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Non-Hodgkin Lymphoma

• What Is Non-Hodgkin Lymphoma?
• Types of B-cell Lymphoma
• Types of T-cell Lymphoma
• Key Statistics for Non-Hodgkin Lymphoma

What’s New in Non-Hodgkin Lymphoma Research and Treatment?

• Non-Hodgkin Lymphoma Risk Factors
• What Causes Non-Hodgkin Lymphoma?
• Can Non-Hodgkin Lymphoma Be Prevented?
• Can Non-Hodgkin Lymphoma Be Found Early?
• Signs and Symptoms of Non-Hodgkin Lymphoma
• Tests for Non-Hodgkin Lymphoma
• Non-Hodgkin Lymphoma Stages
• Survival Rates and Factors That Affect Prognosis (Outlook) for Non-Hodgkin Lymphoma
• Questions to Ask About Non-Hodgkin Lymphoma
• Chemotherapy for Non-Hodgkin Lymphoma
• Immunotherapy for Non-Hodgkin Lymphoma
• Targeted Drug Therapy for Non-Hodgkin Lymphoma
• Radiation Therapy for Non-Hodgkin Lymphoma
• High-Dose Chemotherapy and Stem Cell Transplant for Non-Hodgkin Lymphoma
• Surgery for Non-Hodgkin Lymphoma
• Palliative and Supportive Care for Non-Hodgkin Lymphoma
• Treating B-Cell Non-Hodgkin Lymphoma
• Treating T-Cell Non-Hodgkin Lymphoma
• Treating HIV-Associated Lymphoma
• Living as a Non-Hodgkin Lymphoma Survivor
• If You Have Non-Hodgkin Lymphoma

Research into the causes, prevention, and treatment of non-Hodgkin lymphoma (NHL) is being done in many medical centers throughout the world.

Scientists are making a lot of progress in understanding how changes in the DNA inside normal lymphocytes can cause them to develop into lymphoma cells. Once this is understood, medicines may be developed that block these processes.

Progress in understanding DNA changes in lymphoma cells has already led to improved tests for detecting this disease. Some of these tests are already in use, and others are being developed. They may be used to:

• Detect lymphoma cells in a biopsy sample
• Determine what type of lymphoma a person has
• Help determine if a lymphoma is likely to grow and spread, even within a certain subtype of lymphoma
• Help figure out if a certain treatment is likely to be helpful
• Help determine if a lymphoma has been destroyed by treatment or if a relapse is likely

For example, in recent years, genetic tests have shown that there are different subtypes of diffuse large B-cell lymphoma (DLBCL), even though they look the same under the microscope. These subtypes seem to have different outlooks (prognoses) and responses to treatment. The hope is that such tests can be used to help guide treatment decisions.

Much of the research being done on NHL is focused on looking at new and better ways to treat this disease.

Chemotherapy

Many new chemotherapy drugs are being studied in clinical trials . These studies have led to the approval of medicines such as bendamustine (Treanda) and pralatrexate (Folotyn) for use against certain types of lymphoma. Other studies are looking at new ways to combine chemo drugs, either with each other or with other types of cancer medicines.

Stem cell transplants

Researchers continue to improve stem cell transplant methods, including new ways to collect the stem cells before the transplant.

Autologous transplants (which use the patient’s own stem cells rather than cells from a donor) have the risk of reintroducing lymphoma cells back into the patient after treatment. Researchers are testing new and improved ways to separate out the last traces of lymphoma cells from the stem cells before they are returned to the patient. Some of the new monoclonal antibodies developed for treating lymphoma may help remove these remaining cells.

Researchers are also studying the effectiveness of non-myeloablative (reduced-intensity) stem cell transplants in people with lymphoma. This approach may allow more people to benefit from stem cell transplants, especially those who are older or in poor health.

Targeted drug therapies

As researchers have learned more about lymphoma cells, they have developed newer medicines that target specific parts of these cells. These targeted drugs are different from standard chemotherapy drugs, which work by attacking rapidly growing cells. Targeted drugs may work in some cases where chemotherapy doesn’t, and they often have different side effects.

Some targeted drugs  are already being used to treat some types of NHL, and are being studied for use against other types.

Many other targeted drugs are now being studied in clinical trials.

