title: Homoharringtonine in patients with myelodysplastic syndrome (MDS) and MDS evolving to acute myeloid leukemia.
abstract: Current anti-leukemic chemotherapy in patients with myelodysplastic syndromes (MDS) and MDS evolving to acute myeloid leukemia (AML) is associated with low response rates and high treatment-related toxicity. Homoharringtonine (HHT) is a novel cephalotaxime alkaloid with reported efficacy in relapsed and de novo AML and more recently, chronic myeloid leukemia. Although its mechanism(s) of action is not completely understood, in vitro studies have demonstrated both cytotoxic and differentiating activity in leukemic cells, as well as intra-cellular changes suggestive of apoptotic cell death. In a phase II trial, HHT was administered at a dose od 5 mg/m2 by 24-h continuous infusion daily for 9 days to patients with MDS and MDS evolving to AML (MDS/AML). Twenty-eight patients (MDS 16, MDS/AML 12) with a median age of 67 years (range 23-83) were entered. A complete remission was achieved in seven patients, a partial remission was achieved in one patient for an overall response rate of 28% (8/28). There were four of 13 responders in MDS/AML patients and four of 15 in patients with MDS. The median duration of complete response was 7 months (range 2-10). Significant myelosuppression was universal and resulted in a high incidence of induction deaths (13/28) due to neutropenic-related infections. Extramedullary toxicity was mild and consisted of hypo-tension, fluid retention, hypoglycemia, diarrhea, nausea and vomiting. HHT given in this dose and schedule demonstrated limited activity in MDS and MDS/AML and was associated with prolonged pancytopenia and marrow hypoplasia in many patients. Administration of HHT at a lower dose or in combination with hematopoietic growth factors may lead to better results, but treatment with HHT as single agent at this dose and schedule is not currently recommended for these patients.
authors.affiliation: New York Medical College, Division of Oncology/Hematology, Valhalla 10595, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Feldman
authors.forename: K P
authors.initials: KP
authors.lastname: Seiter
authors.forename: T
authors.initials: T
authors.lastname: Ahmed
authors.forename: P
authors.initials: P
authors.lastname: Baskind
authors.forename: Z A
authors.initials: ZA
authors.lastname: Arlin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006248:Harringtonines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077863:Homoharringtonine; D006801:Humans; D007262:Infusions, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D012074:Remission Induction
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D006248:Harringtonines; D000077863:Homoharringtonine