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

Differentiation induction therapy is being tested in myelodysplastic s yndromes to ameliorate maturation defects and to restore normal hemato poietic function. To this end, 17 patients (eight with refractory anem ia. two with refractory anemia and ring sideroblasts, and seven with r efractory anemia and excess of blast cells) were treated with a combin ation of all-trans-retinoic acid (ATRA), granulocyte colony-stimulatin g factor (G-CSF), erythropoietin (EPO), and alpha-tocopherol for durat ions of 8-16 weeks. Absolute neutrophil counts increased in all patien ts; platelet counts increased in five patients with discontinuation of transfusion needs in two of four transfusion-dependent patients, Stim ulation 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 reticulo cyte counts as the only parameter in two patients. Clinically importan t multilineage responses with increases of hemoglobin levels or discon tinuation 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 no nresponders, but the erythroid response was accompanied by a rise in t he 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. C ytogenetic analysis demonstrated the persistence of the abnormal clone s. Prior to therapy, nonresponders had a significantly higher serum TN F 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 I L-2 receptor and soluble ICAM-1 concentrations both increased. This pi lot study demonstrates that treatment with ATRA/G-CSF/EPO/tocopherol i s well tolerated, leading to normalization of neutrophil counts in mos t, and to improvement of platelets and red blood cells in a significan t subgroup of patients.