Immunotherapy

Doctors have known for some time that people’s immune systems may help fight their cancer. Scientists are now trying to develop ways to encourage this immune reaction. Some types of immunotherapy are already being used to treat lymphoma, as discussed in Immunotherapy for Non-Hodgkin Lymphoma .

Monoclonal antibodies: Lymphoma cells have certain proteins on their surface. Monoclonal antibodies can be made to target these proteins and destroy the lymphoma cells while causing little damage to normal body tissues. This treatment strategy has already proven effective. Several such drugs, including rituximab (Rituxan), are already used to treat lymphoma.

Some newer antibodies are attached to substances that can poison cancer cells. These are known as antibody-drug conjugates (ADCs) . They act as homing devices to deliver the toxins directly to the cancer cells. For example:

• Brentuximab vedotin (Adcetris) is made up of an antibody to CD30 that is attached to a cell poison. It has been shown to help treat people with anaplastic large cell lymphoma (ALCL) and is now being studied for use against other types of lymphoma.
• Moxetumomab pasudotox targets the CD22 antigen on certain lymphoma cells, bringing along a toxin known as PE38. It’s being used in clinical trials to treat hairy cell leukemia (HCL).

Other ADCs are now being studied as well.

Immune checkpoint inhibitors: Immune system cells normally have proteins that act as checkpoints to keep them from attacking other healthy cells. Cancer cells sometimes take advantage of these checkpoint proteins to avoid being attacked by the immune system. Some newer medicines, such as pembrolizumab (Keytruda) and nivolumab (Opdivo), work by blocking these checkpoints, which can boost the immune response against cancer cells. These drugs have shown promise in treating several types of cancer and are now being studied for use against some types of lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy: In this treatment, immune cells called T cells are removed from the patient’s blood and altered in the lab to have specific receptors (called chimeric antigen receptors , or CARs ) on their surface. These receptors can attach to proteins on the surface of lymphoma cells. The T cells are then multiplied in the lab and given back into the patient’s blood, where they can seek out the lymphoma cells and launch a precise immune attack against them.

This technique has shown encouraging results in early clinical trials against some hard-to-treat lymphomas. Doctors are still improving how they make the T cells and are learning the best ways to use them. Several CAR T-cell therapies are now FDA approved to treat certain kinds of advanced or recurrent lymphomas, and many others are now being studied in clinical trials.

Lymphoma vaccines: Unlike vaccines against infections like measles or mumps, these vaccines are designed to help treat, not prevent, lymphomas. The goal is to create an immune reaction against lymphoma cells in people who have very early disease or in people whose disease is in remission. One possible advantage of these types of treatments is that they seem to have very limited side effects. At this time, lymphoma vaccines are only available in clinical trials .

The American Cancer Society medical and editorial content team

Our team is made up of doctors and oncology certified nurses with deep knowledge of cancer care as well as editors and translators with extensive experience in medical writing.

Freedman AS, Freidberg JW, Aster JC. Clinical presentation and initial evaluation of non-Hodgkin lymphoma. In: Post T, ed. Uptodate . UpToDate; 2022. Accessed September 13, 2023.

Mohty R, Kharfan-Dabaja MA. CAR T-cell therapy for follicular lymphoma and mantle cell lymphoma. Therapeutic Advances in Hematology . 2022;13. https://doi.org/10.1177/20406207221142133

National Cancer Institute. Physician Data Query (PDQ). Adult Non-Hodgkin Lymphoma Treatment. 2023. Accessed at https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq#_190 on September 29, 2023.

Papageorgiou SG, Thomopoulos TP, Liaskas A, Vassilakopoulos TP. Monoclonal antibodies in the treatment of diffuse large B-cell lymphoma: Moving beyond rituximab. Cancers . 2022;14(8):1917.

Vassilakopoulos TP, Liaskas A, Pereyra P, et al. Incorporating monoclonal antibodies into the first-line treatment of classical Hodgkin lymphoma. Int J of Mol Sci. 2023;24(17):13187.

Wei J, Liu Y, Wang C, et al. The model of cytokine release syndrome in CAR T-cell treatment for B-cell non-Hodgkin lymphoma. Signal Transduction and Targeted Therapy. 2020 Jul 29;5(1):134.

