Advances in Lymphoma Research
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: Hodgkin lymphoma and non-Hodgkin lymphoma (sometimes called NHL). But more than 70 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 lymphoma research, including clinical advances that may soon translate into improved care and research findings from recent studies.
Treatment of Non-Hodgkin Lymphoma (NHL)
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 lymphoma grows 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. But sometimes an indolent lymphoma can turn into aggressive lymphoma, which requires immediate treatment.
Indolent non-Hodgkin lymphoma 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 targeted therapy. A stem cell transplant is sometimes used for lymphoma that has recurred, but this procedure has serious side effects, and can be fatal. Four 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.
New 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 is being used and tested in a number of ways:
- In the last several years, the drug has been approved for the treatment of small lymphocytic lymphoma and Waldenstrom macroglobulinemia, both indolent non-Hodgkin lymphomas. It has also received approval for mantle cell lymphoma (which can be aggressive or indolent) and marginal zone lymphoma (indolent).
- NCI took part in a randomized clinical trial that tested the addition of ibrutinib to chemotherapy and rituximab (Rituxan) in people newly diagnosed with a certain type of diffuse large B-cell lymphoma. People over the age of 60 had worse outcomes with the addition of ibrutinib. However, patients under the age of 60 who were given ibrutinib had substantially improved survival.
- Other studies have suggested that people whose diffuse large B-cell lymphoma has specific genetic characteristics may especially benefit from treatment with ibrutinib.
- An early-phase NCI-sponsored study tested ibrutinib plus chemotherapy in people with primary central nervous system lymphoma, a very aggressive subtype of non-Hodgkin lymphoma. More than half of the patients in this small study went into complete, long-term remission. A larger study is now underway at the National Institutes of Health (NIH) Clinical Center. That study is also testing this combination in people with lymphoma that began elsewhere in the body but has spread to the central nervous system.
The FDA has approved two other drugs that target the B-cell receptor signaling pathway. Acalabrutinib (Calquence) is approved for relapsed mantle cell lymphoma and small lymphocytic lymphoma. An ongoing study at NCI is testing acalabrutinib, in combination with chemotherapy and rituximab, in people with previously untreated diffuse large B-cell lymphoma.
In 2019, zanubrutinib (Brukinsa) was approved for relapsed mantle cell lymphoma. A fourth drug targeting the B-cell receptor signaling pathway, called pirtobrutinib, is now being tested in clinical trials.
Many other targeted therapies are being tested in non-Hodgkin lymphoma. Some that are approved for specific subtypes are listed below.
- Polatuzumab vedotin (Polivy) for the treatment of diffuse large B-cell lymphoma. Clinical trials are testing this drug and related drugs for other types of non-Hodgkin lymphoma.
- Copanlisib (Aliqopa) for recurrent follicular lymphoma. A study at NCI is testing copanlisib for previously untreated follicular lymphoma.
- Venetoclax (Venclexta) for chronic lymphocytic leukemia and small lymphocytic lymphoma.
- Loncastuximab (Zynlonta) for large B-cell lymphoma that has recurred or did not shrink after other treatments.
- Selinexor (Xpovio) for large B-cell lymphoma that has recurred or did not shrink after other treatments.
- The combination of tafasitamab (Monjuvi) and lenalidomide (Revlimid) for people with large B-cell lymphoma who cannot undergo a stem cell transplant.
- Tazemetostat (Tazverik) for some people with follicular lymphoma that has recurred or did not shrink after other treatments.
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, ongoing trials led by NCI researchers are testing a five-drug regimen and a six-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 uses substances to stimulate or suppress the immune system to help the body fight cancer. Several immunotherapies have shown promise in treating different types of lymphoma.
CAR T cells. CAR T cells are a type of immunotherapy in which a patient's T cells, a type of immune cell, are changed in the laboratory so they will better attack cancer cells. Four CAR T-cell therapies have been approved for the treatment of non-Hodgkin lymphoma:
- Axicabtagene ciloleucel (Yescarta) for people with large B-cell lymphoma or follicular lymphoma whose cancer has progressed after receiving at least two prior treatment regimens.
- Tisagenlecleucel (Kymriah) received approval for adults with one of three types of non-Hodgkin lymphoma.
