Homoharringtonine/Omacetaxine: The Little Drug that Could

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Hagop Kantarjian, MD

Susan O’Brien, MD

Jorge Cortes, MD

Lowering the price of omacetaxine and allowing for patient self-administration will improve access and compliance, broaden the use of omacetaxine, and reduce the cost of care.

—Hagop Kantarjian, MD, Susan O’Brien, MD, and Jorge Cortes, MD

First, a clarification: Homoharringtonine is a natural plant alkaloid derived from Cephalotaxus fortunei; from the 1970s until the present, it was the subject of intensive research efforts by Chinese investigators to clarify its role as an antileukemic agent.1-3 Omacetaxine mepesuccinate (Synribo) is a semisynthetic highly purified homoharringtonine compound (99.7% purity) used in recent studies in chronic myeloid leukemia (CML) and approved by the FDA on October 26, 2012, for the treatment of CML. In the authors’ historical experience, milligram for milligram, omacetaxine is more myelosuppressive than homoharringtonine.

Homoharringtonine/omacetaxine probably holds a record for the longest time of development of an anticancer agent until FDA approval—almost 40 years.

Past and Present Research

Over several decades, the Chinese investigators have identified homoharringtonine as an active anticancer agent in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute promyelocytic leukemia (APL), polycythemia vera, and as intrathecal therapy for central nervous system (CNS) leukemia.1,2 In AML, homoharringtonine resulted in complete response rates of 25% as single-agent therapy. In combination with standard chemotherapy in front-line AML therapy, the complete response rates were 70% to 90%, and the cure rates 30% to 40 %.1,4

A recent randomized study showed that the addition of homoharringtonine to standard AML chemotherapy improved complete response and cure rates significantly. A total of 620 patients younger than 60 years old were randomized to DA (cytarabine at 100 mg/m2 daily × 7 and daunorubicin at 40 to 45 mg/m2 daily × 3), vs HAD (cytarabine, daunorubicin, and homoharringtonine at 2 mg/m2 IV daily × 7), vs HAA (cytarabine, aclarubicin [an improved anthracycline not marketed in the United States] at 40 mg/m2 daily × 3, and homoharringtonine).5

The complete response rates after one course of therapy were significantly higher with the addition of homoharringtonine (66% vs 54%, P = .005 for HAA vs DA; P = .03 for HAD vs DA). The 3-year event-free survival rates were higher with the addition of homoharringtonine: HAA 35% vs DA 23%, P = .002; HAD 33% vs DA 23%, P = .08. Overall survival and relapse-free survival were significantly better for HAA vs DA in patients with favorable or intermediate cytogenetic categories (P = .014 for survival; P = .02 for relapse-free survival).5

In the Chinese studies, the homoharringtonine doses ranged from 2 to 8 mg given as short intravenous infusion or intramuscularly. Cardiovascular complications (severe hypotension, arrhythmias) were significant.

The studies in the United States (in the 1980s) used short intravenous infusions, which were dose-limited by severe cardiovascular complications.1 Later studies in leukemia used continuous infusion schedules over 24 hours at dose ranges of 5 to 9 mg/m2 daily for 7 to 9 days, reporting complete response rates of 15% to 20%, but still serious cardiovascular complications in 30% of patients.6 Lower doses and longer exposure schedules of homoharringtonine at 2.5 to 3 mg/m2 daily × 14 eliminated the cardiovascular complications and were further developed in CML.7

Through the 1980s and 1990s, homoharringtonine was investigated as a single agent, and in combination with low-dose cytarabine, with interferon-alpha, and with both, in late and early chronic-phase CML.1,8-13 These studies, summarized in several previous reviews, confirmed the anti-CML efficacy of homoharringtonine.

Semisynthetic Formulation

The development of homoharringtonine was hampered by several factors: difficult production and unreliable source supply, toxicity profile of the original dose schedules, large quantities of bulk of cephalotaxus trees required (rare, from China), the success of tyrosine kinase inhibitors in CML, and the uncertainty of the role of homoharringtonine in the context of tyrosine kinase inhibitors.

