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.

Chemotherapy, radiation therapy, targeted therapy, and immunotherapy are all used in the treatment of non-Hodgkin lymphoma. A stem cell transplant is sometimes used for lymphoma that has recurred, but this procedure has serious side effects. Four CAR T-cell therapies have been approved to treat some types of recurrent lymphoma. However, these newer therapies still can't cure many people with recurrent lymphoma.

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.
• 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 (Jaypirca), is now being tested in clinical trials for several different types of non-Hodgkin lymphoma. In 2023, it was approved for the treatment of mantle cell lymphoma that has gotten worse after two or more previous treatments.

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.
• 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

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 one prior treatment regimen.
• Tisagenlecleucel (Kymriah) 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 aggressive 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 four 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 tested CAR T cells as initial therapy in people at very high risk of relapse. In early results, over three-quarters of patients had their cancer go into remission. However, long term results are not yet available and CAR T cells are not FDA approved in this setting.

CAR T cells are also being tested in other lymphoma subtypes, both aggressive and indolent, as well as in patients with lymphoma that has spread to the central nervous system.

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 and marginal zone lymphoma. It is also often used to treat 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 (Columvi), which in a phase 1 trial shrank aggressive lymphoma in people who had received several prior treatments
• epcoritamab (Epkinly), 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

Glofitamab and epcoritamab have both received accelerated approval from the FDA for the treatment of some lymphomas that have returned or gotten worse after at least two other treatments.

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.

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 chemotherapy drugs and with immunotherapies. The drug has also been approved by the FDA in combination with chemotherapy for some children and adolescents with Hodgkin lymphoma.

Immunotherapy

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.

September 8, 2023, by Edward Winstead

A cholesterol-lowering drug may help reduce the risk of heart failure in people with lymphoma who receive chemotherapy drugs called anthracyclines, results from a clinical trial suggest.

Anthracyclines, such as doxorubicin, are used to treat many types of cancer. But these drugs may affect the heart’s ability to pump blood, potentially leading to heart failure.

In the trial, atorvastatin (Lipitor) was found to reduce the risk of some cardiac changes linked to heart failure among patients treated with anthracyclines.

Atorvastatin is the most commonly prescribed type of statin, a class of cholesterol-lowering drugs used to help prevent heart disease. Participants were randomly assigned to receive either atorvastatin or a placebo for a year, starting before their first anthracycline infusion.

After a year, people in the atorvastatin group were less likely to have had declines in an indicator of cardiac health called left ventricular ejection fraction. Ejection fraction measures the heart’s ability to pump blood to other parts of the body. As the ejection fraction dips, the risk of heart failure increases.

The results, which appeared in JAMA on August 8, may support the use of atorvastatin in some patients with lymphoma who are at risk of developing heart problems due to treatment with anthracycline-based chemotherapy, the authors concluded.

“We believe that some patients with lymphoma being treated with a certain type of cancer drug called anthracyclines may benefit from the statin therapy,” said study co-leader Tomas Neilan, M.D., of Massachusetts General Hospital.

The statin therapy was also “very safe,” he added. The rates of side effects, such as muscle pain—a common side effect of statins—were similar between the two groups.

For people who are already taking statins when they are diagnosed with lymphoma, the new results would support the continuation of statins throughout anthracycline-based chemotherapy, Dr. Neilan noted.

He cautioned, however, that the current findings apply only to patients with lymphoma, because similar studies have not been conducted for patients with other cancers.

The cardiac side effects of cancer treatments

Anthracyclines, which include daunorubicin, doxorubicin, and epirubicin, damage the DNA in cancer cells, causing the cells to die.

“Anthracyclines are a class of very powerful cancer drugs that have been used since the 1970s,” said study co-leader Marielle Scherrer-Crosbie, M.D., Ph.D., of the Hospital of the University of Pennsylvania in Philadelphia.

These medicines are part of standard chemotherapy regimens used primarily to treat some breast cancers, lymphomas, leukemias, and sarcomas, Dr. Scherrer-Crosbie added.

Within a year of starting anthracyclines, about 20% of patients with lymphoma have a greater than 10% decline in left ventricular ejection fraction, studies have found. Within 5 years, up to 20% of high-risk patients develop heart failure.

Research in cells and in mice has suggested that statins may help protect the heart during anthracycline-containing chemotherapy. There is also evidence from clinical trials that heart failure may be less common in people with cancer being treated with anthracyclines who are also regularly taking statins for heart disease than in those who do not.

