The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial. the results of the LRF AML14 trial

Alan K Burnett, Donald Milligan, Anthony Goldstone, Archibald Prentice, Mary-Frances McMullin, Michael Dennis, Elizabeth Sellwood, Monica Pallis, Nigel Russell, Robert K Hills, Keith Wheatley, United Kingdom National Cancer Research Institute Haematological Oncology Study Group, Mary Frances McMullin

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Abstract

The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m(2) vs. 35 mg/m(2); (ii) Cytarabine 200 mg/m(2) vs. 400 mg/m(2) in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m(2) were also randomized to receive, or not, the multidrug resistance modulator PSC-833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5-year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC-833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC-833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress.
Original languageEnglish
Pages (from-to)318-332
Number of pages15
JournalBritish Journal of Haematology
Volume145
Issue number3
DOIs
Publication statusPublished - May 2009

Keywords

  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols
  • Cyclosporins
  • Cytarabine
  • Cytogenetic Analysis
  • Daunorubicin
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Leukemia, Myeloid, Acute
  • Leukocyte Count
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Myelodysplastic Syndromes
  • Prognosis
  • Remission Induction
  • Survival Rate

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    Burnett, A. K., Milligan, D., Goldstone, A., Prentice, A., McMullin, M-F., Dennis, M., Sellwood, E., Pallis, M., Russell, N., Hills, R. K., Wheatley, K., United Kingdom National Cancer Research Institute Haematological Oncology Study Group, & McMullin, M. F. (2009). The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial. the results of the LRF AML14 trial. British Journal of Haematology, 145(3), 318-332. https://doi.org/10.1111/j.1365-2141.2009.07604.x