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Blood, 15 June 2006, Vol. 107, No. 12, pp. 4614-4622.
Prepublished online as a Blood First Edition Paper on February 16, 2006; DOI 10.1182/blood-2005-10-4202.
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Submitted October 21, 2005
Accepted January 30, 2006
Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomised trial
Donald W Milligan*, Keith Wheatley, Timothy Littlewood, Jenny O Craig, and Alan K Burnett
Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom
Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom
Department of Haematology, John Radcliffe Hospital, Oxford, United Kingdom
Department of Haematology, Addenbrooke's Hospital, Cambridge, United Kingdom
Department of Haematology, University of Cardiff, Cardiff, United Kingdom
* Corresponding author; email: d.w.milligan{at}bham.ac.uk.
The optimum chemotherapy schedule for re-induction of patients with high-risk acute myeloid leukaemia (relapsed, resistant/refractory or adverse genetic disease) is uncertain. The MRC AML Working Group designed a trial comparing fludarabine and high dose cytosine (FLA) with standard chemotherapy comprising cytosine arabinoside, daunorubicin and etoposide (ADE). Patients were also randomized to receive filgrastim (G-CSF) from day 0 until neutrophils >0.5x109/l (or for a maximum of 28 days) and all-trans retinoic acid (ATRA) for 90 days. Between 1998 and 2003, 405 patients were entered: 250 were randomized between FLA and ADE; 356 to G-CSF versus no G-CSF; 362 to ATRA versus no ATRA. The complete remission rate was 61% with four year disease-free survival of 29%. There were no significant differences in the CR rate, deaths in CR, relapse rate or DFS between ADE and FLA although survival at four years was worse with FLA ( 16% versus 27%, p=0.05). Neither the addition of ATRA nor G-CSF demonstrated any differences in the CR rate, relapse rate, DFS or overall survival between the groups. In conclusion these findings indicate that FLA may be inferior to standard chemotherapy in high-risk AML and that the outcome is not improved with the addition of either G-CSF or ATRA.
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