Re-Thinking Epigenetic Therapies for B-Cell Lymphoma

Histone deacetylase inhibitors (HDACi) are small molecules that alter the function of histones, or proteins that bind to DNA and help to determine chromosome shape and gene activity. In cancer treatment, HDACi are traditionally considered epigenetic drugs because of their capacity to modify gene expression to halt tumor cell division, but new research from the Cerchietti Research Laboratory at Weill Cornell Medicine poses rationale for studying the inhibitors’ biological effects through a different lens – their impact on cell metabolism.

Benet Pera, Ph.D., along with Weill Cornell colleagues, as well as researchers from the Helmholtz Institute of Computational Biology in Germany and the Lady Davis Institute for Medical Research in Canada, conducted the study to improve the efficacy of HDACi in people with B-cell lymphoma, which is relatively low compared to that in T-cell lymphoma. Several HDACi, including vorinostat and romidepsin, have been approved by the United States Food and Drug Administration (FDA) for treatment of certain T-cell lymphoma subtypes.

Contrary to their namesake, histone deacetylase inhibitors are able to affect a long list of non-histone proteins, among them metabolic enzymes. These agents can be more appropriately referred to as lysine deacetylase inhibitors (KDACi). Due to the activity of KDACi in proteins involved in metabolic pathways, Pera et al. investigated the effects of the KDACi panobinostat in the cell metabolism of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients enrolled in a phase II trial. Metabolic profiling of the patients’ plasma before and after KDACi-treatment demonstrated that panobinostat prompts DLBCL cells to rely on a certain metabolic pathway, the choline pathway, for survival. The scientists found that in the lab, treating the cancer cells with a choline pathway inhibitor in combination with panobinostat produced superior anti-lymphoma effects in vitro and in animal models.

benet-pera“We are studying these so-called ‘epigenetic’ drugs from a different angle, hoping that metabolomics might hold the key to improving their clinical efficacy,” says Dr. Pera.

The research data recently published in the open-access journal EBioMedicine help to substantiate the team’s innovative re-application of epigenetic reagents, demonstrating the value and promise of the metabolic mechanisms by which KDACi/HDACi can improve current therapeutic options for people with B-cell lymphoma. The results also highlight the need to explore the unknown biological effects of this class of drugs before they can be successfully implemented in a clinical setting.

Dr. Jia Ruan Reviews Updates in T-Cell Lymphoma Research and Treatment

SOSS_Jia_RuanT-cell lymphoma is a complex form of non-Hodgkin lymphoma caused by abnormal clonal growth of mature T-cell lymphocytes. The disease is uncommon, affecting approximately 5-10 percent of lymphoma patients in the United States.

Historically, T-cell lymphoma was classified according to histological (microscopic anatomy) features, but thanks to new technology such as next-generation DNA sequencing and gene expression profiling, we are now able to refine disease classification based on molecular features and cell of origin. Dr. Jia Ruan discussed some of these updates at the OncLive State of the Science Summit on Hematologic Malignancies.

The most common subtypes of systemic peripheral T-cell lymphoma (PTCL) are: peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large-cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL). Cutaneous T-cell lymphoma (CTCL) primarily affects the skin and tends to be less aggressive compared to systemic subtypes.

While outcomes vary by T-cell lymphoma subtype, the five-year overall survival rate for systemic PTCL (with the exception of ALK+ ALCL) is between 20-30 percent, which Dr. Ruan said is suboptimal and indicative of a need for progress from a clinical research and clinical management standpoint.

Physician-researchers are taking steps to improve efficacy of initial T-cell lymphoma therapy so that as many patients as possible can achieve complete remission (CR) and stay in remission for as long as possible. Strides include incorporating frontline stem cell transplant as a way to prolong progression-free survival (PFS) in a portion of patients, as well as moving novel agents into initial combination therapy.

To date, four FDA-approved novel agents, namely pralatrexate (anti-folate), romidepsin (histone deacetylase or HDAC inhibitor), brentuximab vedotin (CD30 antibody-drug conjugate), and belinostat (HDAC inhibitor), are being evaluated in clinical trials for evidence of enhanced effectiveness when combined with cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisone (CHOP)-like chemotherapy. Clinicians eagerly await the results of these studies.

In CTCL, Weill Cornell Medicine (WCM) and NewYork-Presbyterian’s (NYP) multidisciplinary approach to healthcare allows medical oncologists and dermatologists to collaboratively diagnose and manage cases, as well as offer a range of treatment options. For cases with thin layers of skin involvement, skin-directed therapies include steroids, topical chemicals, light therapy, and electron beam radiation. For cases that progress from the skin to the lymphatic and blood system, treatment may include systemic agents like romidepsin, retinoid analogues like bexarotene, and vorinostat, an oral HDAC inhibitor. Combinations of topical therapy and systemic treatment, as well as novel options through clinical trials, are also considered whenever appropriate.

At the Lymphoma Program at WCM/NYP, the overarching goal in the context of T-cell lymphoma is to use cutting-edge next-generation sequencing of patient samples in order to better understand T-cell lymphoma biology, and to then apply a personalized approach to pair patients with the appropriate clinical trials and optimal conventional therapies.

Watch Dr. Ruan speak with OncLive about classification of T-cell lymphomas in this video:

Health Disparities and the Global Landscape of Lymphoma Care Today

The American Society of Clinical Oncology (ASCO) Annual Meeting brings together more than 30,000 oncology professionals each year to encourage discourse on leading research, state-of-the-art treatments, and ongoing controversies in the field. At this year’s Annual Meeting in Chicago, our own Dr. Adrienne Phillips was selected to present a review of the current health disparities in lymphoma care.

Adrienne Phillips

According to the National Institute on Minority Health and Health Disparities, health disparities are defined as “differences in incidence, prevalence, morbidity, mortality and burden of diseases and other adverse health conditions that exist among specific population groups.”

Dr. Phillips explained that health disparities may be due to a variety of factors, including race, gender, biology, and social and environmental differences such as socioeconomic status, health literacy, trust in the healthcare system, proximity to a healthcare facility, and access to and type of health insurance. For example, being uninsured or receiving government-assisted insurance increases patients’ risk of death by 1.5 times. Even patients’ place of residence may play a role, with treatment in rural, community-based settings being associated with inferior overall survival (OS) rates compared to treatment in urban, academic-based settings.

What Dr. Phillips and other physicians find most disconcerting about disparity in lymphoma care is that the disease is often amenable to effective therapy, but a significant segment of the population does not, or cannot, access appropriate care. For example, survival rates for some lymphomas skew lower for black people than for white people. Dr. Phillips conjectured that while African Americans tend to have poorer outcomes, the disparity is likely due to issues related to healthcare access and socioeconomic status.

According to an analysis of 701 people with diffuse large B-cell lymphoma (DLBCL) treated at two southern referral centers with a large black patient population (University of Alabama at Birmingham and Emory University in Atlanta), race did not influence outcomes. Black and white patients who received standard DLBCL chemotherapy drug combination rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) achieved similar OS rates (5y OS, 79% vs 70%).

Biological factors may also play a role in health disparities, and scientists are constantly working to better understand molecular factors in tumor development regardless of patient ethnicity.

In general, lymphoma is less common among African Americans and Asian Americans, but specific subtypes – like T-cell lymphoma in African Americans and natural killer T-cell (NKT) lymphoma in Asian Americans – are more common in these populations. Thus, Dr. Phillips highlighted a need for ethnic and racial diversity in clinical trial recruitment and in future studies of socioeconomic status and disease biology in order to better understand and improve outcomes for all patients.