Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009

• Published in: Cancer Vol. 115; no. 23; pp. 5382 - 5393
• Main Authors: Quintás‐Cardama, Alfonso, Kantarjian, Hagop, Cortes, Jorge
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2009; Wiley-Blackwell
• Subjects: Algorithms; Antineoplastic Agents, Phytogenic - therapeutic use; BCR‐ABL1 mutations; Benzamides; Biological and medical sciences; chronic myeloid leukemia; Clinical Trials as Topic; Drug Discovery; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Harringtonines - chemistry; Harringtonines - therapeutic use; Hematologic and hematopoietic diseases; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; omacetaxine mepesuccinate; Piperazines - therapeutic use; Pyrimidines - therapeutic use; T315I; Tumors; Antineoplastic agent; Chronic myelogenous leukemia; homoharringtonine; Malignant hemopathy; Abl1 gene; Myeloproliferative syndrome; T315I; Alkaloid; Cancerology; bcr gene; BCR-ABL1 mutations; Genetics; chronic myeloid leukemia; Mutation; omacetaxine mepesuccinate; Hybrid gene; Cancer
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.24601

Homoharringtonine (HHT) is a natural alkaloid that is obtained from various Cephalotaxus species. The mechanism of action by which HHT exerts its antitumor activity is through inhibition of protein synthesis and promotion of apoptosis. In the 1990s, HHT proved to be significantly active as salvage therapy for patients with chronic myeloid leukemia (CML) after failure on interferon‒α therapy. However, the remarkable success of imatinib mesylate in the treatment of CML relegated HHT to oblivion. The development of omacetaxine mepesuccinate, a subcutaneously bioavailable semisynthetic form of HHT, and its activity in imatinib‐resistant CML has established this agent for the second time as a valuable option in the management of this disease. Preliminary results appear to support the use of this agent for patients who have imatinib‐resistant CML, including those who carry the tyrosine kinase inhibitor‐insensitive mutation that exchanges the amino acids threonine and isoleucine at position 315 (the T315I mutation). In this article, the authors discuss the current data on omacetaxine and the prospects of this agent to be integrated into the state‐of‐the‐art treatment algorithms for CML. Cancer 2009. © 2009 American Cancer Society. In the 1990s, homoharringtonine (HHT) was regarded as the most active drug for patients with chronic myeloid leukemia (CML) after failure on interferon alpha. The remarkable clinical activity of imatinib brought to a sudden halt the clinical development of this agent in CML. Omacetaxine mepesuccinate, a semysinthetic form of HHT that can be administered subcutaneously, demonstrated high activity in patients with advanced phase CML and in those who carried kinase domain mutations of the breakpoint cluster region‐Abelson murine leukemia viral homolog 1 BCR‐ABL1. Preliminary results indicated that omacetaxine is effective in the treatment of patients with CML who carry the BCR‐ABL1 mutation that exchanges the amino acids threonine and isoleucine at position 315 (the T315I mutation), which renders ineffective all available adenosine triphosphate‐competitive tyrosine kinase inhibitors.