STIMULATION OF HEMATOPOIESIS BY AMIFOSTINE IN PATIENTS WITH MYELODYSPLASTIC SYNDROME

The aminothiol, amifostine (Ethyol; U.S. Bioscience, West Conshohocken , PA), is a cytoprotective agent that ameliorates the toxicities of an ticancer therapy. In vitro, amifostine promotes the formation and surv ival of primitive hematopoietic progenitors derived from myelodysplast ic bone marrow (BM) specimens. To evaluate the hematological effects o f amifostine, 18 patients with myelodysplastic syndrome (MDS) and one or more refractory cytopenias received treatment with amifostine in a Phase I/II study. Four cohorts received intravenous treatment with 100 , 200, or 400 mg/m(2) amifostine three times a week, or 740 mg/m(2) we ekly for three consecutive weeks followed by 2 weeks observation. Nonr esponding patients received a second course of therapy at the next hig her dose level depending upon drug tolerance. Bane marrow (BM) progeni tor growth was assessed before treatment and after day 21. Diagnoses i ncluded refractory anemia (7), refractory anemia with ringed siderobla sts (5), refractory anemia with excess blasts (RAEB) (4), and RAEB-in transformation (RAEB-t) (2). Single- or multi-lineage hematologic resp onses occurred in 15 patients (83%) treated with the three-times-a-wee k dose schedule. Fourteen patients had a 50% or greater increase in ab solute neutrophil count with amifostine treatment (range, 426 to 11,34 8/mu L), Platelet count increased in 6 (43%) of 14 patients with throm bocytopenia (absolute increase, 16,000 to 110,000/mu L), and 5 of 15 r ed blood cell transfusion-dependent patients had a 50% of greater redu ction in transfusion needs, Assayable hematopoietic progenitors increa sed in 13 of 15 evaluable patients; including CFU-GEMM (12), BFU-E (8) , and CFU-GM (6). Amifostine doses less than or equal to 200 mg/m(2) w ere well tolerated, whereas grade II nausea, vomiting, and fatigue was limiting at higher doses. Three patients with excess blasts before en rollment experienced an increase in BM blast percentage and two patien ts had evolution to acute leukemia that persisted after treatment with drawal. We conclude that amifostine administered at doses less than or equal to 200 mg/m(2) three times a week is well tolerated and has hem atologic activity in patients with MDS. (C) 1997 by The American Socie ty of Hematology.