Dr. Sarah Rutherford Sheds Light on Double-Hit, Double-Expressor Lymphomas

Diffuse large B-cell lymphoma (DLBCL), a fast-growing cancer of abnormal B lymphocyte cells that ordinarily help to fight infection and inflammation in the body, is the most common type of lymphoma. Approximately two-thirds of DLBCL patients are cured by six cycles of the chemotherapy drug combination rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) that serves as a standard treatment, but chromosomal changes involving MYC, BCL-2, and BCL-6 have been linked to more aggressive disease that is harder to cure.


Normally, MYC plays a role in cell growth, protein synthesis, metabolism, DNA replication, and blood vessel formation (known as angiogenesis), while BCL-2 regulates the natural death of cells when they are no longer needed in the body (known as apoptosis), and BCL-6 helps regulate genes that suppress tumor growth.

At the OncLive State of the Science Summit on Hematologic Malignancies, Dr. Sarah Rutherford provided an overview of two aggressive variations of B-cell lymphoma involving MYC and BCL-2 or BCL-6 that are characterized by resistance to chemotherapy: double-hit lymphoma and double protein-expressor lymphoma.

Double-hit lymphoma occurs due to alterations in two chromosomes involving MYC, BCL-2, and/or BCL-6, with the majority of cases involving MYC and BCL-2. This variant is fairly uncommon and has an incidence rate estimated at 5-10 percent of DLBCL cases, which can include instances in which patients’ follicular lymphoma transformed into DLBCL. Many double-hit lymphomas also tend to infiltrate sites outside the lymph nodes, such as the bone marrow and central nervous system.

According to Dr. Rutherford, outcomes for double-hit lymphomas are poor, even when intensive therapies like autologous stem cell transplant are added to treatment. Overall survival (OS) for double-hit lymphoma patients ranges between 5-24 months when treated with six cycles of R-CHOP, but dose-adjusted chemotherapy drug combination etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) has become the standard frontline therapy for double-hit cases. DA-EPOCH-R is more intensive than the R-CHOP approach and appears to have improved outcomes, but data is still limited and new strategies are being planned to increase response rates in the double-hit patient population.

Double protein-expressor lymphomas have increased protein expression of MYC and BCL-2 or BCL-6 in the absence of the chromosomal changes seen in double-hit lymphomas. This variant is more common than double-hit lymphoma, with an incidence rate of about 30-40 percent of DLBCL cases, but it is not as difficult to cure. It is, however, more aggressive and has less favorable outcomes than classical DLBCL cases (those without changes in MYC, BCL-2, and BCL-6). The standard treatment for double protein-expressor lymphomas is six cycles of R-CHOP.

Dr. Rutherford said that the Lymphoma Program at Weill Cornell Medicine/NewYork-Presbyterian Hospital – along with other institutions, including Massachusetts General Hospital – is working hard to develop novel strategies that will improve outcomes for these patients. For example, the team currently has a multi-center investigator-initiated clinical trial open to determine the maximum tolerated dose of BCL-2 inhibitor venetoclax combined with DA-EPOCH-R. The goal is to then open a second clinical trial with an objective of evaluating the efficacy of this promising combination in the double-hit and double-expressor lymphoma population.

Watch Dr. Rutherford speak with OncLive about the discrepancy between double-hit and double protein-expressor lymphoma here:

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.

Dr. John Leonard Discusses CHOP Versus DA-EPOCH-R for the Use of Untreated Diffuse Large B-Cell Lymphoma


In an interview during the 2016 American Society of Hematology Annual Meeting, Dr. John Leonard discusses results from a phase III trial where researchers compared the treatments R-CHOP to DA-EPOCH-R in DLBCL patients specifically from either the GCB or ABC subtypes.

A full link to the video of Dr. Leonard discussing the trial can be found by clicking above or be seen on Healio.com.