Who should get statins?

Atorvastatin had previously shown promise as a way to protect the heart in a small study involving people with various cancers. Based on that research, Dr. Scherrer-Crosbie and her colleagues selected atorvastatin for the current trial.

The study, called Statins TO Prevent the Cardiotoxicity from Anthracyclines (STOP-CA) trial, enrolled 300 people with lymphoma. Most participants had non-Hodgkin lymphoma, the median age was 52, and most were White.

Overall, 13 of 150 (9%) patients in the atorvastatin group had decreases of more than 10% in left ventricular ejection fraction, compared with 33 of 150 (22%) in the placebo group.

These results demonstrate that statins can prevent or lessen the severity of cardiac side effects caused by anthracycline-containing chemotherapy, said Patrice Desvigne-Nickens, M.D., a medical officer and program official at the National Heart, Lung, and Blood Institute who studies heart failure but was not involved in the trial.

“It’s not yet clear, however, how best to use statins in patients being treated with anthracyclines,” she continued. “More studies are needed to determine which patients are most likely to benefit from statin treatments, the optimal doses, and when and for how long statins should be used.”

Dr. Neilan said that since the results were published, several cancer doctors have asked him which patients might benefit from statin therapy. “The answer to this question depends on a person’s risk of heart failure and the dose of anthracyclines,” he said.

For instance, a young patient who has no significant cardiac risk factors is very unlikely to develop heart failure and therefore would be unlikely to benefit from statin therapy, whereas an older patient, who is overweight, and has other cardiac risk factors might derive a benefit, Dr. Neilan explained.

Studying the biology of cardiotoxicity

Chemotherapy can cause or worsen cardiovascular problems, including high blood pressure, abnormal heart rhythms, and heart failure. When cardiac side effects occur during cancer treatment, doctors may decide to interrupt or stop therapy. Symptoms may also arise years after cancer treatment.

Various biological mechanisms could help explain the cardiac side effects of anthracyclines, Dr. Scherrer-Crosbie noted. For instance, studies have explored the role of anthracyclines in increasing the production of molecules called reactive oxygen species that can damage heart muscle cells.

Statin drugs are typically prescribed to lower cholesterol and prevent heart attacks caused by blockages in the coronary arteries. But atorvastatin may benefit people with lymphoma through a different mechanism, the researchers said.

“When we give anthracyclines in animal models, we see inflammation in cardiac muscle cells and some of these cells die,” Dr. Neilan said. “Statin therapy can help dampen this effect.”

By preventing damage to heart muscle cells, atorvastatin may help sustain the pumping function of the heart, he added.

The new results should encourage more research on how to protect the cardiovascular system while treating cancer, Dr. Desvigne-Nickens said. Atorvastatin is already being studied as a way to reduce cardiac side effects in some patients with breast cancer who are being treated with anthracyclines.

“There is much more to learn about the cardiac side effects of current therapies,” Dr. Desvigne-Nickens said. “We also need to be aware of potential cardiac side effects arising from the use of multiple therapies or new treatment strategies.”

July 14, 2023, by Carmen Phillips

Transplants using stem cells from a donor are essential treatments for people with blood cancers like lymphoma and leukemia. But donor transplants—known as allogeneic transplants—also harbor a substantial risk of a serious, and potentially fatal, side effect called graft-versus-host disease (GVHD).

A large clinical trial has identified a more effective way for reducing the risk of this dangerous complication.

In the clinical trial, funded in part by NCI, about 430 people who had an allogeneic transplant were randomly assigned to receive one of two treatments for preventing GVHD: The standard two-drug regimen of tacrolimus and methotrexate, or a more recently developed three-drug regimen anchored by the chemotherapy drug cyclophosphamide. All patients in the trial had transplants from closely matched donors.

One year after receiving the transplant, 53% of people in the three-drug group had not experienced GVHD and their cancer had not relapsed, compared with 35% of those in the two-drug group. The findings were reported June 22 in the New England Journal of Medicine.

“It’s clearly a very wide difference” between the groups, said the trial’s senior investigator, Javier Bolaños-Meade, M.D., of Johns Hopkins Kimmel Comprehensive Cancer Center. “This is the first time since the 1980s it’s been shown that something is clearly superior” to the standard two-drug treatment.

