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For most chronic myelogenous leukemia (CML) patients, Gleevec (imatinib) is nothing less than miraculous, wiping out the disease and restoring a normal life expectancy. But Gleevec doesn’t work for everyone—as many as 20 percent of patients have tumors that eventually stop responding to Gleevec in the first five or six years. Studies suggest that Gleevec works best in patients who are diagnosed in the early stages of the disease. Over time, mutations can develop that change the shape of the drug’s target, the BCR-ABL protein, so that Gleevec no longer fits in the slot. It’s “like sticking gum in a lock, so the key doesn’t work,” explains Charles Sawyers, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York City.

In 2006 and 2007, the U.S. Food and Drug Administration approved two new drugs, Sprycel (dasatinib) and Tasigna (nilotinib), as second-line therapies for CML patients who don’t respond to Gleevec. Like Gleevec, both work by targeting BCR-ABL, but they are able to bind to it more strongly or in a slightly different way. In 2010, the two drugs were also approved as first-line therapies after studies suggested that in most cases they are superior to Gleevec at inducing complete remissions.

These two newer drugs may continue to provide miraculous results for the vast majority of CML patients. But resistance to them could also become a problem. “The most significant mechanism of treatment failure is likely to be the T315I mutation, known as the gatekeeper, which confers resistance to all three drugs,” says Sawyers. This genetic abnormality may exist in newly diagnosed patients or develop later during treatment. Thankfully, a newer drug, ponatinib, has shown promising results in clinical trials of CML patients with the T315I mutation.

12/05/2011