Precision Medicine Combination Treatment Shows Anti-Tumor Activity in Preclinical DLBCL Models

By Sucharita Mistry, PhD

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.

Lisa“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.

 

Dr. Lisa Roth Highlights Differences in Treatment Approaches for Pediatric Vs. Adult Hodgkin Lymphoma

SOSS_Roth_FurmanAt OncLive’s State of the Science Summit on Hematologic Malignancies, Dr. Lisa Roth, head of the Adolescent and Young Adult (AYA) Lymphoma Program at Weill Cornell Medicine and NewYork-Presbyterian, outlined some of the differences in treatment approaches between pediatric and adult patients with Hodgkin lymphoma (HL), a cancer commonly diagnosed in young adults in their twenties.

According to the National Institutes of Health (NIH), patients between 15 and 39 years of age are considered part of the AYA population.

“A patient in this age range can walk into a pediatric oncologist’s office or a medical oncologist’s office and receive vastly different treatment for the exact same diagnosis,” said Dr. Roth, highlighting the medical landscape’s current lack of and need for research in order to understand how to optimize care for AYA patients.

To compare and contrast the approaches, Dr. Roth broke down the components of the pediatric and adult treatment regimens for a standard case of Hodgkin lymphoma.

A HL patient treated under the pediatric regimen would typically receive four cycles of the chemotherapy drug combination doxorubicin hydrochloride, bleomycin, vincristine sulfate, etoposide phosphate, prednisone, and cyclophosphamide (ABVE-PC) over 12 weeks, as compared to the adult regimen of six cycles of chemotherapy drug combination doxorubicin hydrochloride, bleomycin, vinblastine sulfate, and dacarbazine (ABVD) over 24 weeks. About half of pediatric patients would receive radiation following ABVE-PC while very few adult patients would receive the same following ABVD.

Compared to its adult counterpart, the pediatric regimen has lower cumulative exposure to anthracycline, a drug class associated with cardiac toxicity that includes doxorubicin, as well as a lower dosage of bleomycin, a drug associated with pulmonary toxicity.

On the other hand, the adult ABVD regimen does not contain drugs etoposide or cyclophosphamide, both of which are associated with risk of secondary malignancies and infertility.

Dr. Roth explained that outcome improvements in adolescent and young adult patients are lagging behind those in both pediatric and adult populations – a disparity partially connected to the deficit of clinical and translational research focusing specifically on this age group. Other contributing factors may relate to differences in tumor biology in the AYA group that doctors do not yet fully understand, as well as the group’s tendency to delay physician consultation and to have limited healthcare access due to being under or uninsured.

Because the AYA population has such unique needs, they require a multidisciplinary team to guide them through each stage of their treatment process. The Weill Cornell Medicine/NewYork-Presbyterian Adolescent and Young Adult Lymphoma Program is composed of pediatric and medical oncologists, radiation oncologists, bone marrow transplant experts, fertility preservation specialists, and psychologists and social workers. The team also includes physicians who specialize in survivorship to allow for seamless care from treatment to beyond, which is specifically relevant for patients of this age range who are very likely to have many years of life to look forward to once cured of their disease.

WCM’s AYA Lymphoma Program is working hard to expand pediatric patients’ access to upcoming clinical trials and to develop trials specific to the AYA population.

For more from Dr. Roth on the intricacies of treating the AYA population, watch this video courtesy of OncLive: