Epigenetic Drugs Reverse Leukemia Resistance

Drugs that curtail certain epigenetic changes can reverse resistance to immunotherapy in a rare and incurable type of leukemia, a new study suggests. This treatment might also work against other cancers.

T-cell prolymphocytic leukemia (T-PLL) accounts for about 1% of leukemia cases and typically doesn't respond to single-agent or multidrug chemotherapy. The anti-CD52 monoclonal antibody alemtuzumab, which is approved for treating B-cell chronic lymphocytic leukemia, has proven to be a more effective treatment. However, the cancer gradually becomes resistant to it.

Elliot Epner, MD, PhD, of the New Mexico VA Health Care System in Albuquerque, and colleagues came up with a strategy for reversing this resistance. Cancer cells often show abnormal patterns of histone acetylation and DNA methylation. Such epigenetic alterations can promote cancer growth by silencing tumor suppressor genes and preventing apoptosis. Several FDA-approved drugs curb these epigenetic changes. For example, cladribine blocks methylation. Histone deacetylase (HDAC) inhibitors such as vorinostat (Zolinza; Merck), romidepsin (Istodax; Celgene), and valproic acid prevent the removal of acetyl groups from histones.

Epner and colleagues treated eight patients who had T-PLL with alemtuzumab and cladribine. Four of the patients had relapsed on other therapies, and for the others, this was their first treatment. Three patients also received one or more HDAC inhibitors. Combining alemtuzumab with the epigenetic drugs induced complete remission in seven patients, including the four patients who had previously relapsed, and a partial remission in one person. The median survival was 15.3 months.

The researchers found evidence that the combination treatment counteracts resistance. At the beginning of the study, two patients were resistant to alemtuzumab. Their expected survival time was 4 months. Instead, one patient lived for 34.3 months, and the other is still alive more than a year after starting treatment. “People are going into remission quickly, and the remissions appear durable,” says Epner.

Alemtuzumab and epigenetic drugs were not as effective as an initial therapy, however. Of the four patients in this category, one had a bone marrow transplant and stopped the treatment. The three who continued to receive the therapy survived between 5.7 and 15.3 months, versus the 20 months a previous study recorded for alemtuzumab alone as an initial treatment. That difference suggests that the drugs work better together after a patient has relapsed, the researchers conclude.

How epigenetic drugs restore T-PLL's vulnerability to alemtuzumab remains unclear because the patients' abnormal T cells weren't undergoing apoptosis. The researchers speculate that the epigenetic drugs reactivate genes in natural killer or other immune cells, stimulating them to kill malignant T cells marked by alemtuzumab.

Alemtuzumab is too toxic for long-term use, Epner notes, but the antibody and epigenetic drugs might keep patients in remission until they can receive a bone marrow transplant, the only way to cure T-PLL.

Other combinations of monoclonal antibodies and epigenetic drugs might have broader uses, he says. The researchers are testing whether the combination of cladribine and rituximab (Rituxan; Genentech) is effective against several hematologic cancers, including B-cell lymphoma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia. Cladribine and HDAC inhibitors, in combination with the appropriate antibodies, could also work against solid tumors, Epner says.

“It's highly promising and very good news,” says Nicholas La Thangue, PhD, of the University of Oxford in the United Kingdom, who wasn't connected to the study. He adds that clinical trials of the approach should include second-generation HDAC inhibitors that are under development or have been recently approved, such as panobinostat (Farydak; Novartis).