title: Improved multilineage response of hematopoiesis in patients with myelodysplastic syndromes to a combination therapy with all-trans-retinoic acid, granulocyte colony-stimulating factor, erythropoietin and alpha-tocopherol.
abstract: Differentiation induction therapy is being tested in myelodysplastic syndromes to ameliorate maturation defects and to restore normal hematopoietic function. To this end, 17 patients (eight with refractory anemia, two with refractory anemia and ring sideroblasts, and seven with refractory anemia and excess of blast cells) were treated with a combination of all-trans-retinoic acid (ATRA), granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), and alpha-tocopherol for durations of 8-16 weeks. Absolute neutrophil counts increased in all patients; platelet counts increased in five patients with discontinuation of transfusion needs in two of four transfusion-dependent patients. Stimulation of erythropoiesis was seen in eight patients with an increase in hemoglobin concentration in three, a discontinuation of transfusion requirements in another three, and a significant increase in reticulocyte counts as the only parameter in two patients. Clinically important multilineage responses with increases of hemoglobin levels or discontinuation of transfusion needs were thus seen in six patients (35.3%) with three patients having a trilineage response. Serum erythropoietin concentrations did not differ significantly between responders and nonresponders, but the erythroid response was accompanied by a rise in the serum transferrin receptor levels. In the bone marrow, the myeloid-to-erythroid ratio and the maturation index of myeloid cells increased during therapy, while the percentage of blast cells did not change. Cytogenetic analysis demonstrated the persistence of the abnormal clones. Prior to therapy, nonresponders had a significantly higher serum TNF level than responders. Serum concentrations of TNF-alpha and soluble TNF-alpha receptor significantly increased during therapy, but mainly in the patients without an erythroid and platelet response. Soluble IL-2 receptor and soluble ICAM-1 concentrations both increased. This pilot study demonstrates that treatment with ATRA/G-CSF/EPO/tocopherol is well tolerated, leading to normalization of neutrophil counts in most, and to improvement of platelets and red blood cells in a significant subgroup of patients.
authors.affiliation: Department of Hematology, University of Frankfurt, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ganser
authors.forename: A
authors.initials: A
authors.lastname: Maurer
authors.forename: C
authors.initials: C
authors.lastname: Contzen
authors.forename: G
authors.initials: G
authors.lastname: Seipelt
authors.forename: O G
authors.initials: OG
authors.lastname: Ottmann
authors.forename: C
authors.initials: C
authors.lastname: Schadeck-Gressel
authors.forename: K
authors.initials: K
authors.lastname: Kolbe
authors.forename: R
authors.initials: R
authors.lastname: Haas
authors.forename: C
authors.initials: C
authors.lastname: Zander
authors.forename: R
authors.initials: R
authors.lastname: Reutzel
authors.forename: D
authors.initials: D
authors.lastname: Hoelzer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001772:Blood Cell Count; D001853:Bone Marrow / Q000187:drug effects; D004359:Drug Therapy, Combination; D004921:Erythropoietin / Q000008:administration & dosage*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000188:drug therapy*; D014212:Tretinoin / Q000008:administration & dosage*; D014810:Vitamin E / Q000008:administration & dosage*
chemical_list: D004921:Erythropoietin; D014810:Vitamin E; D016179:Granulocyte Colony-Stimulating Factor; D014212:Tretinoin