Although conventional cytotoxic drugs are the mainstay of therapy for most cancers, immunotherapies (and more recently, the protein tyrosine kinase inhibitor imatinib) have played a more prominent role in chronic myelogenous leukemia. Accordingly, few antineoplastic agents are in active development for chronic myelogenous leukemia. We discuss only ChemGenex’s version of homoharringtonine (Ceflatonin) in this section. The Chinese Academy of Medical Science has also launched a version of homoharringtonine.
Mechanism Of Action
Conventional cytotoxic agents interrupt the DNA replication and repair processes required for functional cell division. They act in several ways, including alkylating DNA, resulting in strand breakage; inhibiting crucial enzymes required for DNA strand formation; and interfering with spindle formation. Homoharringtonine inhibits the initiation of protein, DNA, and RNA biosynthesis.
Homoharringtonine (ChemGenex’s Ceflatonin, formerly CGX-653) is an intravenous formulation of a natural product derived from the cephalotaxus evergreen tree. Homoharringtonine affects several cellular pathways, including the regulation of genes associated with apoptosis and angiogenesis. In the several years prior to the launch of imatinib, homoharringtonine was extensively investigated for chronic-phase chronic myelogenous leukemia, in first- and second-line therapy, alone, and in combination with interferon-a and/or cytarabine (Pfizer’s Cytosar-U, generics). ChemGenex has initiated a combination Phase II trial of homoharringtonine and imatinib in chronic myelogenous leukemia patients who are developing resistance to imatinib. Phase II trials are ongoing in the acute myelogenous leukemia setting.
A preclinical study in four paired imatinib-sensitive/resistant cell lines investigated the potency of homoharringtonine, cytarabine, daunorubicin, and hydroxyurea, alone or in combination with imatinib. Primary blasts from advanced-stage, imatinib-refractory chronic myelogenous leukemia patients were studied using semi-solid media clonogenic assays to test the sensitivity of the tumor cells to homoharringtonine. Investigators found that homoharringtonine achieved major inhibition of chronic myelogenous leukemia cell-line proliferation.
In a clinical trial, homoharringtonine, combined with interferon-a in the first-line setting, achieved a CHR in 85% of patients, a cytogenetic response in 21% of patients, and an major cytogenetic response in 49% of patients. Combined with low-dose cytarabine as a second-line treatment, homoharringtonine induced a CHR among 72% of patients, major cytogenetic response in 15% of patients, and cytogenetic response in 5% of patients. In a triple-therapy study among patients with early chronic-phase chronic myelogenous leukemia, 90 patients received treatment with interferon-a, cytarabine, and homoharringtonine. Patients received 5 million units (MU)/m2 interferon-a and cytarabine 10 mg, both subcutaneously daily, and homoharringtonine 2.5 mg/m2 by continuous infusion over 24 hours daily on days 1-5 every 28 days. After a median duration of 16.5 months of therapy, 78 patients switched to imatinib 400 mg orally daily.
With the triple regimen, 94% of patients achieved a CHR and 74% achieved a cytogenetic response. The cytogenetic response was complete (Ph-positive cells 0%) in 22% of treated patients and major in 46% of treated patients. Significant myelosuppression occurred, resulting in major dose reductions. After 12 months of therapy, the median interferon-a dosage was 1.6 MU/m2 daily, the median cytarabine dosage was 1.85 mg daily, and the median number of homoharringtonine-treated days was two every month. Only three patients developed blastic-phase disease while receiving the triple regimen. After switching to imatinib, and after a median follow-up of 46 months from the start of triple therapy, 63% of patients achieved a cytogenetic response and a further 13% achieved an major cytogenetic response. Nine percent of patients had entered the blastic phase. Investigators estimate that five-year survival will stand at 88%.
In a small Phase I/II trial, nine patients with Ph-positive accelerated-phase chronic myelogenous leukemia previously treated with imatinib received treatment with a semi-synthetic formulation of homoharringtonine by daily subcutaneous injection for seven days, every 28 days. With a median follow-up of 12 months, 80% of patients had achieved a second chronic phase, and 67% of patients had achieved a complete hematologic response. No patient achieved a cytogenetic response. According to investigators, homoharringtonine was well tolerated with minimal nonhematologic toxicity. Grade IV neutropenia was observed in three patients, and grade IV thrombocytopenia requiring platelet support occurred in two patients. All patients were monitored for mutations in the ABL kinase domain, and, in one patient, a kinase domain mutation detected at the start of treatment was no longer detectable after six months of treatment.
One problem facing older drugs in clinical trials for chronic myelogenous leukemia, such as homoharringtonine and arsenic trioxide, is that physicians would rather place patients in clinical trials testing the new tyrosine kinase inhibitors and use these older agents only as last resorts. However, the primary limitations of homoharringtonine are its hematologic toxicity and its relatively low incidence of CCRs. The hematologic toxicity has restricted the dose of homoharringtonine in clinical trials, and most patients ultimately received only two days, rather than the planned five days, of treatment per month. Homoharringtonine’s hematologic toxicity profile will probably preclude a role in combination with imatinib in the first-line setting.