In a small study, most patients given low doses of azacitidine prior to standard chemotherapy for diffuse large B-cell lymphoma (DLBCL) remained cancer-free for up to 28 months.
The most urgent challenge in the clinical management of persons with DLBCL is the problem of chemoresistant disease, wrote study senior investigator Leandro Cerchietti, MD, of Weill Cornell Medical College in New York, New York, and colleagues in their Cancer Discovery report (2013;3:1002-1019). In approximately one-third of those with DLBCL, either the disease does not respond to initial chemotherapy or the person experiences a relapse subsequent to treatment. Most of these patients will die within two years of diagnosis, according to a statement issued by Weill Cornell Medical College and other organizations.
After Cerchiette and associates discovered that chemoresistance in DLBCL is associated with aberrant DNA methylation programming, they found that in lab experiments, prolonged exposure to DNA methyltransferase (DNMT) inhibitors reprogrammed chemoresistant cells to become sensitive to doxorubicin, without major toxicity.
The team then conducted a phase 1 clinical study involving 12 persons with a new diagnosis of high-risk DLBCL. The participants were given low doses of the DNMT inhibitor azacitidine for 5 days, and then began the usual DLBCL chemotherapy regimen. Azacitidine, which is already approved for the treatment of myelodysplastic syndrome, kills abnormal cells in bone marrow and helps bone marrow produce normal cells.
All but one patient achieved complete remission, and 10 remained cancer-free for up to 28 months.
“By pretreating patients with a low dose of azacitidine…we achieved a profound and stable degree of [cell] reprogramming and chemosensitization that was very surprising to us,” affirmed Cerchietti in the Weill Cornell statement. “Oncologists have long believed that using high doses of an anticancer drug is the best strategy; our study shows that this is not the case in this kind of lymphoma, and suggests this new approach can potentially be translated to other tumor types.”