Stimulation of Hematopoiesis by Amifostine in Patients With Myelodysplastic Syndrome

Abstract

The aminothiol, amifostine (Ethyol; U.S. Bioscience, West Conshohocken, PA), is a cytoprotective agent that ameliorates the toxicities of anticancer therapy. In vitro, amifostine promotes the formation and survival of primitive hematopoietic progenitors derived from myelodysplastic bone marrow (BM) specimens. To evaluate the hematological effects of 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/m2 amifostine three times a week, or 740 mg/m2 weekly for three consecutive weeks followed by 2 weeks observation. Nonresponding patients received a second course of therapy at the next higher dose level depending upon drug tolerance. Bone marrow (BM) progenitor growth was assessed before treatment and after day 21. Diagnoses included refractory anemia (7), refractory anemia with ringed sideroblasts (5), refractory anemia with excess blasts (RAEB) (4), and RAEB-in transformation (RAEB-t) (2). Single- or multi-lineage hematologic responses occurred in 15 patients (83%) treated with the three-times-a-week dose schedule. Fourteen patients had a 50% or greater increase in absolute neutrophil count with amifostine treatment (range, 426 to 11,348/μL). Platelet count increased in 6 (43%) of 14 patients with thrombocytopenia (absolute increase, 16,000 to 110,000/μL), and 5 of 15 red blood cell transfusion-dependent patients had a 50% of greater reduction in transfusion needs. Assayable hematopoietic progenitors increased 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/m2 were well tolerated, whereas grade II nausea, vomiting, and fatigue was limiting at higher doses. Three patients with excess blasts before enrollment experienced an increase in BM blast percentage and two patients had evolution to acute leukemia that persisted after treatment withdrawal. We conclude that amifostine administered at doses ≤200 mg/m2 three times a week is well tolerated and has hematologic activity in patients with MDS.

A pilot study of the recombinant soluble human tumour necrosis factor receptor (p75)‐Fc fusion protein in patients with myelodysplastic syndrome

“…Although our trial was not designed to detect differences in the disease progression, the increase in the blasts in the bone marrow and evolution of leukaemia occurred at a rate similar to other trials, e.g. with amifostin (List et al , 1997).…”

New Approaches to the Treatment of Myelodysplasia

“…Of these patients, 78% (14/18) demonstrated a ≥50% increase in neutrophil count, and 43% (6/14) of patients with thrombocytopenia experienced a similar increment in platelet counts. One third (5/15) of the transfusion-dependent patients had decreased transfusion needs [59]. Although amifostine treatment improved blood counts in the treated population, abnormal karyotypes persisted.…”

“…In a phase I/II study in patients with MDS, i.v. amifostine was administered to four cohorts of patients at doses of 100, 200, or 400 mg/m 2 three times per week, or 740 mg/m 2 once weekly, for three consecutive weeks, followed by an observation period of 2 weeks [59]. Single-lineage or multilineage responses were observed in 83% of patients (15/18) treated with the three-times-per-week dose schedule.…”

“…The number of blasts increased in three patients who enrolled with excess blasts, and evolution to AML occurred in two treated patients and persisted after withdrawal of amifostine. Patients treated with amifostine doses >200 mg/m 2 , three times weekly, experienced dose-limiting toxicities of grade 2 nausea, vomiting, and fatigue [59]. Results of phase II trials using more stringent response criteria suggest that response rates are somewhat lower when amifostine is used as a single agent.…”

Differentiation Therapy of Myelodysplastic Syndromes: Fact or Fiction?

“…As amifostine not only protects but also stimulates haemopoiesis ( List et al , 1996 ), it has been proposed as a possible therapeutic agent in MDS, where most clinical complications are related to cytopenia. In a phase I/II study ( List et al , 1997 ), 18 MDS patients (five RARS, seven RA, four RAEB, two RAEB‐T) received intravenous treatment with 100, 200 or 400 mg/m 2 amifostine three times a week, or 740 mg/m 2 (corresponding to recommended radioprotective dose) once a week for three consecutive weeks. 17/18 patients received more than one course of therapy.…”