In 1998, Jean-Pierre Robin et al reported on the first semisynthetic formulation of homoharringtonine.14 Pilot studies confirmed the efficacy of the semisynthetic homoharringtonine, known later as omacetaxine.15,16 In 2004, ChemGenex provided a stable source of omacetaxine for future studies.

This led to the development, conduct, and completion of the FDA pivotal trials of omacetaxine in CML after failure of several tyrosine kinase inhibitors and in the setting of CML and T315I mutations.17 In a phase II study of subcutaneous omacetaxine at 1.25 mg/m2 twice daily for 14 days during induction and for 7 days during maintenance, 62 patients in chronic phase with T315I mutation were treated. A complete hematologic response was achieved in 77%, with a median response duration of 9.1 months. Twenty-three percent of patients achieved a major cytogenetic response, which was complete in 16%. The estimated 3-year survival rate was 60%.17

In the context of the phase II studies conducted, an updated analysis involved 122 patients (81 in chronic-phase CML, 41 in accelerated-phase CML) treated regardless of mutation status, who had previously been treated with two or more tyrosine kinase inhibitors (including imatinib [Gleevec]). Among the 81 patients in chronic phase, 16 (20%) achieved a major cytogenetic response (complete in 10%, partial in 10%). The median duration of major cytogenetic response was 18 months. Four patients (5%) had a minor cytogenetic response. The median overall survival was 34 months. Among the 41 patients in accelerated phase, 11 (27%) had a major hematologic response for a median duration of 9 months. Six patients (14%) had a cytogenetic response. The median overall survival was 16 months.18

The first submission to the FDA resulted in a negative Oncologic Drugs Advisory Committee (ODAC) vote for omacetaxine approval in CML and T315I mutation, because of the lack of a standardized molecular test for T315I. The subsequent FDA submission for omacetaxine in the setting of CML after failure of two or more tyrosine kinase inhibitors resulted in the FDA approval in October 2012.

Future Research

The FDA approval of omacetaxine in CML for the narrow indication of CML in chronic or accelerated phases post failure of two or more tyrosine kinase inhibitors is the beginning of the real research into different potential uses of omacetaxine in leukemia. This is analogous to the ongoing research with high-dose cytarabine on different schedules in AML and lymphoma, and with high-dose daunorubicin in AML, 30 to 40 years after their FDA approval.

The high level of activity of omacetaxine in CML and its efficacy against dormant CML clones makes it an ideal agent to eradicate residual CML disease and for CML molecular cure. Future studies should investigate the addition of omacetaxine to tyrosine kinase inhibitors in patients with CML in complete cytogenetic response with persistent molecular disease.

In AML, omacetaxine could be investigated as low-intensity therapy in combination with low-dose cytarabine or hypomethylating agents for treatment of older patients with AML not fit for intensive chemotherapy, or in whom intensive chemotherapy is not beneficial. Combinations of omacetaxine with standard chemotherapy in younger patients with AML should be further explored. Omacetaxine could also be investigated in all patients with AML following completion of standard therapy, as consolidation-maintenance therapy to eradicate minimal residual disease.

In MDS, omacetaxine should be evaluated in patients who fail therapy with hypomethylating agents and in whom the expected median survival is about 6 months. It may be useful in combination therapy with hypomethylating agents in front-line MDS therapy.

Additional uses of omacetaxine may be in the settings of APL, myeloproliferative conditions such as polycythemia vera, and as intrathecal therapy for resistant CNS leukemia.

Additional Issues

Two elephants in the room need to be addressed: (1) the high cost of the drug (about $24,000 for induction and $12,000 for a maintenance course), and (2) the FDA mandate that the drug cannot be self-administered (even though all prior research studies with subcutaneous omacetaxine were self-administered without any safety concerns). Lowering the price of omacetaxine and allowing for patient self-administration will improve access and compliance, broaden the use of omacetaxine, and reduce the cost of care.

Now, the future looks quite bright for the little drug that could. ■

Disclosure: Dr. Kantarjian has received research grants from ChemGenex. Dr. O’Brien has consulted for Teva. Dr. Cortes has received research grants from ChemGenex and is a consultant for Teva.

Dr. Kantarjian is Professor of Medicine and Department Chair, Dr. O’Brien is Professor of Medicine, and Dr. Cortes is Professor of Medicine and Deputy Department Chair, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.


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