Safety and efficacy of subcutaneous-administered omacetaxine mepesuccinate in imatinib-resistant chronic myeloid leukaemia (CML) patients who harbour the BCR-ABL T315l mutation – results of an ongoing multicenter phase 2/3 study

Over the past several years, tyrosine kinase inhibitors, which target BCR-ABL (an abnormal protein that drives the overproduction of white blood cells characteristic of leukaemia), have become standard therapy for the treatment of CML. In the United States, the number of people living with CML has doubled since 2001 and this trend is expected to continue; an estimated 5,050 people are expected to be diagnosed with CML in 2009.

A total of 90 patients were enrolled, with data available for analysis on 66 patients: 40 in chronic phase (the initial, stable phase),16 in accelerated phase (when leukaemia cells multiply more aggressively), and 10 in blast phase (when symptoms become severe and hard to treat) CML with a confirmed BCR-ABL T315I mutation. All patients had previously failed imatinib therapy. In addition, 79 percent had also failed therapy with at least one more tyrosine kinase inhibitor. Patients were started on cycles of 1.25 mg/m2 of omacetaxine twice daily for 14 days, to be repeated every 28 days until a hematologic response was achieved (when abnormal parameters in the blood, such as high white blood cell count, and enlarged spleen normalize). Once a response was demonstrated, patients received 1.25 mg/m2 of omacetaxine twice daily for seven days, approximately every 28 days as maintenance therapy. However, there is a small subset of patients who do not respond to tyrosine kinase inhibitors because they have an additional mutation called BCR-ABL T315I. For these patients, there are currently no approved treatments. Led by researchers from The University of Texas M. D. Anderson Cancer Center in Houston, the study evaluated the safety and efficacy of a potential new therapy called omacetaxine in patients with CML who have the T315I mutation and are resistant to first-line imatinib therapy. Given by subcutaneous injection, omacetaxine is a potential treatment for CML that has a unique mechanism of action that is independent of tyrosine kinase inhibition.

The study demonstrated that omacetaxine produced both strong hematologic responses and cytogenetic responses (no presence of the Philadelphia chromosome, a major feature of CML) with a safety profile consisting mainly of hematologic toxicities, such as thrombocytopenia (low platelet count, experienced by 58 percent of study patients), anemia (low red blood cell count, 36 percent), and neutropenia (low neutrophil count, a type of white blood cells, 33 percent). Specifically, median overall survival was 18.8 months for accelerated-phase patients and 1.8 months for blast-phase patients, while median overall survival for chronic-phase patients had not yet been reached. Median time to disease progression was 11.2 months for chronic-phase, 3.1 months for accelerated-phase, and 1.2 months for blast-phase patients.

“Omacetaxine is the first drug to show consistent activity in patients with chronic myeloid leukaemia who are affected with the T315I mutation,” said lead study author Jorge Cortes, MD, Internist and Professor, Deputy Chair, Department of leukaemia, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center in Houston. “Our findings show that omacetaxine may be a viable treatment option for this patient population that currently has no other available drug therapies.”