Drug developers unveil strategies aimed at imatinib-resistant CML.

W ith the arrival of imatinib (Gleevec) a decade ago, chronic myelogenous leukemia (CML) turned into a chronic disease. Clinicians hailed its estimated 85% success rate in the rare but deadly cancer as a triumph for the new field of targeted therapeutics. Last year, Novartis to pursue development of imatinib and ran its pivotal clinical trials, received the prestigious Lasker-DeBakey Award for Clinical Medical Research for his decades-long quest to come up with a successful drug for the condition. However, one in seven CML patients did not respond to initial imatinib therapy, and they were soon joined by a small group who developed resistance, estimated at 10% – 15% of patients who initially benefited from the drug. Resistance usually developed in the fi rst 5 years of taking the tyrosine kinase inhibitor (TKI). U.S. Food and Drug Administration approval of follow-on TKIs for treating CML — dasatinib (Sprycel) from Bristol-Myers Squibb in 2006 and nilotinib (Tasigna) from Novartis in 2007 — offered alternatives for some, but not all, of those patients. One group that did not respond to any TKIs were patients who had developed the T315 → I mutation of the BCR-ABL gene on the abnormal Philadelphia chromosome that causes the disease. An estimated 2% – 3% of patients — about 200 people a year in the U.S. — develop the drug-resistant T315 → I mutation. In recent months, drug developers have unveiled several strategies for dealing with the T315 → I mutation. One seeks to restrict its emergence by limiting overall resistance. Another would treat it with a new chemo-therapy agent. Others are working on new drugs that will target the mutation.