Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma in adults. DLBCLs are aggressive and typically represent a heterogeneous collection of diseases that can be grouped into different subtypes depending on their particular genetic lesions.
One such subtype, described as the C3 or EZB cluster, features alterations in the BCL2 gene and mutations in chromatin remodeling genes such as EZH2. The malignant growth of this particular subtype of DLBCL is likely dependent on genetic abnormalities in EZH2 and BCL2. Both these oncogenes (genes with the potential to cause cancer) mediate their effects on tumor growth through distinct mechanisms, providing new opportunities for rational therapeutic strategies that inhibit EZH2 and BCL2 concurrently.
Dr. Lisa Roth and colleagues from the Weill Cornell Medicine and NewYork-Presbyterian Hospital Lymphoma Program evaluated the efficacy of EZH2 inhibitor tazemetostat and BCL2 inhibitor venetoclax as single agents and in combination using different preclinical models.
Tazemetostat and venetoclax were administered alone and in combination in a panel of DLBCL cell lines with and without mutations in EZH2 and translocation (a genetic abnormality in which a chromosome breaks and reattaches to a different chromosome) in BCL2. In DLBCL cells harboring EZH2 mutation and BCL2 translocation, the combination treatment markedly enhanced cell killing compared to either drug alone. Although these findings are encouraging, cell culture models are limited as lymphoma cells grown on a plastic surface in liquid cultures cannot recapitulate the physiologic environment within the human body.
To test the efficacy of the drugs in models with increased clinical relevance, Weill Cornell researchers established three-dimensional (3D) organoids that closely mimic the lymph node architecture in humans. The tazemetostat/venetoclax combination therapy was tested in two different novel organoid systems 1) organoids derived from lymphoma cells, and 2) patient-derived xenograft (PDX) organoids generated from a patient tumor and propagated in mice. The PDX tumor carried both EZH2 mutation and BCL2 translocation. In both types of organoids, tazemetostat and venetoclax had minimal activity as single agents, whereas the tazemetostat/venetoclax combination resulted in significant cell killing.
Using novel model systems, this study demonstrated that EZH2 inhibition combined with BCL2 inhibition results in synergistic anti-tumor effects. Learn more about the findings here.
“The synergistic anti-lymphoma activity mediated by the combination of tazemetostat and venetoclax is quite promising,” says Dr. Roth. “This combination therapy is anticipated to be especially effective as precision therapy for DLBCL patients with EZH2 mutation and BCL2 alteration.”
A clinical trial of this combination treatment is currently in development in collaboration with Drs. Ari Melnick, John Leonard and Peter Martin.
Patients with CLL who relapse after or become refractory to treatments like ibrutinib or idelalisib have poor outcomes. Venetoclax (also known as ABT-199) is an oral inhibitor of the BCL-2 (B-cell lymphoma 2) protein. The BCL-2 protein plays a critical role in preventing cells from undergoing apoptosis (cell death), in healthy cells and in CLL cells. In a recent study presented at the 2016 annual ASH meeting, we evaluated the effectiveness of venetoclax in treating people who relapsed after or were refractory to ibrutinib or idelalisib.
During this phase 2 trial 64 people with CLL were divided into two arms. The first arm consisted of those who were relapsed or refractory to ibrutinib, while the second arm included those who were relapsed or refractory to idelalisib. 43 patients were enrolled in the first arm and were on ibrutinib for a median of 17 months, receiving venetoclax for a median of 13 months, while 21 patients in the second arm were on idelalisib for a median of 8 months and received venetoclax for a median of 9 months. Thirty-nine patients in the ibrutinib arm and 21 patients in idelalisib arm completed the full course of treatment. The objective response rate as determined by investigators was 69% (27/39) for people who were ibrutinib resistant, and 57% (12/21) for the idelalisib resistant. At the time of analysis no median progression free survival or overall survival has been reached. Overall the progression free survival was 72% and overall survival was 90% for all participants.
The results from this trial demonstrate that venetoclax has displayed robust activity and is tolerable for people whose CLL has progressed after treatment with ibrutinib and idelalisib. Although there have been few complete responses, patients will continue to be monitored to chart any further improvements. Additional follow up will be required to assess how long lasting venetoclax responses will be.
Recently the director of the CLL Research Center at Weill Cornell Medicine, Dr. Richard Furman sat down with Targeted Oncology to discuss how he treats patients with CLL. Although he emphasized the importance of physician autonomy in the selection of treatments they should be willing to use the latest treatments approved by the FDA. Referring to venetoclax, which received FDA approval earlier this year for CLL patients with del 17p CLL he said,
“If you have a patient with CLL of any type and you believe venetoclax is best for [that patient], you absolutely should use it. There’s nothing about the specificity of the FDA approval that should prevent you. Insurance coverage may be another matter, but clinically speaking, you’re on solid ground.”
Additionally he noted the importance of progression free survival (PFS), which refers to the length of time during and after a treatment in which a disease has not gotten worse. He said,
“Hands down, PFS is the single most important thing to patients. As oncologists who must balance many clinical concerns, it can be easy for us to forget that fact.”
You can continue reading about Dr. Furman’s treatment options in the article.