Next Line of Defense: New drugs take on resistant leukemia

In the past few years, the breakthrough drug imatinib has changed chronic myeloid leukemia from a death sentence to a treatable disease. But 17 percent of patients taking the drug, also called Gleevec, become resistant to its protective effects over 5 years, and their cancer recurs.

Now, two experimental drugs pick up where imatinib leaves off. In many patients with chronic myeloid leukemia (CML) that’s impervious to imatinib, the new compounds suppress the malignancy, two studies show.

“In the 1990s, when we saw a patient with CML, we gave them the bad news that they were going to live 3 to 5 years,” says hematologist-oncologist Hagop Kantarjian of the M.D. Anderson Cancer Center in Houston, who coauthored both studies. With imatinib and the new drugs, most CML patients may live a normal life. “And with some refinements, these drugs might cure most patients,” Kantarjian adds.

The new drugs, called dasatinib and nilotinib, target the same protein that imatinib does (SN: 1/1/05, p. 14: Available to subscribers at Expanding the therapeutic arsenal). Called Bcr-Abl, this abnormal protein causes the leukemia by disconnecting the brakes on cells’ replication machinery. Like imatinib, both nilotinib and dasatinib bind to Bcr-Abl, thereby killing the cancerous cells that harbor it.

However, the new drugs bind tightly even after the gene that encodes Bcr-Abl has mutated such that imatinib can no longer bind to the altered protein.

Kantarjian and his colleagues tested nilotinib and dasatinib in 180 patients with CML and 23 with a related leukemia. All were resistant to or couldn’t tolerate imatinib. Patients received nilotinib for 2 to 9 months or dasatinib for 2 to 19 months.

Patients with the less aggressive phase of the cancer showed the best results. Of 40 such patients given dasatinib, 37 had their disease go into remission, as indicated by their normal blood cell counts. So did 11 of 12 such patients who received nilotinib, the researchers report in the June 15 New England Journal of Medicine.

Patients benefited less if their imatinib-resistant CML had already turned aggressive. Fewer than half of such patients went into remission during treatment with either drug. Some patients with highly aggressive leukemia died during the study.

In the United States, more than 90 percent of CML cases are diagnosed in the least aggressive phase, says hematologist Brian J. Druker of the Howard Hughes Medical Institute (HHMI) and the Oregon Health and Science University in Portland.

Some patients had extremely low bone marrow concentrations of Bcr-Abl after treatment. Among such patients taking imatinib, Druker found that the relapse rate dropped to only 7 percent over the next 5 years.

However, such patients may not be cured, cautions cancer biologist Charles J. Sherr of HHMI and St. Jude Children’s Research Hospital in Memphis, Tenn. Evidence of a cure would require that these patients remain free of cancer for 5 years after ending drug treatment, he says.

The studies were funded by Novartis Pharmaceuticals of East Hanover, N.J., the maker of nilotinib, and Bristol-Myers Squibb of New York City, the maker of dasatinib.