Last Revised: February 15, 2024

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More in Non-Hodgkin Lymphoma

• About Non-Hodgkin Lymphoma
• Causes, Risk Factors, and Prevention
• Early Detection, Diagnosis, and Staging
• After Treatment

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• Recent findings and future directions in non-Hodgkin's lymphoma therapy

July 01, 2021

Complex, multifaceted therapy is the name of the game in non-Hodgkin's lymphoma treatment, according to research by Stephen M. Ansell, M.D., PhD. , a hematologic oncologist at Mayo Clinic's campus in Rochester, Minnesota. This and other findings were published in February 2021 in the Journal of Clinical Oncology (JCO).

Dr. Ansell had hoped that immune checkpoint blockade might combat immune dysfunction in non-Hodgkin's lymphomas as effectively as in Hodgkin's lymphoma. However, that didn't prove to be the case.

Previously, Dr. Ansell and colleagues discovered in a clinical trial of nivolumab that immune checkpoint blockade is a safe and effective therapy for refractory Hodgkin's lymphoma. The New England Journal of Medicine published their results in 2015.

Dr. Ansell explains that for non-Hodgkin's lymphoma, it was curious to him and others studying tumor microenvironment (TME) that the T cells were not effectively targeting the cancer. What they have discovered is that continuous activation has worn out these cells, exhausting and suppressing them and hindering their readiness to attack tumors.

Therefore, with the exception of a few patient subsets, immune checkpoint blockade alone has proven ineffective as a single therapy for non-Hodgkin's lymphomas. From this study, Dr. Ansell determined the following:

• The immune system needs more support to activate and prevent suppression, targeting tumor cells rather than aiding the development of malignancy.
• A combination approach is necessary to mount a sufficient response to these lymphomas: immune checkpoint blockade plus chemotherapy, or other immune-active agents.

"I think we're coming to realize that one thing alone is not the answer for non-Hodgkin's lymphomas," says Dr. Ansell. "An integrated approach of bringing multiple components together and changing various facets of the immune system is really where we're trying to get to — to create a whole new reprogrammed tumor environment."

Specifically, according to the paper in JCO , an effective non-Hodgkin's lymphoma therapy needs to address these obstacles:

• Inadequate presentation of tumor-associated antigens
• Immunosuppressive cells in the TME
• Cancerous cells overexpressing immunosuppressive ligands
• Cytokine secretion leading to immune exhaustion or immune activation suppression

Background for the JCO findings

Dr. Ansell's lymphoma research program, which focuses on the TME and B cell cancer biology, has produced over 450 journal articles, including the 2021 paper in JCO . A fellowship at Mayo Clinic piqued his interest in this line of research, and during that period, he became interested in lymphoma — particularly lymphoma biology — while working in a B cell malignancy lab. His focus during the fellowship — and since then — has been the TME .

He explains that initially the lymphoma program's research focused on one or two immune checkpoint therapies, but now multiple possibilities have arisen with these therapies. An area of new research that he considers exciting is one that not only exploits the adaptive immune system — the T cell side — but also targets the malignant cells with the innate immune system, the macrophages and monocytes, or the so-called trash collectors of the immune system.

While investigators have made great strides in the last 10 years in treating B-cell lymphomas, progress with T-cell lymphoma has been more modest, according to Dr. Ansell.

Considerations for physicians on reaching a precise diagnosis

As there are numerous non-Hodgkin's lymphoma subtypes, experts may disagree about a precise diagnosis. Dr. Ansell indicates that an adequate biopsy is a crucial component in identifying the exact type of non-Hodgkin's lymphoma.

In addition, expertise in recognizing the various subtypes is critical to an accurate diagnosis, he says. He recommends a second opinion on pathology and also referring a patient to a medical center such as Mayo Clinic with broad experience in distinguishing non-Hodgkin's lymphomas.

Future perspectives on lymphoma research and treatment

Dr. Ansell is positive about the future of non-Hodgkin's lymphoma research and treatment.

"In lymphoma treatment and research, this is a remarkable time with an almost overwhelming amount of riches as regards available novel treatment approaches," says Dr. Ansell. "Twenty years ago, we focused entirely on the tumor cell. But now we understand we can change the environment in which these tumor cells are growing and get the immune system to engage with the tumor in a far greater way. I think the big advance we are likely to see in the future is taking multiple agents that are really promising and utilizing them in combination."

