Pretreating aggressive lymphoma with targeted therapy improves chemo effectiveness

Patients with diffuse large B-cell lymphoma (DLBCL), which often relapses and kills within 2 years, experienced a remission of their cancer and stayed disease-free as long as 28 months after taking a commercially available drug that made chemotherapy more effective. This strategy has the potential to change the standard of care for patients with DLBCL and possibly for other kinds of tumors also.

The targeted drug they used, azacitidine, is designed to “reawaken” molecular mechanisms that typically trigger cell death but are switched off as cancer, including lymphoma, progresses. The research team discovered that pretreating aggressive lymphoma with azacitidine enables the death signal to turn back on when chemotherapy triggers it.

This proof-of-concept, phase III study enrolled 12 patients with high-risk DLBCL, and 11 of these patients achieved a complete remission of their cancer, including 10 who remained cancer-free for up to 28 months. The patients were given low doses of azacitidine for 5 days before standard chemotherapy was used. The study,  published in Cancer Discovery (2013; doi: 10.1158/2159-8290.CD-13-0117), was led by Peter Martin, MD, assistant professor of medicine and a hematologist/oncologist at New York-Presbyterian Hospital/Weill Cornell Medical Center in New York, New York.

"To have any hope for helping patients with aggressive lymphoma, we need to make this resistant cancer sensitive to treatment. We found we could do this by reprogramming the cancer to a more benign disease, which can then respond to chemotherapy," said the study's senior investigator, Leandro Cerchietti, MD, also of Weill Cornell Medical College.

Approximately one-third of patients have DLBCL that either does not respond to initial chemotherapy or relapses after treatment. Because the majority of those patients will die within 2 years of their diagnoses, new treatments that will increase the time patients survive free of their disease are urgently needed, Cerchietti added.

"By pretreating patients with a low-dose of azacitidine--a targeted drug approved for use in myelodysplastic syndrome--we achieved a profound and stable degree of reprogramming and chemosensitization that was very surprising to us," Cerchietti said.

"Oncologists have long believed that using high doses of an anticancer drug is the best strategy," he continued. "Our study shows that is not the case in this kind of lymphoma, and suggests this new approach can potentially be translated to other tumor types."

The researchers are expanding the study to additional DLBCL patients in a multicenter clinical trial that will soon enroll patients, and they also plan to study their pretreatment strategy in other tumor types, including additional lymphomas.
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