December 7, 2009 (New Orleans, Louisiana) — Tyrosine kinase inhibitors that target BCR-ABL mutations, such as imatinib (Gleevec), have become standard therapy in the treatment of chronic myeloid leukemia (CML). Although these agents have had a dramatic impact on survival, currently available tyrosine kinase inhibitors have not demonstrated activity in CML patients who harbor the Bcr-Abl T315I mutation.
There are currently no approved treatments for this small subset of patients, but a new therapeutic option might be on the horizon. According to data presented here at the American Society of Hematology 51st Annual Meeting, an experimental agent — omacetaxine (Omapro, ChemGenex) — is a potential treatment for CML that has a unique mechanism of action that is independent of tyrosine kinase inhibition.
Omacetaxine is a first-in-class cetaxine, and has demonstrated clinical activity as a single agent for a range of hematologic malignancies. It has a novel mechanism of action, in that it specifically binds to the ribosomal A-site cleft. This action inhibits the protein translation of short-lived oncoproteins that are upregulated in leukemic cells — in particular, Cyclin-D1, Mcl-1, and c-Myc. In January 2009, the US Food and Drug Administration granted orphan drug status to omacetaxine for the treatment of myelodysplastic syndromes.
This drug has shown durable hematologic and cytogenetic responses in CML, along with a tolerable safety profile, in a phase 2/3 study, reported lead author Jorge Cortes, MD, professor and deputy chair of the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center in Houston.
New Drugs Needed
"There was interest in this agent at the time when interferon was the treatment of choice in CML," said Dr. Cortes. "However, imatinib came along and displaced everything else because its impact was so spectacular. Now there is a renewed interest in this agent."
Richard A. Larson, MD, professor of Medicine at the University of Chicago in Illinois, and moderator of the press briefing at which the results were presented, said that there will always be a need for new agents. "Resistance occurs in chemotherapy, the same as it does in antimicrobial therapy," he explained.
"We now have a better understanding of mutations," he said. "So there may be other drugs sitting on shelves that may turn out to be useful."
High Response Rate Observed
Dr. Cortes and colleagues evaluated the safety and efficacy of subcutaneously administered omacetaxine in 90 patients with imatinib-resistant T315I+ Philadelphia chromosome positive CML. All of the patients enrolled so far have failed treatment with imatinib and 79% have failed therapy with at least 1 other tyrosine kinase inhibitor — either dasatinib, nilotinib, or both.
Dr. Jorge Cortes
Patients received 1.25 mg/m2 omacetaxine by subcutaneous injection twice daily for 14 days, every 28 days, until hematologic response. They then received omacetaxine 1.25 mg/m2 twice daily for 7 days, every 28 days, as maintenance therapy.
Data were available from 81 patients in the trial. Of this group, 49 were in the chronic phase, 17 were in the accelerated phase, and 15 were in the blast phase.
A complete hematologic response was seen in 86% (n = 42) of the chronic-phase patients, Dr. Cortes reported, and the median duration of that response was 9 months. A total cytogenetic response rate of 41% was observed in chronic-phase patients, with a major cytogenetic response rate of 27.5%. Nine of these patients achieved a complete response, and a reduction in the baseline T3151 clone was achieved in 57% of patients in this group. Median survival time has not yet been reached.
For accelerated-phase patients, 35% (n = 6) experienced hematologic responses, with 5 patients achieving a complete response and 1 returning to chronic phase. The median duration of the response was 7 months, and median survival was 18.8 months.
Among those in blast phase, 47% had an overall hematologic response, with 3 complete responses. There was median response duration of 2 months, and median survival was 2.1 months.
Treatment was well tolerated overall, explained Dr. Cortes. Grade 3/4 adverse events were experienced by 68% of the cohort, and these were primarily hematologic. The most commonly reported events were thrombocytopenia, anemia and neutropenia. Nonhematologic toxicities were uncommon, with primarily grade 1/2 with diarrhea, fatigue, pyrexia, nausea, and asthenia being the most frequently reported.
Omacetaxine might provide a treatment option for a patient population that currently has no approved drug therapies, Dr. Cortes concluded.
Dr. Cortes and several of his coauthors report a relationship with ChemGenex, the manufacturer of the drug.
American Society of Hematology (ASH) 51st Annual Meeting: Abstract 644. Presented December 6, 2009.
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Cite this: Novel Agent Shows Promise for T1351 Positive Chronic Myeloid Leukemia - Medscape - Dec 07, 2009.