He says patient outcomes now far exceed what they were 10 years ago. "There's a wave of immunotherapies happening across cancer, in part driven by some of the work done here at Mayo Clinic," he says. "So what's really exciting now is to see the biology coming full circle to impact patients and seeing great clinical success, particularly for patients with lymphoma."

Dr. Ansell considers the treatment horizon for lymphoma very promising with novel treatments, novel combinations and the use of these agents in combination with standard treatments to profoundly change patient outcomes.

For more information

Ansell SM. Checkpoint blockade in lymphoma. Journal of Clinical Oncology. 2021;5:525.

Ansell SM, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. The New England Journal of Medicine. 2015;372:311.

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Nivolumab Appears to Boost Cure Rate in Advanced Hodgkin Lymphoma

November 14, 2024 , by Carmen Phillips

An imaging scan of a man with advanced Hodgkin lymphoma, showing multiple areas with cancer (red and yellow-orange) throughout the upper body.

The immunotherapy drug nivolumab (Opdivo) should be part of the initial treatment of teens and adults with advanced forms of classic Hodgkin lymphoma, according to updated results from a large NCI-funded clinical trial. 

In the nearly 1,000-patient trial, treatment with nivolumab and a three-drug chemotherapy regimen called AVD was better at eliminating cancer and keeping it at bay than the current standard initial treatment for the disease, AVD combined with the targeted therapy brentuximab (Adcetris) .

Two years after starting treatment, about  92% of trial participants randomly assigned to the nivolumab–AVD group were alive without their cancer starting to grow again —a measure known as progression-free survival —compared with 83% in the brentuximab–AVD group. People in the nivolumab–AVD group also had fewer side effects overall and fewer serious side effects, according to findings reported October 17 in the New England Journal of Medicine .

The trial’s lead investigator, Jonathan Friedberg, M.D., director of the Wilmot Cancer Institute at the University of Rochester, explained that, historically, most people with advanced Hodgkin lymphoma whose cancer has not returned within 2 years of completing their initial treatment are cured. 

Based on these new findings, Dr. Friedberg said, “we’re curing substantially more patients” with the nivolumab–AVD regimen.

During a press briefing on the study’s results, Dr. Friedberg explained that only seven people in the study received radiation therapy after completing their drug treatment—even though one-quarter of trial participants were between the ages of 12 and 17. 

Many people in this age group diagnosed with Hodgkin lymphoma get radiation therapy, often as a safeguard to help prevent the cancer from coming back. But the radiation can have severe downsides, including causing long-term health problems like second cancers, he said. To limit these long-term side effects , the trial was designed so that radiation therapy would only be used under very strict conditions in this age group. 

Given the excellent outcomes seen in people treated with nivolumab and AVD, Dr. Friedberg said, oncologists can feel confident following this approach.

“We've largely eliminated radiation therapy as part of the [initial] treatment,” he said. “We now have a more effective, less toxic regimen that should not only have fewer short-term side effects, but also fewer long-term side effects.”

A shift from brentuximab to nivolumab

Most people diagnosed with classic Hodgkin lymphoma will be cured, even those who are diagnosed when the cancer is advanced.

Brentuximab–AVD has been a standard initial, or first-line, treatment for advanced Hodgkin lymphoma for about a decade. Although it’s been shown to modestly improve progression-free survival , brentuximab can have substantial side effects, including intense pain and tingling in the hands and feet (known as peripheral neuropathy ), along with diarrhea and other stomach problems. In fact, many people stop taking the regimen because of side effects.

Nivolumab is already used as a stand-alone treatment for advanced Hodgkin lymphoma that has returned after first-line treatment. The results with nivolumab as a second-line treatment have been so good , Dr. Friedberg said, that the next logical step was to test nivolumab as part of the initial treatment.

Better progression-free survival, fewer side effects, almost no radiation

Conducted by the SWOG Cancer Research Network, an NCI-funded clinical trials group, the study enrolled nearly 1,000 participants from hospitals across the United States. Overall, 12% of the participants were Black and 13% were Hispanic, Dr. Friedberg noted, with this diversity meaning its results are applicable to the general population of people with this disease.

