NEW YORK—The promise of molecularly targeted therapies has been validated in chronic myelogenous leukemia (CML), Brian J. Druker, MD, of Oregon Health Sciences University, Portland, said at the Chemotherapy Foundation Symposium XVIII. "This disease has provided an ideal opportunity to test the concept that drugs targeted against a tumor-specific abnormality will have therapeutic utility," he said.
That molecular abnormality is the Bcr-Abl fusion protein, which results from a chromosome translocation and causes several kinds of leukemia. It is unique to tumor cells and is present in almost every CML patient.
Bcr-Abl kinase activity has been shown to be essential to CML pathogenesis. Thus, as predicted, the investigational tyrosine kinase inhibitor STI571 was a selective and effective therapy in this disease. [See article on page 2 for results in interferon-failure CML patients.]
"STI571 represents an example of successful drug development based on a specific molecular abnormality present in human malignancy," Dr. Druker said.
Preclinical testing showed that STI571 was selectively toxic to cells that express the constitutively active Bcr-Abl protein tyrosine kinase. It was highly bioavailable in an oral formulation. Antitumor activity was seen in mice that had been injected with cells expressing Bcr-Abl and treated with STI571. No safety concerns emerged in animal testing.
In a phase I trial of CML patients who had failed previous treatment, all 31 patients with chronic phase disease achieved hematologic remissions after reaching therapeutic dosing levels. Cytogenetic responses were seen in a "growing fraction" of patients after prolonged therapy of 5 months or more, he said.
