Lenalidomide has hematologic activity in patients with low-risk myelodysplastic syndromes who have no response to erythropoietin or who are unlikely to benefit from conventional therapy.

Amifostine (WR-2721, Ethyol) is a phosphorylated aminothiol that affords broad cytoprotection from the myelosuppressive effects of antineoplastics. To further characterize its hematopoietic activities, we investigated the effects of amifostine and its dephosphorylated metabolite, WR1065, on the in vitro growth of human bone marrow progenitors. Preincubation exposure to amifostine or WR1065 stimulated the growth of colony-forming units granulocyte, erythroid, macrophage, megakaryocyte (CFU-GEMM) and erythroid bursts (BFU-E) from bone marrow mononuclear cells in a dose-dependent fashion. Over the concentration range tested (0.1-1000 M), pretreatment with the aminothiols enhanced formation of CFU-GEMM up to five-fold and BFU-E nine-fold, compared to a three-fold increase in myeloid colony recovery. In CD34؉ selected cells, preincubation with amifostine increased formation of CFU-GEMM up to 38-fold and produced macroscopic colonies, exceeding colony number in cultures initiated with optimal concentrations of interleukin-1 (IL-1), IL-3, or kit ligand (KL). When compared with recombinant human cytokines, amifostine enhanced IL-1 and IL-3 induced colony formation, although its stimulatory effect was less than additive. In contrast, pretreatment with amifostine antagonized the stimulatory effects of KL, whereas synergy was observed with concurrent exposure. Ex vivo expansion studies showed that amifostine alone supported and augmented the production of myeloid progenitors in secondary cultures. Similarly, under cytokine-deficient conditions, amifostine promoted cell survival and delayed apoptosis as measured by nucleosome generation. These data indicate that amifostine is a novel multipotent hematopoietic stimulant that augments the formation and survival of bone marrow progenitors.

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.