The United States Food and Drug Administration (FDA) recently approved brentuximab vedotin in combination with chemotherapy as a first-line treatment for people with advanced-stage classical Hodgkin lymphoma.
Also known as Adcetris, brentuximab vedotin is an antibody drug conjugate that targets the CD30 protein present on lymphoma cells and delivers a toxin designed to promote cancer cell death. The drug has been previously approved to treat systemic anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma that has returned after prior therapy.
The FDA’s approval follows the encouraging results of the phase III ECHELON-1 clinical trial, presented at the 2017 American Society of Hematology (ASH) Meeting and Exposition and published in the New England Journal of Medicine. The trial, which was open at Weill Cornell Medicine and NewYork-Presbyterian Hospital, compared standard therapy with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) versus adriamycin, vinblastine and dacarbazine plus brentuximab vedotin (A+AVD).
Of the 1,300+ enrolled patients, those receiving A+AVD were demonstrated to be 23 percent less likely to experience disease progression, a need for additional therapy, or death, as compared to the cohort receiving the standard of care therapy.
“ABVD has been the standard therapy for a couple decades because it works really well, but it’s great to have new treatments available for people with Hodgkin lymphoma,” said Peter Martin, Chief of the Lymphoma Program. “I’m proud that we were able to offer this treatment at Weill Cornell a long time ago through the ECHELON-1 trial. Like any treatment, the A+AVD combination may not be right for everyone and requires consideration of side effects, like infection risk and neuropathy. Decisions between patients and physicians regarding the best treatment should follow an open discussion of the evidence.”
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.
Chemotherapy for diffuse large B-cell lymphomas can have side effects and is not always effective. By targeting proteins that drive and define the lymphoma, it may be possible to reduce our reliance on chemotherapy. Most B-cell lymphomas arise from a structure called the “germinal center” in lymph nodes. During the normal immune response, B-cells from germinal centers express high levels of proteins called BCL6 and EZH2. The combined and coordinated action of BCL6 and EZH2 can induce specific genetic changes that result in the development of malignant lymphomas. Our research, presented as 1 of 6 papers chosen from over 6,000 during the plenary session of the recent 2013 American Society of Hematology, suggests that combinations of BCL6 and EZH2 inhibitors are highly effective in destroying lymphomas and thus represent an exciting new, rationally designed treatment regimen. Fortunately, EZH2 inhibitors are already in phase I clinical trials, and specific and effective BCL6 inhibitors will be going into clinical trials.
In the Melnick Lab at Weill Cornell Medical College we are working with colleagues to develop new strategies to eradicate lymphoma and improve patient care. Please look to this space for further updates on lymphoma research in the Lymphoma Program at Weill Cornell.