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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2478-2484
Randomized Phase II Study of Fludarabine + Cytosine Arabinoside + Idarubicin ± All-Trans Retinoic Acid ± Granulocyte
Colony-Stimulating Factor in Poor Prognosis Newly Diagnosed Acute
Myeloid Leukemia and Myelodysplastic Syndrome
Elihu H. Estey,
Peter F. Thall,
Sherry Pierce,
Jorge Cortes,
Miloslav Beran,
Hagop Kantarjian,
Michael J. Keating,
Michael Andreeff, and
Emil Freireich
From the Department of Leukemia, Division of Medicine, The University
of Texas M.D. Anderson Cancer Center, Houston, TX.
Preclinical data suggest that retinoids, eg, all-trans retinoic acid
(ATRA), lower concentrations of antiapoptotic proteins such as bcl-2,
possibly thereby improving the outcome of anti-acute myeloid leukemia
(AML) chemotherapy. Granulocyte colony-stimulating factor (G-CSF) has
been considered to be potentially synergistic with ATRA in this regard.
Accordingly, we randomized 215 patients with newly diagnosed AML (153 patients) or high-risk myelodysplastic syndrome (MDS) (refractory
anemia with excess blasts [RAEB] or RAEB-t, 62 patients)
to receive fludarabine + ara-C + idarubicin (FAI) alone, FAI + ATRA, FAI + G-CSF, or FAI + ATRA + G-CSF. Eligibility required
one of the following: age over 71 years, a history of abnormal blood
counts before M.D. Anderson (MDA) presentation, secondary AML/MDS,
failure to respond to one prior course of chemotherapy given outside
MDA, or abnormal renal or hepatic function. For the two treatment arms
containing ATRA, ATRA was given 2 days (day-2) before beginning and
continued for 3 days after completion of FAI. For the two treatment
arms including G-CSF, G-CSF began on day-1 and continued until
neutrophil recovery. Patients with white blood cell (WBC) counts
>50,000/µL began ATRA on day 1 and G-CSF on day 2. Events (death,
failure to achieve complete remission [CR], or relapse
from CR) have occurred in 77% of the 215 patients. Reflecting the poor
prognosis of the patients entered, the CR rate was only 51%, median
event-free survival (EFS) time once in CR was 36 weeks, and median
survival time was 28 weeks. A Cox regression analysis indicated that,
after accounting for patient prognostic variables, none of the three
adjuvant treatment combinations (FAI + ATRA, FAI + G, FAI + ATRA + G) affected survival, EFS, or EFS once in CR compared with
FAI. Similarly, there were no significant effects of either ATRA
ignoring G-CSF, or of G-CSF ignoring ATRA. As previously found, a
diagnosis of RAEB or RAEB-t rather than AML was insignificant. There
were no indications that the effect of ATRA differed according to
cytogenetic group, diagnosis (AML or MDS), or treatment schedule.
Logistic regression analysis indicated that, after accounting for
prognosis, addition of G-CSF ± ATRA to FAI improved CR rate versus
either FAI or FAI + ATRA, but G-CSF had no effect on the other
outcomes. We conclude that addition of ATRA ± G-CSF to FAI had no
effect on CR rate, survival, EFS, or EFS in CR in poor prognosis, newly
diagnosed AML or high-risk MDS.
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