Treatment with the three-drug regimen, which also includes tacrolimus and mycophenolate, did not lead to more serious infections or a higher risk of the cancer coming back, Dr. Bolaños-Meade continued.

Both findings are particularly important, he said, because other treatments have been found to effectively protect against GVHD, but that protection came at the cost of more dangerous infections or the cancer returning.

“If [the patient] doesn’t develop GVHD but they relapse, that can’t be considered a success,” Dr. Bolaños-Meade said.

An effective treatment with a potentially serious drawback

For many people with blood cancers, allogeneic stem cell transplants can cure their disease.

The transplants, however, can extract a hefty physical price in some people. Even with preventive measures, up to half of people who get an allogeneic stem cell transplant develop GVHD. This condition occurs when immune cells that linger among the donated stem cells (the graft) view healthy cells in the patient (the host) as foreign or dangerous and attack them.

GVHD can occur shortly after the transplant, known as acute GVHD, and it can also arise months after the transplant, called chronic GVHD.

Painful skin rashes, severe nausea, and diarrhea are among the most common symptoms of acute GVHD, explained Salyka Sengsayadeth, M.D., who specializes in treating blood cancers at Vanderbilt University Medical Center. And if these symptoms are bad enough, Dr. Sengsayadeth said, they can be fatal.

These same symptoms are also common in chronic GVHD, along with frequent mouth sores, fatigue and weakness, and shortness of breath, among others. Chronic GVHD symptoms “mostly tend to affect [people’s] quality of life,” she noted, although occasionally they can be fatal as well.

The combination of methotrexate and drugs known as calcineurin inhibitors—of which tacrolimus is the most commonly used—has been the standard treatment to protect against GVHD since the 1980s. Dr. Bolaños-Meade is part of a team at Hopkins that led the way in studying the cyclophosphamide-based regimen—and not just in people with cancer, but also in those undergoing stem cell transplants for noncancer health conditions like sickle cell disease.

In this new trial, the research team wanted to confirm findings from a smaller clinical trial they had conducted that strongly suggested the cyclophosphamide-based three-drug regimen could substantially reduce GVHD risk in those receiving closely matched transplants.

Cyclophosphamide-based regimen shows multiple advantages

The trial was conducted at 37 cancer centers in the United States, under the auspices of the Blood and Marrow Clinical Trials Network. About half of the participants had acute myeloid leukemia; the remainder had other forms of leukemia, lymphoma, or a blood cancer called myelodysplastic syndrome.

Prior to their transplant, all patients in the trial received a reduced-intensity conditioning regimen. Conditioning regimens enable the donated stem cells to more readily take up residence in the bone marrow and begin reproducing.

The benefit of the three-drug regimen went beyond the improvement in GVHD-free, relapse-free survival at 1 year. In particular, when people treated with the cyclophosphamide-based regimen did develop acute or chronic GVHD, it tended to be less severe. And people who received the three-drug regimen also were less likely to need treatment to suppress an out-of-control immune response caused by the transplant.

However, it took longer for levels of platelets to return to normal in people in the three-drug group than the standard-treatment group (low platelet levels increase the risk of internal bleeding), and they also had a higher rate of lower-grade infections.

Based on the limited follow-up time (median time of 1 year), there is no difference in how long patients in either group have lived overall. The team will continue to follow participants to track survival and other measures, Dr. Bolaños-Meade said.

Changing treatment with allogeneic transplants

Excitement about the cyclophosphamide-based regimen in people receiving well-matched transplants began when the results from the smaller trial were reported in 2019, said the trial’s lead investigator, Shernan Holtan, M.D., of the University of Minnesota School of Medicine.

Combined with the results of this larger trial, which were presented late last year at the annual meeting of the American Society of Hematology, the impact on patient care is already being seen.

“I am hearing from colleagues around the globe that practice patterns are changing” based on the trial’s findings, Dr. Holtan continued. “This cyclophosphamide-based regimen could indeed become the new standard of care for [allogeneic stem cell transplants], especially considering the reduction in both severe acute and chronic GVHD.”

Another key aspect of the trial is that the median age of its participants was 66, Dr. Bolaños-Meade stressed. Most diagnoses of AML are in people aged 65 and older. And a decade or so ago, most oncologists were not willing to offer patients of that age a stem cell transplant, he noted.

But that has changed with the advent of reduced-intensity conditioning and improvements in the management of complications and side effects of transplantation.

