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.
Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma, rising in incidence among older populations. The standard of care for the approximate one-third of DLBCL patients who do not achieve remission with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone) is salvage high-dose chemotherapy followed by consolidative autologous stem cell transplant, which leads to long-term disease-free survival for only 10-20 percent of relapsed/refractory patients. Patients who relapse within a year of initial therapy, those who relapse after transplant, and those who are ineligible for transplant due to age or comorbidities face the most significant unmet treatment need.
With an eye toward improving therapeutic options and outcomes for this patient population, the Lymphoma Program team, led by Dr. Jia Ruan, collaborated with colleagues nationwide and contributed significantly to a study examining the maximum tolerated dose and preliminary safety and activity of a novel three-drug combination – ibrutinib plus lenalidomide and rituximab – in treatment of relapsed/refractory DLBCL. The team’s encouraging findings were published in the American Society of Hematology’s Blood journal.
The study population consisted of 45 transplant-ineligible DLBCL patients whose disease returned after at least one prior therapy. Patients received oral ibrutinib daily, intravenous rituximab on every first day of six 28-day cycles, and oral lenalidomide on the first 21 days of each cycle. The treatment was provided as continuous chronic therapy in an outpatient clinic setting for as long as patients could derive benefit.
Forty-four percent of patients responded to the triplet, and 28 percent achieved a complete response. The combination performed particularly well (ORR: 65%, CR: 41%) in patients with non-germinal center b cell (non-GCB) DLBCL, a molecular subtype based on disease cell of origin that is not typically associated with favorable prognosis. Common treatment side effects included gastrointestinal complications, fatigue, myelosuppression (reduced blood cell production), hypokalemia (low blood potassium), peripheral edema and skin rash. Side effects could be monitored and mitigated by dose adjustment in the outpatient setting.
“This novel treatment consists of two oral agents typically used to treat B-cell lymphoma, plus the anti-CD20 antibody rituximab, and can be easily administered in the clinic or patient’s home,” said Dr. Jia Ruan. “This effective low-intensity approach makes it very appealing to a broad range of R/R DLBCL patients in need of treatment.”
The oral Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has become a mainstay in the treatment of mantle cell lymphoma (MCL), producing a response in nearly 70 percent of all patients. Yet, the majority of MCL patients treated with ibrutinib develop resistance to the drug within about a year.
Preclinical research conducted at Weill Cornell Medicine demonstrated that sustained inhibition of CDK4 (a protein that promotes growth of MCL cells) by the oral drug palbociclib can not only prevent proliferation of MCL cells, but also make them more sensitive to attack by ibrutinib.
Based on these findings, Weill Cornell Medicine and NewYork-Presbyterian Lymphoma Program Chief Dr. Peter Martin and colleagues initiated a phase I study of palbociclib plus ibrutinib (PALIBR) in patients with previously treated MCL. Results from the all-oral regimen were recently published online in the American Society of Hematology (ASH) Blood Journal.
The addition of palbociclib to ibrutinib appeared to produce deeper, more durable responses compared to what is traditionally produced by ibrutinib alone, with over half of all patients remaining free of disease progression at the two-year post-treatment mark. The most prevalent side effect was low blood counts.
“The first person to be treated on the study in August of 2014 achieved a complete response within three months and remains in a complete response today,” said Dr. Martin. “We were all excited by the results.”
Physicians and researchers at the Lymphoma Program look forward to learning more about the efficacy of PALIBR in the ongoing AFT-32 phase II trial, which incorporates genetic profiling that may help to identify the features associated with drug resistance.