OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Omacetaxine	26833-87-4	C29-H39-N-O9

ANNOTATED BIBLIOGRAPHY

References updated: 06 January 2017

• Zimmerman HJ. Hepatotoxic effects of oncotherapeutic and immunosuppressive agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 673-708.

  (Expert review of hepatotoxicity of cancer chemotherapeutic agents published in 1999 before the availability of omacetaxine).
• DeLeve LD. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam, Elsevier, 2013, p. 541-68.

  (Review of hepatotoxicity of cancer chemotherapeutic agents; omacetaxine is not discussed).
• Moy B, Lee RJ, Smith M. Hormone therapy in prostate cancer. Natural products in cancer chemotherapy: hormones and related agents. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1763-9.

  (Textbook of pharmacology and therapeutics).
• Cortes J, Lipton JH, Rea D, Digumarti R, Chuah C, Nanda N, Benichou AC, et al.; Omacetaxine 202 Study Group. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood 2012; 120: 2573-80. [PMC free article: PMC4916583] [PubMed: 22896000]

  (Among 62 patients in the chronic phase of CML with a T351I mutation in the BCR-ABL gene and failure of imatinib therapy treated with omacetaxine [1-41 cycles], the hematologic response rate was 77% and side effects were largely due to myelosuppression; ALT elevations above 5 times ULN occurred in 2 patients [3%], but there were no liver related serious adverse events or discontinuations).
• Cortes J, Digumarti R, Parikh PM, Wetzler M, Lipton JH, Hochhaus A, Craig AR, et al.; Omacetaxine 203 Study Group. Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol 2013; 88: 350-4. [PMC free article: PMC5558840] [PubMed: 23468307]

  (Among 46 patients with CML in the chronic phase refractory to at least 2 tyrosine kinase inhibitors treated with omacetaxine [1 to 39 cycles], hematologic responses occurred in 67% and overall survival averaged 30 months, while side effects included thrombocytopenia [67%], anemia [54%], neutropenia [50%], infection [57%], diarrhea [44%], nausea [30%], fatigue [24%], and headache [20%]; there were no liver related serious adverse events, drug discontinuations or delays).
• Daver N, Vega-Ruiz A, Kantarjian HM, Estrov Z, Ferrajoli A, Kornblau S, Verstovsek S, et al. A phase II open-label study of the intravenous administration of homoharringtonine in the treatment of myelodysplastic syndrome. Eur J Cancer Care (Engl) 2013; 22: 605-11. [PMC free article: PMC3745781] [PubMed: 23701251]

  (Among 9 patients with myelodysplasic syndromes treated with intravenous homoharringtonine [1-3 cycles], one had a complete response and 8 no response while side effects included serious cardiac and renal toxicities).
• Cortes JE, Nicolini FE, Wetzler M, Lipton JH, Akard L, Craig A, Nanda N, et al. Subcutaneous omacetaxine mepesuccinate in patients with chronic-phase chronic myeloid leukemia previously treated with 2 or more tyrosine kinase inhibitors including imatinib. Clin Lymphoma Myeloma Leuk 2013; 13: 584-91. [PMC free article: PMC3775895] [PubMed: 23787123]

  (Among 108 patients with chronic phase CML who had received at least two tyrosine kinase inhibitors and were treated with omacetaxine in two phase 2 trials, the overall hematologic response rate was 69% and side effects including myelosuppression, diarrhea, nausea, fatigue, infections and fever; no mention of ALT elevations and of liver related serious adverse events).
• Kantarjian HM, O'Brien S, Cortes J. Homoharringtonine/omacetaxine mepesuccinate: the long and winding road to food and drug administration approval. Clin Lymphoma Myeloma Leuk 2013; 13: 530-3. [PMC free article: PMC3775965] [PubMed: 23790799]

  (History of the development of omacetaxine as a therapy of CML; initially homoharringtonine, a natural plant alkaloid from Cephalotaxus trees, was studied extensively in China and reported to have activity against CML among other conditions; its cardiac toxicity and variability in purity led to semisynthetic modifications of the molecule [omacetaxine] and pharmacologically based dosing regimens and to its evaluation in cases of CML resistant to tyrosine kinase inhibitor therapy; future studies might focus on the combination of omacetaxine with tyrosine kinase inhibitors as first line therapy of CML).
• Alvandi F, Kwitkowski VE, Ko CW, Rothmann MD, Ricci S, Saber H, Ghosh D, et al. U.S. Food and Drug Administration approval summary: omacetaxine mepesuccinate as treatment for chronic myeloid leukemia. Oncologist 2014; 19: 94-9. [PMC free article: PMC3903068] [PubMed: 24309980]

  (Description of the results of phase 2 open label studies of omacetaxine on which the FDA based an accelerated approval, but requesting follow up studies to document the duration of responses and studies of the safety of home preparation and administration of the subcutaneous injections).
• Khoury HJ, Cortes J, Baccarani M, Wetzler M, Masszi T, Digumarti R, Craig A, et al. Omacetaxine mepesuccinate in patients with advanced chronic myeloid leukemia with resistance or intolerance to tyrosine kinase inhibitors. Leuk Lymphoma 2015; 56: 120-7. [PubMed: 24650054]

  (Among 95 patients with CML and resistance or intolerance of tyrosine kinase inhibitors who were treated with omacetaxine, 37% in the accelerated and 9% in blast phase had a hematologic response, and side effects were mostly due to myelosuppression; no mention of ALT elevations and no liver related serious adverse events).
• Cortes JE, Kantarjian HM, Rea D, Wetzler M, Lipton JH, Akard L, Khoury HJ, et al. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic- or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up. Cancer 2015; 121: 1637-44. [PMC free article: PMC5650096] [PubMed: 25586015]

  (Among 122 patients with CML resistant or intolerant to tyrosine kinase inhibitors who were treated with omacetaxine in phase 2 trials, final follow up showed overall survival of 40 months in chronic phase and 14 months in accelerated phase cases; hematologic adverse events occurred in 79% and 73% of patients and led to early discontinuation in 10% and 5%; 69 patients [56%] had at least one serious adverse event, but none were liver related).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 5 [0.6%] were attributed to imatinib, but none to omacetaxine or other therapies of CML).
• Omacetaxine (Synribo) for CML. Med Lett Drugs Ther 2015; 57 (1469): e80-1. [PubMed: 26039555]

  (Concise review of the mechanism of action, clinical efficacy, safety and costs of omacetaxine shortly after the FDA gave final approval for its use in adults with CML with resistance to tyrosine kinase inhibitors; no mention of hepatotoxicity or ALT elevations).
• Rosshandler Y, Shen AQ, Cortes J, Khoury HJ. Omacetaxine mepesuccinate for chronic myeloid leukemia. Expert Rev Hematol 2016; 9: 419-24. [PubMed: 26853281]

  (Review of the development, mechanism of action, clinical efficacy and safety of omacetaxine; no mention of hepatotoxicity or ALT elevations).