It’s clear now, he stressed, that allogeneic stem cell transplants are “something that we can perform on our patients who are ‘elderly,’” he said. At Hopkins, he continued, “we have no age limit on who can get a transplant.”

At Vanderbilt, there hasn’t been a shift toward the use of the cyclophosphamide-based regimen yet in patients like those in this trial, Dr. Sengsayadeth said. But she expects that to change.

However, that doesn’t mean every patient will get the three-drug regimen. Cyclophosphamide can affect the heart, so the tacrolimus-methotrexate duo may be preferable for people with heart conditions, particularly those who are older, she said.

Moving toward using the three-drug regimen should be “relatively seamless,” Dr. Sengsayadeth continued. That’s because it’s already commonly used in people receiving allogeneic transplants that are only half matches, called haploidentical transplants, which carry a higher risk of GVHD than well-matched transplants.

The cyclophosphamide-based regimen has also proven to be effective in children and adults who have undergone more intensive conditioning prior to an allogeneic transplant, Dr. Holtan explained, and in people receiving what are called mismatched unrelated donor transplants.

Other options for protecting against GVHD are becoming available. One drug, abatacept (Orencia), was approved by the Food and Drug Administration in December 2021 to protect against acute GVHD in people undergoing allogeneic transplants, she said.

How best to use abatacept is still a challenge for those in the transplantation field, she added, and the cyclophosphamide-based regimen has advantages, including its “comparatively lower cost and … effectiveness in preventing chronic GVHD.”

Taking GVHD Prevention Up a Notch

A drug that blocks a protein in immune cells called DLL4 may help prevent acute GVHD in the intestinal tract, according to a study published June 28 in Science Translational Medicine. DLL4 activates a protein called Notch, which in turn controls a communication pathway in immune cells that is directly linked to intestinal GVHD.

“We found that just a single dose of [anti-DLL4] antibodies to block the Notch signaling pathway, given immediately before the transplant, was able to prevent gastrointestinal GVHD, without impairing immune function in the rest of the body,” said the study’s lead investigator, Ivan Maillard, M.D., Ph.D., of the University of Pennsylvania, in a press release.

The study was conducted in nonhuman primates, following earlier studies in mice showing that this treatment approach had promise. The study team is developing a clinical trial to test the experimental drug in people undergoing stem cell transplants.

July 10, 2023, by Sharon Reynolds

CAR T-cell therapy, a type of personalized immunotherapy, can help cure some people with aggressive non-Hodgkin lymphoma (NHL). That’s according to updated results from a large randomized phase 3 clinical trial of the CAR T-cell therapy axicabtagene ciloleucel (Yescarta).

Most people diagnosed with diffuse large B-cell lymphoma, the most common form of aggressive NHL, will be cured by initial treatment with chemotherapy. But for those who aren’t, the prospects of a cure have been uncertain at best, even with additional grueling chemotherapy and stem cell transplant.

Now, new data from the ZUMA-7 clinical trial strongly suggests that axi-cel, as this CAR T-cell therapy is often called, can offer real hope for this latter group of patients.

The study investigators presented their findings June 5 at the American Society of Clinical Oncology (ASCO) annual meeting. They estimate that about 55% of patients would still be alive 4 years after receiving axi-cel, compared with 46% of those who initially received the standard treatment for relapsed disease.

“This is the first trial in nearly 30 years to significantly improve overall survival for patients with large B-cell lymphoma that is not responding to initial treatment or has relapsed,” said Dr. Jason Westin, M.D., of the University of Texas MD Anderson Cancer Center, who helped lead the study.

And with patients being followed for almost 4 years, those still alive have likely been cured, he added.

Based on these results, axi-cel is now the preferred treatment for people whose diffuse large B-cell lymphoma has recurred quickly or proven resistant to standard initial treatment, explained Christopher Melani, M.D., of NCI’s Center for Cancer Research. And for future studies, axi-cel “is now the benchmark upon which to improve with future treatments,” Dr. Melani explained.

A clear improvement in survival

Until recently, the only treatment with the possibility of eliminating recurrent or treatment-resistant diffuse large B-cell lymphoma was more high-dose chemotherapy, followed by an autologous stem cell transplant. This is where a patient’s healthy blood-forming stem cells are collected from the blood or bone marrow before treatment and then given back to the patient after high-dose intensive chemotherapy.

However, only about half of patients are healthy enough to endure this treatment. And less than a quarter of those who can tolerate it will be cured.

