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Advances in Lymphoma Research

Artist’s rendering of T cells (red and blue spheres) attacking cancer cells. T-cell therapy has been effective in treating certain lymphoma patients.

Credit: iStock

NCI-funded researchers are working to advance our understanding of how to treat lymphoma. All lymphomas start in the cells of the lymph system, which is part of the body’s immune system. Lymphomas are grouped into two main types: non-Hodgkin lymphoma and Hodgkin lymphoma. But more than 50 different subtypes of the disease exist. Advances in understanding the gene changes that can lead to lymphoma are now helping scientists design more personalized treatments for these subtypes.

This page highlights some of the latest research in lymphoma, including clinical advances that may soon translate into improved care and research findings from recent studies.

Treatment of Non-Hodgkin Lymphoma

Most people diagnosed with lymphoma have a subtype of non-Hodgkin lymphoma. Non-Hodgkin lymphoma can either be aggressive or indolent.

Aggressive non-Hodgkin lymphoma grows and spreads quickly and usually requires immediate treatment. With modern treatment regimens, almost 70% of people with aggressive non-Hodgkin lymphoma will be considered cured. Research is now largely focused on finding better treatments for the minority of people with aggressive lymphoma who are not cured with initial therapy.

Indolent non-Hodgkin lymphomas grow slowly, and in some cases may not cause symptoms for years. People with indolent disease can often postpone treatment until their symptoms worsen, with no negative effects on survival.

Indolent non-Hodgkin lymphomas largely cannot be cured. The past two decades have seen improvements in extending the survival of people who are treated for this type of lymphoma. However, researchers are studying how to improve long-term survival further and working toward potentially curative treatments.

The mainstays of treatment for non-Hodgkin lymphoma have been chemotherapy, radiation therapy, and the targeted therapy rituximab (Rituxan). A stem cell transplant is sometimes used for lymphoma that has recurred, but the procedure is toxic, and can be fatal. Two CAR T-cell therapies have been approved to treat some types of recurrent lymphoma. However, most people with recurrent lymphoma will still die of their cancer.

Most research on treatment for non-Hodgkin lymphoma is now focused on targeted therapy and immunotherapy. Researchers are also trying to identify gene changes in different types of lymphoma that might be targets for new drug development.

For example, in 2018, a study led by NCI researchers identified genetic subtypes of diffuse large B-cell lymphoma (the most common type of non-Hodgkin lymphoma) that could help explain why some patients with the disease respond to treatment and others don’t. Further studies may lead to more tailored treatments for patients with this type of lymphoma.

Targeted Therapies

A signaling pathway is a series of chemical reactions that control one or more cell functions. Many types of non-Hodgkin lymphoma are driven by a signaling pathway called the B-cell receptor signaling pathway. A drug called ibrutinib (Imbruvica) has been developed to shut down that pathway. It has been used a number of ways:

FDA has also approved two other drugs targeting the B-cell receptor signaling pathway. Acalabrutinib (Calquence) is a drug that received approval for relapsed mantle cell lymphoma and small lymphocytic lymphoma. In 2019, zanubrutinib (Brukinsa) was also approved for relapsed mantle cell lymphoma.

Many other targeted therapies are being tested in non-Hodgkin lymphoma. Some that have been approved for specific subtypes include:

However, in lymphoma, resistance to a single agent can occur quickly. Researchers are now testing combinations of targeted therapies to treat non-Hodgkin lymphoma to try to overcome this resistance. For example, an ongoing trial led by NCI researchers is testing a five-drug regimen in people with aggressive or indolent B-cell lymphomas whose cancer has relapsed or is resistant to treatment.

Researchers are also trying to make standard treatment regimens less toxic for older patients. In one study, NCI researchers found that the intensity of standard chemotherapy could be reduced in older adults with Burkitt lymphoma, an aggressive type of non-Hodgkin lymphoma, without compromising the potential for a cure.

Immunotherapy

CAR T Cells. CAR T cells are a type of treatment in which a patient's T cells, a type of immune cell, are changed in the laboratory so they will attack cancer cells. In 2017, FDA approved the first CAR T cell therapyaxicabtagene ciloleucel (Yescarta)—for people with large B-cell lymphomas whose cancer has progressed after receiving at least two prior treatment regimens. In 2018, the CAR T-cell therapy tisagenlecleucel (Kymriah) received approval for adults with one of three types of non-Hodgkin lymphoma.

CAR T cells appear to be less toxic than stem cell transplantation. To date, they have provided long-term remissions for about a third of adults with lymphoma who receive them. A large randomized trial is now comparing CAR T-cell therapy to autologous stem cell transplantation at first relapse. A phase 2 trial is testing CAR T cells as initial therapy in people at very high risk of relapse. CAR T cells are also being tested in other aggressive and indolent subtypes of lymphoma.

