In nearly one-third of patients with Waldenström macroglobulinemia, the disease is switched on by a specific genetic mutation. A new drug that blocks the defective gene can arrest the disease in animal models, according to research reported at the 2013 American Society of Hematology (ASH) Annual Meeting, December 7-10, 2013, in New Orleans, Louisiana. These findings may open the way to clinical trials of the drug in Waldenström’s patients whose tumor cells carry the mutation.

Waldenström macroglobulinemia is a form of non-Hodgkin lymphoma diagnosed in 2,000 to 3,000 people in the United States each year. In 2011, researchers led by Steven Treon, MD, PhD, director of the Bing Center for Waldenström Research at the Dana-Farber Cancer Institute in Boston, Massachusetts, and Zachary Hunter, a scientist also at Dana-Farber, showed that tumor cells in 90% of patients with Waldenström macroglobulinemia carry a specific gene mutation—the first time the disease had been traced to a particular genetic flaw. More recently, Treon reported that 29% of a small group of patients with Waldenström macroglobulinemia had mutations in the gene CXCR4.

The current study, led by Irene Ghobrial, MD, also of Dana-Farber, and colleagues examined samples of Waldenstrom tumor cells from a far larger group of patients—250 in all—and found that CXCR4 was indeed mutated in about 30% of them.

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In experiments with laboratory cell samples, the researchers found that Waldenström tumor cells with the CXCR4 mutation proliferated more quickly than those without the mutation.

In mice, Waldenström cells spread further and faster if they carried the CXCR4 mutation than if they did not, metastasizing to the animals’ liver, bone marrow, lymph nodes, kidney, and lungs. When researchers re-examined Waldenström cells from human patients, they found that cells from patients with the most aggressive disease were the most likely to have CXCR4 mutations.

“These findings led us to hypothesize that the CXCR4 mutation drives the disease—that it spurs Waldenström cells to grow, divide, and metastasize,” Ghobrial said. When researchers treated Waldenström-carrying mice with an antibody that targets the mutation, progression of the disease halted.

“We have now identified a specific mutation that drives this rare disease, as well as a potential drug capable of acting against it,” Ghobrial remarked. “We hope this work can be a springboard to clinical trials of drugs for patients with Waldenström.”

The findings are especially important in light of another study presented at the ASH conference. Ibrutinib—a drug that blocks growth signals in Waldenström cells—was tested in 63 patients with Waldenström macroglobulinemia who had received at least one prior treatment.

When researchers examined the bone marrow of 34 patients who had taken ibrutinib for 6 months, they found that the amount of marrow impacted by Waldenström had declined between 45% and 70%. Patients whose Waldenström cells harbored the CXCR4 mutation, however, did not respond as well to the drug, suggesting that they could particularly benefit from an agent that targets that specific mutation.