Reprogramming Aggressive Lymphoma Into More Benign Disease

Zosia Chustecka

August 29, 2013

Aggressive lymphoma can be reprogrammed into a more benign disease, according to a "promising" proof-of-concept trial of 12 patients.

The results were published online August 16 in Cancer Discovery.

The study patients had diffuse large B-cell lymphoma (DLBCL) and were considered to be at high risk for recurrence after initial treatment.

Initial treatment of DLBCL with regimens such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is successful in about 75% of patients.

Patients whose disease recurs often go on to high-dose chemotherapy and autologous stem cell transplantation, which offers a second chance of cure, according to senior author Leandro Cerchietti, MD, assistant professor of hematology and oncology at Weil Cornell Medical College in New York City, and colleagues.

However, they note that many patients do not respond because of refractory disease or are not able to tolerate the therapy.

About one third of patients have disease that is refractory or relapses after initial therapy; the majority of these patients die within 2 years of diagnosis, the researchers write.

"To have any hope of helping patients with aggressive lymphoma, we need to make this resistant cancer sensitive to treatment," Dr. Cerchietti explained in a statement.

The team used azacitidine (Vidaza), which is already marketed for myelodysplastic syndrome, because previous research has suggested that it can deactivate genes involved in programmed cell death, which can sensitize cancer cells to chemotherapy.

The patients were pretreated with low-dose azacitidine, administered subcutaneously in escalating doses (25 mg/m², 50 mg/m², or 75 mg/m² daily for 5 days). Patients were then treated with 6 cycles of R-CHOP.

Eleven of the 12 patients achieved complete remission, and 10 remain cancer-free at 28 months, the researchers report.

"These preliminary efficacy results were promising in this high-risk population," they note, particularly because the majority of such patients die within 24 months.

"These are promising positive results," agrees Richard Winneker, PhD, senior vice-president of research at The Leukemia & Lymphoma Society, who was asked by Medscape Medical News to comment on the findings. However, he noted, these data "need to be confirmed in a larger study and with longer follow-up."

"This overall therapeutic approach is not new," Dr. Winneker explained, although previous efficacy findings efficacy have been mixed.

"Investigators have increasingly appreciated that azacitidine can effectively sensitize cancer cells to standard chemotherapy agents," he said. "Specifically, multiple researchers have reported that azacitidine works, at least in part, by deactivating genes that would otherwise help block cancer cell death."

What is new here — and an "important scientific finding" — is that azacitidine was used at a relatively low dose, which selectively inhibits DNA methylation without inducing broader, less-selective toxic effects. "This seems to have been important to the positive findings in their clinical study," Dr. Winneker noted.

Dr. Cerchietti explained that early preclinical studies with higher doses of azacitidine were failures. "We thought that maybe we were giving the drug in the wrong way."

"One of the first things we realized is that the drug has to be given in a concentration that will remove the methyl groups without affecting the other cellular processes," he said.

Like azacitidine, decitabine (Dacogen), which also marketed for myelodysplastic syndrome, has been studied for its potential to reverse resistance to chemotherapy.

Both drugs are DNA methyltransferase inhibitors that act by reducing the attachment of methyl groups to genes involved in programmed cell death. This aberrant DNA methylation programming results in chemoresistance because the chemotherapy cannot get to the genes and activate them.

Elderly patients and patients with aggressive forms of lymphoma, such as those who participated in the clinical trial, tend to have more chemoresistant disease. "The worse the disease, the higher the degree of aberrant methylation," Dr. Cerchietti noted.

"When lymphomas are formed, they shut down the cellular processes 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," he explained.

We showed that "these fail-safe mechanisms can slowly be awakened to induce lymphoma cell death when chemotherapy is administered [and] that aggressive lymphoma can be reprogrammed to a more benign disease," he concluded.

The team is now conducting trials in patients with lymphoma and considering investigations in patients with other types of cancer, according to a press release.

Dr. Winneker noted that other clinical trials are already exploring the use of azacitidine in breast and prostate cancers. He explained that the gene-altering activity of azacitidine and decitabine, by a mechanism other than mutation, falls in to the field of epigenetics, which is "critical to advances in cancer."

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

Dr. Cerchietti has disclosed no relevant financial relationships. Some of his coauthors report consultancies with Celgene, Genentech, Seattle Genetics, and/or Bio-Reference Laboratories. Coauthor Rebecca L. Elstrom is a medical director at Genentech. Dr. Winneker reports that The Leukemia & Lymphoma Society has funded the work of many of the coauthors, as well as some of the laboratory findings that led to this clinical trial.

Cancer Discov. Published online August 16, 2013. Abstract

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