- Lisocabtagene maraleucel (Breyanzi) for people with some types of B-cell non-Hodgkin lymphoma that has relapsed or has not gotten better after at least two other treatments.
- Brexucabtagene autoleucel (Tecartus) for some people with mantle cell lymphoma that has come back or did not get better with other treatments.
To date, CAR T cells have provided long-term remissions for about one third of adults with lymphoma who receive them. Large randomized trials have been comparing CAR T-cell therapy to autologous stem cell transplantation at first relapse. In one of these trials, more people who received the CAR T-cell therapy were alive two years after treatment compared with those who received chemotherapy followed by stem cell transplantation. Participants in the other trials are still being followed to see if differences in survival emerge over time.
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 lymphoma subtypes, both aggressive and indolent.
Immune checkpoint inhibitors. Other immunotherapy drugs, called immune checkpoint inhibitors, work by encouraging the body’s T cells to attack cancer cells. These drugs have been largely ineffective in treating non-Hodgkin lymphoma. However, a new immune checkpoint inhibitor that interacts with a different type of immune cell called a macrophage has been developed. In a small study, almost one-third of people with an aggressive type of lymphoma and 40% of those with an indolent lymphoma had their disease go into remission with the new drug, magrolimab. In both groups, the responses seen were long-lasting.
A phase 2 trial of magrolimab in combination with rituximab and chemotherapy as a treatment for several types of lymphoma is now underway. A clinical trial underway at NCI is also testing it in combination with two targeted therapies for several different types of indolent lymphoma.
Immunomodulating drugs. Immunomodulators are drugs that either stimulate or suppress the immune system. One such drug, lenalidomide (Revlimid), has been approved in combination with targeted therapies for previously treated follicular lymphoma, marginal zone lymphoma, and diffuse large B-cell 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.
Immunotherapy drugs called bispecific antibodies are also under development. These drugs bind to lymphoma cells and the body’s own immune cells at the same time to bring them together. This allows the immune cells to kill the lymphoma cells. Five bispecific antibodies are in clinical trials for various types of lymphoma, including
- glofitamab, which in a phase 1 trial shrank aggressive lymphoma in people who had received several prior treatments
- epcoritamab, which also shrank previously treated aggressive lymphoma in an early-phase clinical trial
- mosunetuzumab (Mosun), which triggered long-lasting remissions in almost 20% of people with aggressive B-cell non-Hodgkin lymphoma and almost 50% of people with indolent B-cell non-Hodgkin lymphoma in an early-phase clinical trial
Hodgkin Lymphoma Treatment
Hodgkin lymphoma is much less common than non-Hodgkin lymphoma. It is mostly seen in early adulthood (age 20–39) and in late adulthood (age 65 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, deaths from Hodgkin lymphoma among adults have fallen more rapidly than deaths from any other cancer type.
Researchers are now focusing on adjusting standard treatment regimens to reduce the long-term side effects and improve quality of life for survivors. They are also testing better ways to treat the minority of patients whose cancer does recur.
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 chemotherapy drugs and with immunotherapies.
Immune checkpoint inhibitors that help T cells to better kill cancer 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, as well as earlier in treatment for some people with cancer that is likely to recur.
NCI-Supported Research Programs
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 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 non-Hodgkin lymphoma 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 freely available to the wider cancer research community, to spur the development of new targeted drugs. The HIV+ Tumor Molecular Characterization Project (HTMCP) and Burkitt Lymphoma Genome Sequencing Project (BLGSP) are two active CGCI projects.
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 NCI's latest news articles on lymphoma research:
- Brentuximab Approved for High-Risk Hodgkin Lymphoma in Children and Adolescents
- Should CAR T Cells Be Used Earlier in People with Non-Hodgkin Lymphoma?
- Ibrutinib Improves Survival for Younger People with Diffuse Large B-cell Lymphoma
- COVID-19 Vaccines May Be Less Effective in Some People with Cancer
- Brentuximab May Mean Less Radiation for Children, Teens with Hodgkin Lymphoma
- CAR T-Cell Therapy Approved by FDA for Mantle Cell Lymphoma
View the full list of Lymphoma Research Results and Study Updates.