EFFECTS OF TREATMENT WITH 5-AZACYTIDINE ON THE INVIVO AND INVITRO HEMATOPOIESIS IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES

The myelodysplastic syndrome (MDS) comprises a group of clonal hematop oietic disorders derived from an abnormality affecting a multipotent h ematopoietic stem cell. Despite trials testing numerous agents in pati ents with MDS, no single drug has yet emerged as the accepted standard of treatment. Observation and supportive care with blood products and antibiotics, when necessary, continue to be the mainstays of therapy. We administered 5-azacytidine, a cell-cycle specific ring analog of t he pyrimidine nucleoside cytosine, as a continuous intravenous infusio n, 75 mg/m2 per day for 7 days every 4 weeks. Patients had refractory anemia with excess blasts (RAEB) or refractory anemia with excess blas ts in transformation (RAEB-T). Responses were seen in 21 (49%) of 43 e valuable patients: five (1 2 %) in complete remission (CR, complete no rmalization of bone marrow and peripheral blood counts); 11 (25%) in p artial remission (PR, greater-than-or-equal-to 50% restoration of the deficit from normal of all three peripheral blood cell lines, eliminat ion of transfusion requirements, and a decrease in percentage bone mar row blasts by greater-than-or-equal-to 50% from prestudy values); five (12%) improved (greater-than-or-equal-to 50% restoration in the defic it from normal of one or more peripheral blood cell lines and/or a gre ater-than-or-equal-to 50% decrease in transfusion requirements). A tri lineage improvement (CR and PR) occurred in 37% of the patients. The m edian survival for all patients was 13.3 months and the median duratio n of remission for those with CR and PR was 14.7 months. Mild to moder ate nausea and/or vomiting was the most common side effect (63%). Myel osuppression, either bone marrow hypoplasia or drug related cytopenias requiring a reduction in the dose of azacitidine, occurred in only 33 % of the patients. Prior to treatment, bone marrow erythroid progenito r cells were assayed in vitro. Colonies derived from erythroid burst-f orming units (BFU-e) were undetectable in one patient and reduced in t wo. The number of colonies derived from erythroid colony-forming units (CFU-e)) were also reduced in two of the three patients. In the two p atients with detectable colony growth prior to treatment, colony numbe r decreased by day 8 of the first cycle, followed by a subsequent incr ease. Continued treatment with azacitidine led to normalization of the number of CFU-e derived colonies as well as an increase in the number of BFU-e derived colonies. This improvement in erythroid colony numbe r correlated with the spontaneous rise in hemoglobin levels and red ce ll transfusion independence. Subsequent decrease in colony number (CFU -e, BFU-e) preceded a progressive fall in hemoglobin levels by 2 to 4 months. Azacitidine is an effective agent for the treatment of patient s with RAEB and RAEB-T. The trilineage response rate is higher than th ose reported with the hematopoietic growth factors erythropoietin, int erleukin-3, granulocyte-macrophage or granulocyte colony-stimulating f actors (GM-CSF or G-CSF). Further trials testing azacitidine in a regi men administered in an ambulatory setting have been initiated.