Pretreating Aggressive Lymphoma with Targeted Therapy Improves Chemotherapy Effectiveness

Patients with an aggressive lymphoma that often relapses and kills within two 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. Researchers from Weill Cornell Medical College and NewYork-Presbyterian Hospital, who led the study published in Cancer Discovery, say their strategy has the potential to change the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) — and possibly other kinds of tumors.

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.

In a proof-of-concept, Phase 3 study of 12 high-risk DLBCL patients led by Dr. Peter Martin, assistant professor of medicine and a hematologist/oncologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, 11 achieved a complete remission of their cancer, and 10 remained cancer-free for up to 28 months. The patients were given low doses of azacitidine for five days before standard chemotherapy was used.

“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,” says the study’s senior investigator, Dr. Leandro Cerchietti, the Raymond and Beverly Sackler Research Scholar and assistant professor of medicine at Weill Cornell Medical College, who also collaborated with the Medical College’s Dr. Ari Melnick, the Gebroe Professor of Hematology and Oncology and professor of medicine.

“In this remarkable study, Dr. Cerchietti discovered an important new disease mechanism that causes chemotherapy resistance in aggressive lymphomas, developed a new treatment regimen and completed the first clinical trial, demonstrating that his findings are true and directly relevant to those patients with the most severe forms of this tumor,” Dr. Melnick says.

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 two years of their diagnoses, new treatments that will increase the time patients survive free of their disease are urgently needed, Dr. Cerchietti adds.

“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,” Dr. Cerchietti says.

“Oncologists have long believed that using high doses of an anti-cancer drug is the best strategy,” he continues. “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 multi-center clinical trial that will soon enroll patients, and they also plan to study their pretreatment strategy in other tumor types, including additional lymphomas.

Source Weill Cornell Medical College