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A Review of Omacetaxine: A Chronic Myeloid Leukemia Treatment Resurrected.

ABSTRACT: The paradigm of targeted therapy was pioneered for chronic myeloid leukemia (CML). The advent of tyrosine kinase inhibitors (TKIs) has led to marked improvements in responses and overall survival; however, there is still a subset of patients that are either resistant through a multitude of mechanisms or intolerant to standard TKI therapy. Omacetaxine mepesuccinate (omacetaxine), a semisynthetic purified homoharringtonine compound, has been studied for over 40 years and was approved in 2012 by the Food and Drug Administration (FDA) for patients with CML refractory or intolerant to two or more TKIs. Omacetaxine has a novel mechanism of action-inhibition of protein synthesis, which does not overlap with kinase inhibition. Multiple studies have demonstrated that omacetaxine can achieve responses in heavily treated patients with either chronic-phase or accelerated-phase CML, regardless of the presence of mutations in the tyrosine kinase domain. This review will outline the tortuous story of omacetaxine, including preclinical and clinical studies of homoharringtonine, current indications, and management guidelines.

SUBMITTER: Winer ES

PROVIDER: S-EPMC7359993 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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A Review of Omacetaxine: A Chronic Myeloid Leukemia Treatment Resurrected.

Winer Eric S ES DeAngelo Daniel J DJ

Oncology and therapy 20180315 1

The paradigm of targeted therapy was pioneered for chronic myeloid leukemia (CML). The advent of tyrosine kinase inhibitors (TKIs) has led to marked improvements in responses and overall survival; however, there is still a subset of patients that are either resistant through a multitude of mechanisms or intolerant to standard TKI therapy. Omacetaxine mepesuccinate (omacetaxine), a semisynthetic purified homoharringtonine compound, has been studied for over 40 years and was approved in 2012 by th ...[more]

PMID: 32700137

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Project description:The first treatment of chronic myeloid leukemia (CML) included spleen x-radiation and conventional drugs, mainly Busulfan and Hydroxyurea. This therapy improved the quality of life during the chronic phase of the disease, without preventing nor significantly delaying the progression towards advanced phases. The introduction of allogeneic stem cell transplantation (alloSCT) marked the first important breakthrough in the evolution of CML treatment, because about 50% of the eligible patients were cured. The second breakthrough was the introduction of human recombinant interferon-alfa, able to achieve a complete cytogenetic remission in 15% to 30% of patients, with a significant survival advantage over conventional chemotherapy. At the end of the last century, about 15 years ago, all these treatments were quickly replaced by a class of small molecules targeting the tyrosine kinases (TK), which were able to induce a major molecular remission in most of the patients, without remarkable side effects, and a very prolonged life-span. The first approved TK inhibitor (TKI) was Imatinib Mesylate (Glivec or Gleevec, Novartis). Rapidly, other TKIs were developed tested and commercialized, namely Dasatinib (Sprycel, Bristol-Myers Squibb), Nilotinib (Tasigna, Novartis), Bosutinib (Busulif, Pfizer) and Ponatinib (Iclusig, Ariad). Not all these compounds are available worldwide; some of them are approved only for second line treatment, and the high prices are a problem that can limit their use. A frequent update of treatment recommendations is necessary. The current treatment goals include not only the prevention of the transformation to the advanced phases and the prolongation of survival, but also a length of survival and of a quality of life comparable to that of non-leukemic individuals. In some patient the next ambitious step is to move towards a treatment-free remission. The CML therapy, the role of alloSCT and the promising experimental strategies are reviewed in the context of the new therapeutic goals.

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A Review of Omacetaxine: A Chronic Myeloid Leukemia Treatment Resurrected.

Publications

A Review of Omacetaxine: A Chronic Myeloid Leukemia Treatment Resurrected.

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