + ara-C, topotecan→VP-16, and VP-16→topotecan arms, respectively. The principal cause of failure was insufficient anti-leukemia effect rather than death on study, and toxicity was minimal at the final doses used. We concluded that none of the combinations studied here warrants phase II evaluation in very poor prognosis AML salvage patients.

Original languageEnglish (US)
Pages (from-to)89-95
Number of pages7
JournalInvestigational New Drugs
Issue number1
StatePublished - Oct 6 1999
Externally publishedYes



  • Acute myeloid leukemia
  • Cytosine arabinoside
  • Etoposide
  • Salvage therapy
  • Topotecan

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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