New treatment options are needed for chronic myeloid leukemia (CML) patients who are refractory to treatment with second-generation tyrosine kinase inhibitors (TKI). Patients whose disease remains refractory after two or three TKIs may have responses, but these are not usually long lasting, except in some patients with chronic-phase CML.
Omacetaxine mepesuccinate has a different mechanism of action from TKIs and has shown activity in CML patients who have become resistant or intolerant to prior TKIs, noted Jorge Cortes, MD, Chair of the CML Section at the University of Texas MD Anderson Cancer Center.
At this year's ASCO Annual Meeting, Cortes participated in several clinical trials involving omacetaxine derived from subset analyses of two phase II studies. Data from these studies has been submitted to the Food and Drug Administration as part of a new drug application, and were recently accepted for review.
“Omacetaxine has a long track record in CML,” Cortes said in an interview. The drug was first known as homoharringtonine, and was the one drug available to those patients for whom imatinib had failed. The drug, given subcutaneously, is myelosuppressive and has activity in CML, he noted.
Cortes said he foresees omacetaxine having a niche use—“most likely for those patients who have failed TKI therapy or cannot use oral therapies, for example, because of pancreatitis. Omacetaxine captures that population of patients who have exhausted all available TKIs, and will be a valuable option.”
Omacetaxine is an investigational first-in-class cephalotaxine that functions as a protein synthesis inhibitor. It may slow or stop cell growth by disrupting the part of the process involved in creating new cell proteins. The drug binds to the Bcr-Abl hybrid gene present in CML, and has two anti-leukemic actions:
- It reduces the levels of oncoproteins, including the Bcr-Abl oncoprotein associated with CML.
- It induces apoptosis in leukemic stem cells.
Both actions may prevent the first steps in the process of protein reproduction essential for cell growth. At a Poster Discussion session at the meeting, Franck Nicolini, MD, of Centre Hospitalier Lyon Sud in France, presented data on omacetaxine in patients with chronic-phase or accelerated-phase CML who were resistant or intolerant to two or three approved TKIs (Abstract 6513).
As Nicolini explained, omacetaxine is a first-in-class, reversible, transient inhibitor of protein elongation that facilitates tumor cell death without depending on Bcr-Abl signaling. Clinical activity with omacetaxine has been shown in two phase II, open-label, multicenter studies in treatment-resistant CML.
This subset analysis from the phase II studies included 122 CML patients, median age of 60, in chronic or accelerated phase who were resistant or intolerant to at least two approved TKIs. The patients received omacetaxine at 1.25 mg/m2 subcutaneously twice daily for up to 14 consecutive days in a 28-day cycle for induction, and then up to seven days per cycle as maintenance.
About half of the patients had received two TKIs (imatinib plus either dasatinib or nilotinib), and half had received all three approved TKIs. Nicolini noted that prior non-TKI therapies were common, with half the patients taking hydroxyurea and one-third taking interferon.
Twelve of the 45 chronic-phase patients (27%) of the two-TKI group achieved a major cytogenetic response (MCyR), defined as a reduction in the percentage of cells expressing the Philadelphia chromosome to no more than 35 percent, for a median duration of 17.7 months.
Among the 36 chronic-phase CML patients who had three TKIs, four (11%) achieved a MCyR (median duration not reached). And for the accelerated-phase CML patients, six of 17 patients (35%) in the two-TKI group achieved a major hematologic response (median duration of 13.4 months), as did five of the 24 patients (21%) in the three-TKI group (median duration of 6.4 months).
Median survival was 30 months for the two-TKI chronic-phase patients and was not reached for three-TKI chronic-phase patients, and was 12 and 24.6 months, respectively, for the patients with accelerated-phase CML.
Treatment-related grade 3/4 adverse events occurred in 52 patients (84%) in the two-TKI group and 42 patients (70%) in the three-TKI group; the most common adverse event was thrombocytopenia, noted in 71 percent of the two-TKI group and in 48 percent of the three-TKI group.
About one-quarter of the patients discontinued therapy, primarily due to disease progression. There were 20 deaths (primarily disease progression)—11 in the two-TKI group and nine in the three-TKI group; four deaths were considered to be related to treatment.
“In patients with heavily pretreated CML, response to omacetaxine therapy occurred whether they had received two or three prior TKIs. The drug was well-tolerated, and tolerability was similar across the TKI groups in both CP CML and AP CML patients.”
Discussant: Activity, But Relatively Modest
The Discussant for the studies, Neal Shah, MD, PhD, Assistant Professor in the Division of Hematology/Oncology at the University of California, San Francisco, explained, “Omacetaxine is a protein synthesis inhibitor with modest activity in heavily pretreated patients. It is a longstanding— i.e., more than 15 years—investigational agent for CML that reduces levels of multiple oncoproteins, including Bcr-Abl, and induces apoptosis in leukemic stem cells by blocking the initial step of protein translation at the level of the ribosome.”
However, numerous studies have not shown that the drug is highly active and leads to durable responses, he continued. Regarding Nicolini's data, he said, “Clearly, omacetaxine has some activity, but it's rather modest. The CCyR rate is not as high as we would hope.”
Shah did note, though, that not all resistance to TKI therapy is Bcr-Abl dependent and that therapies with alternative mechanisms of action such as omacetaxine may potentiate the activity of Bcr-Abl TKIs in some cases.
In another subset analysis of the two prior phase II studies, Luke Akard, MD, Co-Director of the Stem Cell Transplantation Program at Indiana Blood and Marrow Transplantation in Indianapolis, looked at chronic-phase CML patients who were resistant to and/or intolerant of TKI therapies who responded to omacetaxine therapy. The majority of the 81 patients (median age of 58) were resistant (69 patients); seven patients were intolerant to TKIs, and five were both resistant and intolerant.
After the patients had treatment with omacetaxine, however, a MCyR was achieved by 13 patients (19%) in the resistant group (median duration not reached), two (29%) in the intolerant group (median duration of 7.4 months), and one patient (20%) in the resistant/intolerant group (duration of 17.7 months).
The median overall survival was 34 months among TKI-resistant patients, has not been reached in TKI-intolerant patients, and was 25 months in TKI-resistant/intolerant patients. The most common treatment-related grade 3/4 adverse events were thrombocytopenia and neutropenia. Fifteen patients had an adverse event leading to discontinuation, primarily due to disease progression.
“This subset analysis of patients with CP CML and prior therapy with two or more TKIs shows that omacetaxine provides efficacy and tolerability across resistant, intolerant, and resistant/intolerant groups,” he concluded.