Hodgkin lymphoma is one of the most common cancers diagnosed in adolescents, but adolescents and adults have not generally been included in the same clinical trials and given the same treatments. For this trial, SWOG researchers collaborated with researchers from the NCI-funded Children’s Oncology Group to design the study to enroll adolescents as well as adults, Dr. Friedberg said. Overall, about 240 participants were ages 12 to 17.

Part of that collaboration involved developing criteria for when radiation therapy was allowed to be used. Under these criteria, radiation could only be used in patients who, after completing drug treatment, had evidence of remaining cancer on imaging scans that met very specific conditions. Otherwise, radiation could not be used.

Despite the robust improvement in 2-year progression-free survival in the nivolumab–AVD group, there’s almost no difference between the two treatment groups in the percentage of people alive overall at 2 years: 99% versus 98%. But that’s to be expected, given that these data are based on such short follow-up, Dr. Friedberg said. Even people whose cancer comes back can be cured with second-line treatments or live for many years.

Nearly all side effects were worse in the brentuximab–AVD group, in particular peripheral neuropathy. Side effects considered to be serious were also more common in this group, and more patients stopped treatment altogether because of side effects.

FDA Approves Brentuximab for Hodgkin Lymphoma in Children and Adolescents

The approval was based on the results of an NCI-sponsored clinical trial led by the Children’s Oncology Group.

Seven deaths occurred in the nivolumab–AVD group, three of which were judged to have been related to the treatment. By contrast, there were 14 deaths in the brentuximab–AVD group, eight of which were treatment related.

According to Paul Harker-Murray, M.D., of Children’s Wisconsin and who specializes in treating lymphomas, the findings are convincing.

The nivolumab–AVD regimen and approach to radiation treatment used in the trial “will very likely be considered the new standard of care for the adolescent and young adult population at many [cancer] centers,” said Dr. Harker-Murray, who wasn’t involved in the study.

Many Hodgkin lymphoma researchers had assumed that the ability to cure advanced Hodgkin lymphoma with current therapies “had probably been maximized,” wrote James Armitage, M.D., of the University of Nebraska Medical Center, and Dan Longo, M.D., of Harvard Medical School, in an editorial that accompanied the trial’s results . The SWOG trial “undermines that assumption,” Drs. Armitage and Longo wrote. 

Although trial participants need to be followed for longer to determine how the treatment holds up over time, there’s plenty of reason for optimism about the nivolumab–AVD regimen, they continued.

“Unless remissions induced by immune checkpoint blockade plus chemotherapy are different from those induced by chemotherapy alone, late relapses would be unexpected,” they wrote.

A new standard of care for advanced Hodgkin lymphoma

A spokesperson for Bristol Myers Squibb, which makes nivolumab, said that the company doesn’t comment on their plans for requesting approvals from the Food and Drug Administration. So, it’s unclear when the drug could potentially be approved for this specific use. 

Even in the absence of FDA approval, Dr. Friedberg said he expects that expert guidelines for treating Hodgkin lymphoma in adults and children will be revised to recommend nivolumab – AVD as the preferred initial treatment for people with advanced disease.

Drs. Armitage and Longo explained that the results are particularly important for patients aged 60 and older, who often have “a much poorer treatment outcome” than younger patients. The 2-year progression-free survival rate of 88% among those in this age group treated with nivolumab – AVD “is probably the best ever reported,” they wrote. 

In addition, the brentuximab – AVD regimen had “a particularly unacceptable side-effect profile among older patients, with one-third discontinuing all treatment early,” Dr. Friedberg and his colleagues wrote. “On the basis of these findings, the use of [brentuximab]–AVD should probably be avoided in older patients.”

Trial investigators are now analyzing levels of tumor DNA in blood samples collected from trial participants. The results of those studies can guide future research about whether levels of circulating tumor DNA can help clinicians fine-tune treatment decisions even further, Dr. Friedberg said.

According to Dr. Harker-Murray, there are several ongoing studies testing ways to make treatments safer for adolescents with Hodgkin lymphoma. There’s also potential, he continued, to use nivolumab and brentuximab as an initial treatment. The two are already used together in some people whose cancer has returned after multiple earlier treatments.

“The combination is extremely active in [these] patients … and the side effects are limited,” he said.

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