Immune Checkpoint Inhibitors. Another type of immunotherapy, called immune checkpoint inhibitors, works by encouraging the body’s T cells to attack cancer cells. These drugs have been largely ineffective in treating non-Hodgkin lymphoma. However, an NCI-led phase 1 trial tested a new immune checkpoint inhibitor that interacts with a different type of immune cell called a macrophage. In that trial, about 40% of people with an aggressive type of lymphoma and 70% of those with an indolent lymphoma had their disease go into remission. In both groups, the responses seen were long-lasting. A phase 2 trial of the new drug is now underway.

Immunomodulating Drugs. Immunomodulators are drugs that either stimulate or suppress the immune system. In 2019, FDA approved one such drug, lenalidomide (Revlimid) in combination with the targeted therapy rituximab for previously treated follicular lymphoma and marginal zone lymphoma.

Novel Immunotherapies. Researchers are also testing novel ways to stimulate the immune system to fight lymphoma. In 2018, a small trial showed that combining radiation therapy with the injection of a compound that stimulates the immune system could shrink some indolent B-cell lymphomas. In 2019, a trial that used a vaccine to draw immune cells into tumors in people with indolent non-Hodgkin lymphoma also showed promising results. A phase 2 trial testing this strategy in combination with an immune checkpoint inhibitor is currently underway.

Hodgkin Lymphoma Treatment

Hodgkin lymphoma is much less common than non-Hodgkin lymphoma. It is mostly seen in early adulthood (age 20–39 years) and in late adulthood (age 65 years and older). More than 75% of all adults newly diagnosed with Hodgkin lymphoma can be cured with standard chemotherapy, radiation therapy, or both. Over the last 5 decades, among adults, deaths from Hodgkin lymphoma have fallen more rapidly than deaths from any other cancer type.

Research is now focusing on adjusting standard treatment regimens to reduce the long-term side effects and improve quality of life for survivors. Scientists are also testing better ways to treat the minority of patients whose cancer does recur. 

Targeted Therapies

A protein called CD30 is commonly found on the surface of Hodgkin lymphoma cells. A drug called brentuximab vedotin (Adcetris) that targets this protein has been approved as part of initial treatment for people with advanced Hodgkin lymphoma. Use of this new drug may help older patients avoid what had been the standard treatment with an especially toxic chemotherapy drug. Clinical trials are now testing brentuximab vedotin combined with other chemotherapies and immunotherapies. 

Immunotherapy

Immune checkpoint inhibitors that stimulate T cells have been effective in some people with recurrent Hodgkin lymphoma. Two such drugs—nivolumab (Opdivo) and pembrolizumab (Keytruda)—have been approved for some patients with Hodgkin lymphoma that has recurred after previous treatments. Researchers are now testing these drugs in combination with other therapies, and earlier in treatment for some people with cancer that is likely to recur.

NCI-Supported Research Programs

See a full list of Hodgkin Lymphoma and Non-Hodgkin Lymphoma research projects that NCI funded in FY 2018.

The Lymphoma Specialized Programs of Research Excellence (Lymphoma SPOREs) are designed to quickly move basic scientific findings into clinical settings. The Lymphoma SPOREs support the development of new immunotherapies, novel targeted therapies, and new methods for determining prognosis for individual patients.

The goal of the International Lymphoma Epidemiology Consortium (InterLymph) is to enhance collaboration among epidemiologists studying lymphoma, provide a forum for the exchange of research ideas, and create a framework for collaborating on analyses that compile data from multiple studies. 

The Lymphoma Epidemiology of Outcomes (LEO) Cohort Study was established to address the current and long-term health needs of non-Hodgkin lymphoma (NHL) patients and survivors. The goal is to support a broad research agenda aimed at identifying novel clinical, epidemiologic, host, genetic, tumor, and treatment factors that significantly influence NHL prognosis and survivorship.

The Cancer Genome Characterization Initiative (CGCI) is supporting research to identify common gene changes in adult and pediatric cancers. Its results are being made freely available to the wider cancer research community, to spur the development of new targeted drugs. The project has finished its work in non-Hodgkin lymphoma, and the data is available online. CGCI researchers are currently studying gene changes specifically in Burkitt lymphoma and diffuse large B-cell lymphoma as part of the HIV+ Tumor Molecular Characterization Project.

Within the Center for Cancer Research, the Lymphoid Malignancies Branch focuses on identifying abnormalities in the immune system and looking at molecular disorders that underlie lymphoid malignancies. 

The Clinical Trial Sequencing Project (CTSP) promotes the use of genomics in NCI-sponsored clinical trials. CTSP’s goal is to clarify the molecular basis of response and resistance to therapies studied. Diffuse large B-cell lymphoma is one of the cancer types under study, along with breast and renal cell carcinoma. 

Lymphoma Research Results

The following are some of our latest news articles on lymphoma research:

View the full list of Lymphoma Research Results and Study Updates.
 

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