Last week Weill Cornell researcher Dr. Ari Melnick sat down with Targeted Oncology to briefly summarize the potential of EZH2 in treating diffuse large B-cell lymphoma.
Tag: diffuse large B-cell lymphoma
Two Modes of DLBCL Relapse
Despite improvements in care for patients with diffuse large B-cell lymphoma (DLBCL), roughly one-third of patients do not respond to initial therapy or relapse within the first 2-3 years after treatment. Unfortunately, our current understanding of the molecular mechanisms of relapse is extremely poor.
During the recent 2013 American Society of Hematology meeting, we reported for the first time that there exist at least two distinct scenarios of DLBCL relapse. In the first scenario, the tumor cells at diagnosis are almost genetically identical to tumor cells at relapse. Both tumors harbor the same set of mutations with the relapsed tumor possessing a few additional mutations, suggesting that the relapsed tumor evolved continuously from the tumor present at diagnosis. We termed this scenario “linear” mode. In the second scenario, the tumors at diagnosis and relapse carry different mutations, suggesting that an early divergent event occurred and that the tumors developed in parallel. Therefore, we named this scenario the “divergent” mode. Moreover, we observed that tumors with higher genetic heterogeneity at diagnosis were more likely to relapse through the divergent mode. This may provide a foundation for evaluation of different treatment strategies for different relapse modes.
Currently, we are expanding our study to investigate the role of epigenetics, particularly DNA methylation, in DLBCL relapse. For more research information on DLBCL, and relapsed DLBCL, please visit our websites at the Elemento Lab and the Melnick lab.
Pretreating DLBCL with Targeted Therapy Improves Patient Outcomes and Chemotherapy Effectivenes
Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with high rates of relapse and survival rates that rarely extend beyond two years. However, researchers from the Weill Cornell Lymphoma Program have recently published a study in Cancer Discovery, with the potential to change the standard of care for patients with DLBCL. This study focused on the use of azacitidine (Vidaza), a targeting therapy designed to reawaken the molecular mechanisms that typically trigger cell death but are switched off as lymphoma progresses. Researchers found a resurgence in the death signal on the resumption of chemotherapy for those DLBCL patients treated with azacitidine in advance of chemotherapy.
As 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 noted, “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…By pre-treating 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.”
In the proof of concept, phase 3 study led by Dr. Peter Martin, patients received low doses of azacitidine five days in advance of standard chemotherapy. 11 patients achieved a complete remission of cancer, while 10 remained cancer-free for up to 28 months.
Study collaborator, Dr. Ari Melnick commented, “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.”
The implications for this study are far ranging. Dr. Cerchietti explained, “Oncologists have long believed that using high doses of an anti-cancer drug is the best strategy. 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.”
Researchers plan on expanding the study to additional DLBCL patients in a multi-center clinical trial, while studying pre-treatment strategy options in other tumor types and lymphomas.
Please look to this space for further updates. A full listings of available clinical trials can be found here.
New Developments in Lymphoma 