EFFECT OF COMBINATION THERAPY WITH ALL-TRANS-RETINOIC ACID AND RECOMBINANT HUMAN GRANULOCYTE-COLONY-STIMULATING FACTOR IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES

Since all-trans retinoic acid (ATRA) and granulocyte colony-stimulatin g factor (G-CSF) not only enhance proliferation and differentiation of normal myeloidcells but also synergistically promote the differentiat ion of myeloid leukemic blast cells in vitro, we have started a pilot study of combined treatment with ATRA and G-CSF in patients with myelo dysplastic syndrome, to analyze the effect of these drugs on hematopoi etic differentiation. ATRA was given at 45 mg/m(2)/day p.o. from week 1-12 and G-CSF at 5 mu g/kg/day s.c. from week 5-12 with dose modifica tions according to the absolute neutrophil counts (ANC). A total of 15 patients predominantly with refractory anemia, were treated.During in itial ATRA therapy, a bilineage response with increases of both ANC an d platelet counts occurred in three patients. During combined ATRA/G-C SF therapy, ANC increased in all patients, and platelets increased in three out of 14 evaluable patients. An increase in hemoglobin concentr ation and a decrease in transfusion requirements occurred in one patie nt each. In the bone marrow, the myeloid-to-erythroid ratio increased during ATRA treatment and remained increased during concomitant G-CSF administration, while the maturation index of myeloid cells increased only in response to ATRA therapy, but returned to baseline during ATRA /G-CSF treatment. Cytogenetic analysis demonstrated persistence of the abnormal clones in all patients. The number of circulating progenitor cells CFU-GM increased in all patients studied. Serum concentrations o f the soluble TNF receptor and IL-2 receptor both increased, while TNF -alpha - already elevated prior to therapy and soluble ICAM-1 concentr ations did not significantly change. Adverse effects included dermatit is and cheilosis in most patients, and a drop in platelet counts relat ed to G-CSF in one patient. The pilot study demonstrates that the comb ination treatment with ATRA/G-CSF is well tolerated, leading to normal ization of ANC in most, and improvement of platelets and red blood cel ls in a subgroup of patients.