Chemotherapy-refractory large B-cell lymphomas reprogrammed to respond to Azacitidine

FDA Highlights by Bruce Sylvester – Researchers report from a phase I clinical trial report that diffuse, large B-cell lymphomas (DLBCLs) resistant to chemotherapy have been successfully reprogrammed to respond to azacitidine therapy.

The study was published on Aug. 16 in Cancer Discovery, a journal of the American Association for Cancer Research.

As background the authors noted that patients whose lymphomas recur after initial chemotherapy are treated with combination high-dose chemotherapy and stem cell transplant. But some tumors do not respond, and many such patients die within two years of diagnosis.

They conducted the clinical trial based on the results of preclinical experiments determining  mechanisms by which lymphomas evade chemotherapy drugs.

“When lymphomas are formed, they shut down the cellular programs that sense that something is wrong in the cells. Once these fail-safe mechanisms that trigger cell death are shut down, it becomes difficult to kill the tumor with chemotherapy,” said investigator Leandro Cerchietti, M.D., assistant professor at the Hematology and Oncology Division of Weill Cornell Medical College in New York. “Our study showed that using low concentrations of the DNA methyltransferase inhibitors decitabine or azacitidine, these fail-safe mechanisms can slowly be awakened to induce lymphoma cell death when chemotherapy is administered.”

Cerchietti and colleagues enrolled 12 subjects newly diagnosed with DLBCL. Eleven of the subjects were over 60 years old when at diagnosis, and, therefore, at high risk for tumor recurrence after initial treatment.

They treated the subjects with escalating doses of azacitidine,  eight days before initiation of six cycles of standard chemotherapy.

They reported minimal side effects from pre-treatment with azacitidine.  Two subjects treated with  maximum-dose azacitidine experienced dose-limiting toxicities.

Of the 12 subjects, 11 had a complete response, and 10 remained in complete remission for up to 28 months.

“We showed that aggressive lymphomas can be reprogramed to a more benign disease,” said Cerchietti. “We think this work has the potential to change the standard of care for patients with aggressive lymphomas.”