Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma in adults. While DLBCL is potentially curable, patients with relapsed or refractory DLBCL cannot be cured with chemotherapy due to the aggressive nature of their disease and their tumors lack of response to chemotherapy. Therefore treating this subset of DLBCL patients requires new treatment options. Recently researchers from Dr. Leandro Cerchietti’s lab published a paper on a potential new target for DLBCL.
DLBCL tumor cells grow because malignant cancer cells disturb cell processes like DNA methylation and histone acetylation that are two key parts of the “epigenomic” machinery. Researchers in Leandro Cerchietti's lab have previously reported that inhibiting one of these epigenomic pathways by using DNA methyltransferase inhibitors (DNMTI), makes tumors more susceptible to chemotherapy treatments. His group hypothesized that inhibiting both epigenomic pathways by combining DNMTI with a histone deacetylase inhibitor (HDI) could be a potential treatment option for DLBCL patients that relapsed after chemotherapy or never responded to chemotherapy.
Researchers decided to evaluate the effectiveness of combining the HDI, vorinost with the DNMTI’s, azacitidine or decitabine in pre-clinical models to determine the feasibility of beginning phase I human trials. Researchers found no significant toxicity increase in initial laboratory and animal trials. In the ensuing trial 18 patients with a median of 3 prior therapies were treated with 4 different dose levels of azacitidine and vorinostat. The most common side effects were manageable and included hematological, gastrointestinal, and metabolic toxicities.
The clinical benefit to the combined epigenetic treatment was low as only one patient experienced a partial response. However, 2 of the 7 patients, who received chemotherapy after the study achieved a complete response, while 3 others patients derived a significant clinical benefit. This suggests that the proposed epigenetic combination could make tumors more susceptible to chemotherapy treatments.
Further research in pre-clinical models confirmed that DNMTI is the most important drugs in the combination to achieve chemosensitization, which makes tumors more susceptible to chemotherapy treatment. The data supports the strategy of using DNMTI in relapsed and refractory DLBCL patients to overcome disease resistance and improve their outcomes. This treatment could potentially be a new option for patients with relapsed or refractory DLBCL.