This landscape began to change in 2021, when the results of two large clinical trials showed that CAR T cells could improve the time that people with treatment-resistant or recurrent large B-cell lymphoma lived without their cancer getting worse.

Earlier findings from the ZUMA-7 trial, which began recruiting patients in 2018, led the Food and Drug Administration (FDA) to approve axi-cel in 2022 for adults with diffuse large B-cell lymphoma that wasn’t eliminated by their initial treatment or that returned within 12 months of initial chemotherapy. That approval was based on improvements in a measure called event-free survival, which includes the length of time it takes after treatment for the NHL to begin getting worse. But whether axi-cell would also improve how long patients lived overall wasn’t yet clear.

ZUMA-7 enrolled people deemed healthy enough to undergo additional high-dose chemotherapy and, potentially, an autologous stem cell transplant. This combination is currently considered the standard of care for treatment-resistant or relapsed diffuse large B-cell lymphoma.

Like all currently approved CAR T-cell therapies, axi-cel is truly personalized, in that it uses a patient’s own immune cells to create the treatment.

In the ZUMA-7 trial, which was funded by Kite Pharma, axi-cel’s manufacturer, researchers randomly assigned 180 people to receive axi-cel and 179 people to receive standard treatment. Differences between the groups emerged quickly. While 94% of people in the axi-cel group received their CAR T cells, only 36% of those in the standard-treatment group were able to have a stem cell transplant because in most cases their disease continued to progress despite chemotherapy, Dr. Westin explained at the ASCO meeting.

Because of this rapid disease progression, 57% of the participants in the standard-treatment group went on to receive CAR T-cell therapy (in most cases with axi-cel) after their disease got worse.

The substantial improvement in how long people in the axi-cel group lived held up even though so many in the standard treatment group rapidly switched to CAR T-cell therapy, Dr. Westin stressed.

Axi-cel was originally approved by the FDA in 2017 as a third or later-line treatment, meaning it could be given only to people whose disease continued to get worse or came back after two or more forms of therapy, explained Dr. Melani. But the ZUMA-7 findings indicate that waiting that long to use axi-cel is no longer the best treatment approach. “Patients who got chemotherapy first showed worse survival, even when most crossed over to receive CAR T cells,” he said. “This study puts axi-cel as the preferred second-line option.”

CAR T-cell therapies, including axi-cel, can have serious long-term side effects that are different from those seen after chemotherapy. In the short term, these include a dangerous immune system reaction called cytokine release syndrome, neurological effects, and the reactivation of dormant viruses in the body. In the long term, they can include immunosuppression, which may in turn lead to second cancers.

At the time of the most recent data analysis, 82 patients in the axi-cel group had died, compared with 95 in the standard care group. Seven people in the axi-cel group died of side effects related to treatment, compared with two in the standard care group. However, since the analysis of the ZUMA-7 data that led to the most recent FDA approval, no new deaths related to treatment with axi-cel had occurred.

Issues of equity and access

Even as CAR T-cell therapy has proven to be effective for more and more people with blood cancers like NHL, lack of access has plagued this treatment option.

“That’s kind of the kicker [for CAR T-cell therapy],” Dr. Melani said. “Not everyone is going to be able to get it.”

One of the biggest issues around CAR T-cell therapies is the cost. Between their production and the extensive hospitalization and monitoring required, “this [treatment] can cost upwards of half a million dollars or more,” Dr. Melani explained.

“We must bring the costs [down] to … affordable levels,” said Asher Chanan-Khan, M.D., from the Mayo Clinic Cancer Center, speaking at the ASCO meeting. Some university hospitals have been producing CAR T cells in-house, explained Dr. Melani, which could potentially cut the price down substantially.

But there are also other aspects of CAR T-cell therapy that affect equitable access to this treatment, explained Leyla Shune, M.D., from the University of Kansas Cancer Center, who discussed issues related to equity and CAR T-cell therapy at the ASCO meeting.

Managing the unique—and often dangerous—side effects of CAR T-cell therapy requires extensive training and practice. So CAR T-cell therapies can currently only be given at certain specialty centers—which can often be hundreds of miles away from many patients’ homes, Dr. Shune explained. And because of the chemotherapy given before receiving CAR T-cell therapies and the recovery time required after receiving it, patients may need to take weeks or months off work.

