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, Emil Freireich

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2478-2484
Number of pages7
JournalBlood
Volume93
Issue number8
StatePublished - Apr 15 1999
Externally publishedYes

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Idarubicin
Myelodysplastic Syndromes
Cytarabine
Granulocyte Colony-Stimulating Factor
Tretinoin
Acute Myeloid Leukemia
Refractory Anemia with Excess of Blasts
Disease-Free Survival
Refractory materials
Chemotherapy
fludarabine
Regression analysis
Blood
Regression Analysis
Drug Therapy
Survival
Retinoids
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

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. / Estey, Elihu H.; Thall, Peter F.; Pierce, Sherry; Cortes, Jorge; Beran, Miloslav; Kantarjian, Hagop; Keating, Michael J.; Andreeff, Michael; Freireich, Emil.

In: Blood, Vol. 93, No. 8, 15.04.1999, p. 2478-2484.

Research output: Contribution to journalArticle

Estey, Elihu H. ; Thall, Peter F. ; Pierce, Sherry ; Cortes, Jorge ; Beran, Miloslav ; Kantarjian, Hagop ; Keating, Michael J. ; Andreeff, Michael ; Freireich, Emil. / 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. In: Blood. 1999 ; Vol. 93, No. 8. pp. 2478-2484.
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abstract = "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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T1 - 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

AU - Estey, Elihu H.

AU - Thall, Peter F.

AU - Pierce, Sherry

AU - Cortes, Jorge

AU - Beran, Miloslav

AU - Kantarjian, Hagop

AU - Keating, Michael J.

AU - Andreeff, Michael

AU - Freireich, Emil

PY - 1999/4/15

Y1 - 1999/4/15

N2 - 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.

AB - 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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