Randomized phase II study of fludarabine plus cytosine arabinoside plus idarubicin +/- all-trans retinoic acid +/- granulocyte colony-stimulating factor in poor prognosis newly diagnosed acute myeloid leukemia and myelodysplastic syndrome

Preclinical data suggest that retinoids, eg, all-trans retinoic acid (ATRA) , lower concentrations of antiapoptotic proteins such as bcl-2, possibly th ereby improving the outcome of anti-acute myeloid leukemia (AML) chemothera py. Granulocyte colony-stimulating factor (G-CSF) has been considered to be potentially synergistic with ATRA in this regard. Accordingly, we randomiz ed 215 patients with newly diagnosed AML (153 patients) or high-risk myelod ysplastic syndrome (MDS) (refractory anemia with excess blasts [RAEB] or RA EB-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 befor e M.D. Anderson (MDA) presentation, secondary AML/MDS, failure to respond t o one prior course of chemotherapy given outside MDA, or abnormal renal or hepatic function. For the two treatment arms containing ATRA, ATRA was give n 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 a nd continued until neutrophil recovery. Patients with white blood cell (WBC ) counts >50,000/mu L began ATRA on day 1 and G-CSF an day 2. Events (death , failure to achieve complete remission [CR], or relapse from CR) have occu rred in 77% of the 215 patients. Reflecting the poor prognosis of the patie nts entered, the CR rate was only 51%, median event-free survival (EFS) lim e once in CR was 36 weeks, and median survival time was 28 weeks. A Cox reg ression analysis indicated that, after accounting for patient prognostic va riables, none of the three adjuvant treatment combinations (FAI + ATRA, FAI + G, FAI + ATRA + G) affected survival, EFS, or EFS once in CR compared wi th FAI. Similarly, there were no significant effects of either ATRA ignorin g G-CSF, or of G-CSF ignoring ATRA. As previously found, a diagnosis of RAE B or RAEB-t rather than AML was insignificant. There were no indications th at the effect of ATRA differed according to cytogenetic group, diagnosis (A ML or MDS), or treatment schedule. Logistic regression analysis indicated t hat, after accounting for prognosis, addition of G-CSF +/- ATRA to FAI impr oved CR rate versus either FAI or FAI + ATRA, but G-CSF had no effect on th e other outcomes. We conclude that addition of ATRA +/- CSF to FAI had no e ffect on CR rate, survival, EFS, or Eff in CR in poor prognosis, newly diag nosed AML or high-risk MDS. (C) 1999 by The American Society of Hematology.