homoharringtonine and Fatigue

The outcome of patients with myelodysplastic syndromes (MDSs) after failure of hypomethylating agents (HMAs) failure is poor with a median overall survival (OS) of only 4-6 months. Omacetaxine mepesuccinate (OM) is safe and effective in myeloid malignancies but has not been studied in MDS with HMA failure. We conducted a phase II study of OM in patients with MDS or chronic myelomonocytic leukemia (CMML) who had previously failed or been intolerant to HMAs. Patients received OM at a dose of 1.25 mg/m

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Chromosome Aberrations; Disease-Free Survival; DNA Mutational Analysis; Drug Administration Schedule; Drug Resistance, Neoplasm; Drug Substitution; Fatigue; Febrile Neutropenia; Female; Gastrointestinal Diseases; Hemorrhage; Homoharringtonine; Humans; Kaplan-Meier Estimate; Leukemia, Myelomonocytic, Chronic; Male; Middle Aged; Myelodysplastic Syndromes

Homoharringtonine (HHT) is a cephalotaxus alkaloid that inhibits the synthesis of proteins leading to apoptosis. Intravenous HHT has demonstrated activity in patients with chronic myeloid leukemia (CML) after failure with interferon.. A Phase I study was completed of subcutaneous (s.c.) HHT in patients with CML in accelerated or blast phases and demonstrated efficacy and good tolerance at the same doses used by intravenous (i.v.) administration. The maximal tolerated dose (MTD) was 1.25 mg/m(2) s.c. twice daily. The cohort was then expanded to treated at the MTD to include patients in late chronic phase CML after imatinib failure. Therapy consisted of an i.v. loading dose of HHT 2.5 mg/m(2) over 24 hours, followed by 1.25 mg/m(2) s.c. twice daily for 14 days every 28 days until remission, then for 7 days every 28 days. Six patients (median age, 53 years) who had failed imatinib were treated and 5 were evaluable. Patients received a median of 4.5 courses of s.c. HHT.. Complete hematologic remission was obtained in all 5 evaluable patients and 3 had cytogenetic (CG) responses: 1 complete and 2 minor. The 2 patients with BCR-ABL kinase domain mutations at the start of therapy with HHT had a CG response and in both instances the mutations became undetectable. All patients developed myelosuppression and 3 had their HHT dose reduced due to prolonged neutropenia. Nonhematologic toxicity was mild and manageable.. Subcutaneous HHT is well tolerated and may have clinical activity in patients with CML after imatinib failure.

Topics: Adult; Aged; Anemia; Antineoplastic Agents, Phytogenic; Benzamides; Blast Crisis; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Injections, Intravenous; Injections, Subcutaneous; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Nausea; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Treatment Failure; Treatment Outcome