By Ingfei Chen
Gleevec: The Sequel
When the wonder drug doesn't work, the next generation of targeted medicines can step in
By Ingfei Chen
Although Gleevec has been a godsend against a rare leukemia, the drug can allow disease to resurge. This summer, the U.S. Food and Drug Administration (FDA) approved a new pill for resistant cases, and a second one is on the horizon.
That’s a big relief for patients. “A lot of them are at the tail end of their response to Gleevec, so they are catching the new wave,” says oncologist Hagop Kantarjian of M. D. Anderson Cancer Center in Houston.
The latest five-year clinical follow-up analyses confirm that Gleevec (imatinib mesylate) prolongs the lives of people with chronic myeloid leukemia—CML—or with another rare malignancy called gastrointestinal stromal tumor, a.k.a. GIST. Yet either cancer sometimes outsmarts the drug: For example, roughly 17 percent of CML patients acquire Gleevec resistance over five years of treatment.
Normally, the drug binds to and inactivates a wayward protein called BCR-ABL, which goads white blood cells in the bone marrow to multiply wildly. But resistance commonly arises when mutations in BCR-ABL subtly alter its shape—so Gleevec can’t lock onto it, says Charles Sawyers, an oncologist at Memorial Sloan-Kettering Cancer Center in New York City.
Two newer drugs, Sprycel (dasatinib) and Tasigna (nilotinib), each have a different way of docking to BCR-ABL. Promising results from phase I safety trials for both medications appeared in the June 15 New England Journal of Medicine.
Made by Bristol-Myers Squibb, Sprycel won fast-track FDA approval for treating Gleevec-resistant patients with CML or a form of acute lymphoblastic leukemia that’s also fueled by BCR-ABL. Sprycel circumvented Gleevec resistance in 68 of 84 such patients in the phase I study, conducted by Sawyers and his colleagues at the University of California, Los Angeles, and at M. D. Anderson. The drug packed the most punch for patients with early “chronic” stage CML: 92 percent saw elevated white-cell counts drop to normal levels, and 45 percent showed a major decrease in bone marrow cells carrying the gene for BCR-ABL.
The second drug, Tasigna, is a modified version of Gleevec. When a team led by Kantarjian tested it in 106 CML patients, the “son of Gleevec” worked best against early disease too. It achieved complete white-cell remission in 92 percent of chronic CML patients; and in 35 percent, it substantially or completely reduced the number of cells hosting the BCR-ABL gene. Tasigna’s maker, Novartis, will soon seek FDA approval for it, says Kantarjian.
The two drugs are a major step forward in the battle against Gleevec resistance, says Brian Druker, an oncologist at the Oregon Health & Science University Cancer Institute in Portland. But they won’t solve the problem entirely, he notes, partly because one notoriously stubborn mutant BCR-ABL protein still defies all three drugs.
Additional trials will tell whether Sprycel or Tasigna could become first-line therapies. “I think they almost certainly will, and the reason is that they’re more potent,” says oncologist Richard Van Etten of Tufts–New England Medical Center in Boston.
Lawyers even speculates that a cocktail combo of the pills might best stem resistance to Gleevec. But Van Etten cautions that such a strategy requires careful testing because it could cause more toxicity. Researchers still have much to learn about how to effectively use the targeted medicines and when to recommend switching to a bone marrow transplant, the only option proved to fully eradicate CML. The ultimate, elusive goal still remains, Van Etten says: Not just suppressing CML, but finding real cures.