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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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CLINICAL TRIALS AND OBSERVATIONS
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 randomized trial
Donald W. Milligan,
Keith Wheatley,
Timothy Littlewood,
Jenny I. O. Craig,
Alan K. Burnett, for the NCRI Haematological Oncology Clinical Studies Group
From the Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom; the Department of Haematology, John Radcliffe Hospital, Oxford, United Kingdom; the Department of Haematology, Addenbrooke's Hospital, Cambridge, United Kingdom; the University Department of Haematology, Cardiff, United Kingdom; and Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom.
The optimum chemotherapy schedule for reinduction of patients with high-risk acute myeloid leukemia (relapsed, resistant/refractory, or adverse genetic disease) is uncertain. The MRC AML (Medical Research Council Acute Myeloid Leukemia) 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 randomly assigned to receive filgrastim (G-CSF) from day 0 until neutrophil count was greater than 0.5 x 109/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 randomly assigned 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 4-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 4 years was worse with FLA (16% versus 27%, P = .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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