Gene 'driver' of Waldenström's Macroglobulinemia in up to one-third of patients identified


Drug that targets the driver mutation proves effective in animal studies

Steven Treon, MD, PhDSteven Treon, MD, PhD

In nearly one-third of patients with Waldenström's Macroglobulinemia, a specific genetic mutation switches on the disease, and a new drug that blocks the defective gene can arrest the disease in animal models, researchers at Dana-Farber Cancer Institute and allied institutions will report at the 2013 annual meeting of the American Society of Hematology (ASH). The finding may open the way to clinical trials of the drug in Waldenström's patients whose tumor cells carry the mutation.

Waldenström's 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's Macroglobulinemia at Dana-Farber, and Zachary Hunter, showed that tumor cells in 90 percent of Waldenström's patients carry a specific gene mutation — the first time the disease had been traced to a particular genetic flaw. More recently, Treon reported 29 percent of a small group of Waldenström's patients had mutations in the gene CXCR4.

In a study to be presented at the ASH meeting, Irene Ghobrial, MD, director of the Michele & Stephen Kirsch Laboratory at Dana-Farber, and Aldo Roccaro, MD, PhD, also of Dana-Farber, and their colleagues examined samples of Waldenström's tumor cells from a far larger group of patients — 250 in all — and found that CXCR4 was indeed mutated in about 30 percent of them.

Irene Ghobrial, MDIrene Ghobrial, MD

In experiments with laboratory cell samples, the researchers found that Waldenström's tumor cells with the CXCR4 mutation proliferated more quickly than those without the mutation. In mice, Waldenström's 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's 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's cells to grow, divide, and metastasize," Ghobrial said. When researchers treated Waldenström's-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's."

The findings are especially important in light of another study presented at the ASH conference. In it, researchers led by Treon and Maria Lia Palomba, MD, of Memorial Sloan-Kettering Cancer Center, tested ibrutinib — a drug that blocks growth signals in Waldenström's cells — in 63 Waldenström's patients who had received at least one prior treatment.

When researchers examined the bone marrow of 34 patients who had taken ibrutinib for six months, they found that the amount of marrow impacted by Waldenström's had declined between 45 and 70 percent. Patients whose Waldenström's 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.

"The results show that ibrutinib is very active and well tolerated in patients with relapsed or hard-to-treat Waldenström's," Treon remarked. "The discovery of CXCR4 mutations in Waldenström's is an important milestone, and provides a means to identify which patients are more likely to benefit from ibrutinib. Our findings also provide a framework for studying combinations of ibrutinib with CXCR4 inhibitors."

The co-lead author of the CXCR4 study is Antonio Sacco, of Dana-Farber. Co-authors are Patricia Maiso, PhD, Michele Moschetta, MD, and Yuji Mishima, PhD, of Dana-Farber; Cristina Jimenez and Ramon Garcia-Sanz of Hospital Clinico de Salamanca, in Salamanca, Spain; Michelle Kuhne, PhD, and Pina Cardarelli, Ph.D, of Bristol-Myers Squibb; and Jesus San Miguel, MD, PhD, of Hospital Clinico Universitario, Salamanca Spain.

The co-lead author of the ibrutinib study is Christina Tripsas, MA, of Dana-Farber. Co-authors are Guang Yang, PhD, Yang Cao, MD, Lian Xu, Zachary Hunter, Steven Cropper, Patrick Mostyn, Kirsten Meid, MPH, Diane Warren, Christopher Patterson, Jacob Laubach, MD, Claudia Paba-Prada, MD, Janet Kunsman, NP, Irene Ghobrial, MD, and Sandra Kanan, NP, of Dana-Farber; Gaurav Varma, MSPH, of Stanford University Medical Center; and Ranjana Advani, MD, Stanford University School of Medicine.

The CXCR4 study was supported by the NIH (1R 01F0003743), the International Waldenström's Macroglobulinemia Foundation, the Kirsch Lab for Waldenström's Macroglobulinemia, the Heje Fellowship for Waldenström's Macroglobulinemia and by Bristol Myers Squibb.

The ibrutinib study was supported by a research grant from Pharmacyclics Inc. Funding for the whole genome sequencing project which made the genomic discoveries possible was provided by the Peter Bing Fund for Waldenström's Macroglobulinemia, and the International Waldenström's Macroglobulinemia Foundation.

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