homoharringtonine and Thrombocythemia--Essential

The advent of targeted oncolytic agents has created a revolution in the treatment of malignancies. Perhaps best exemplified in myeloproliferative neoplasms (MPN), the tyrosine kinase inhibitors, including inhibitors of BCR-ABL tyrosine kinase and JAK2, have dramatically changed outcomes in persons with MPN. However, clinically relevant dosing of these adenosine triphosphate-mimetic agents in humans leads to inhibition of numerous tyrosine kinases beyond those touted by drug manufacturers and studied in landmark clinical trials. These so-called off-target effects have been linked to both clinical efficacy and toxicity. Rational drug development and serendipitous discovery of drug molecules allows the clinician to select targeted oncolytic agents to treat a specific clinical diagnosis and/or avoid exacerbation of concomitant disease states due to effects upon signaling pathways. Understanding the off-target binding and effects upon signaling pathway of the agents approved for the treatment of MPN will empower the clinician to adroitly select pharmacotherapy, predict toxicities, and utilize these agents in clinical practice for indications beyond MPN.

Topics: Aniline Compounds; Antineoplastic Agents; Carbazoles; Dasatinib; Drug-Related Side Effects and Adverse Reactions; Eosinophilia; Furans; Fusion Proteins, bcr-abl; Gastrointestinal Stromal Tumors; Graft vs Host Disease; Harringtonines; Homoharringtonine; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Imidazoles; Janus Kinase 2; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mastocytosis; Myeloproliferative Disorders; Nitriles; Polycythemia Vera; Primary Myelofibrosis; Protein Kinase Inhibitors; Pulmonary Fibrosis; Pyrazoles; Pyridazines; Pyrimidines; Quinolines; Scleroderma, Systemic; Smallpox; Thrombocythemia, Essential; Tuberculosis, Multidrug-Resistant

At present, the treatment of polycythemia vera (PV) and essential thrombocythemia (ET) is still largely supportive and symptomatic. Homoharringtonine (HHT), a valid drug for treating chronic myelogenous leukemia, has shown some effect on leukemic stem cells. The aim of this study was to observe the effect of HHT on patients with high-risk PV and ET.. Patients with high-risk PV (n = 17) or ET (n = 18) who had failed or were intolerant to hydroxycarbamide or interferon-α therapy received HHT at a dose of 1.5 mg/m(2) daily by continuous infusion for 7 days every month. Hematological responses were evaluated at the 6th month after HHT therapy.. After six courses of HHT therapy, the hematological response rates were 64.7 % (11/17) in PV and 72.2% (13/18) in ET. In PV, the single sign remission rates of constitutional symptoms, symptomatic splenomegaly, pruritus and bone pain were 70.0% (7/10), 77.8% (7/9), 50% (1/2) and 100% (3/3), respectively. The remission rates of constitutional symptoms and symptomatic splenomegaly in ET were 66.7% (6/9) and 71.4% (5/7), respectively. The rates of grade 1 granulocytopenia and thrombocytopenia were 1.8 and 0.9%, respectively. No grade 2 or over events, or pancytopenia were observed.. Low-dose HHT alone has considerable short-term efficacy for high-risk PV/ET and may used as a second-line drug for PV/ET treatment in patients who have failed or were intolerant to hydroxycarbamide or interferon-α therapy.

Topics: Adult; Aged; Cephalotaxus; Dose-Response Relationship, Drug; Female; Harringtonines; Homoharringtonine; Humans; Hydroxyurea; Interferon-alpha; Male; Middle Aged; Polycythemia Vera; Thrombocythemia, Essential