“I live in a state where we only have two CAR T centers, and my patients have to travel [up to] 8 hours to get to me,” said Dr. Shune. In the future, to provide more equitable access to CAR T-cell treatment, patient assistance programs may need to include services like travel assistance and subsidized lodging, she explained.

Other options in the pipeline

For now, CAR T cells look to be a game changer for many people with relapsed or resistant diffuse large B-cell lymphoma. But they’re not the only game in town.

Clinical trials are also testing another type of immunotherapy called bispecific antibodies, or BiTEs, in people with relapsed or treatment-resistant diffuse large B-cell lymphoma, explained Dr. Melani. These drugs simultaneously attach to immune cells and cancer cells, enabling the immune cells to easily find and destroy the cancer cells by bringing them closer together.

Two BiTEs, glofitamab (Columvi) and epcoritamab (Epkinly), have recently received accelerated approval as third or later-line treatments for diffuse large B-cell lymphoma, and are being tested as earlier treatments in other trials.

Unlike CAR T-cell therapies, BiTEs are “off-the-shelf” drugs, meaning they don’t have to be manufactured for each patient. That feature will likely make them more accessible to patients because they can be given at smaller hospitals, where most people with cancer are treated, Dr. Melani explained.

Other clinical trials, such as the ViPOR and ViPOR-P studies being conducted at the NIH Clinical Center, are testing cocktails of targeted drugs selected to hit known vulnerabilities in lymphoma cells.

“It’s an exciting time in [treating] aggressive lymphoma, with lots of newer therapies that are helping patients live longer,” said Dr. Melani.

December 15, 2022, by Edward Winstead

The Food and Drug Administration (FDA) has approved the drug brentuximab vedotin (Adcetris) in combination with chemotherapy for the treatment of some children and adolescents with Hodgkin lymphoma.

The approval, announced on November 10, covers use of the combination as an initial treatment for people 2 to 21 years of age with high-risk classical Hodgkin lymphoma.

In 2018, FDA approved brentuximab vedotin as an initial, or first-line, treatment for adults with advanced Hodgkin lymphoma.

The approval in younger people was based on an NCI-sponsored clinical trial conducted by the Children’s Oncology Group. In the trial, approximately half of the participants were randomly assigned to receive brentuximab vedotin and a chemotherapy-based regimen consisting of doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide.

The other patients received the same chemotherapy-based regimen along with bleomycin, which was a standard of care for children and adolescents with high-risk classical Hodgkin lymphoma.

In the study, brentuximab vedotin plus chemotherapy was superior to standard-care chemotherapy based on a measure known as event-free survival. In the trial, event-free survival was the length of time from when a patient was randomly assigned to a treatment group until disease progression or relapse, second cancer, or death due to any cause.

At a median follow-up of 42 months, 92.1% of those in the brentuximab vedotin group had not experienced an event compared with 82.5% of those in the standard-care chemotherapy group, according to findings published November 3 in the New England Journal of Medicine (NEJM).

“These results describe an important advance,” said Malcolm Smith, M.D., Ph.D., of NCI’s Cancer Therapy Evaluation Program.

“The improvement in event-free survival is clinically meaningful and establishes the role of brentuximab vedotin as an important agent for successfully treating Hodgkin lymphoma in this patient population,” Dr. Smith added.

A targeted drug for kids with Hodgkin lymphoma

In people with classical Hodgkin lymphoma, cancer cells form in the lymph system. Although this type of lymphoma is uncommon in the general population, it is one of the most commonly diagnosed cancers in adolescents aged 15–19.

Brentuximab vedotin, which is given by intravenous injection, is a type of targeted therapy called an antibody-drug conjugate. The antibody part of the drug recognizes a protein called CD30, which is often found at high levels on Hodgkin lymphoma cells called Reed-Sternberg cells. When the antibody binds to CD30 on these cancer cells, it delivers the drug vedotin to the cell, which interferes with cell division and leads to the cell’s death.

To conduct the trial, Sharon Castellino, M.D., MSc, of Winship Cancer Institute of Emory University and Children’s Healthcare of Atlanta and her colleagues in the Children’s Oncology Group enrolled 600 children and adolescents with stage IIB with bulk tumor, or stage IIIB, IVA, or IVB Hodgkin lymphoma.

“The study enrolled a significant percentage of patients from minority populations that are [usually] underrepresented in clinical trials, which is extremely important,” said Ann S. LaCasce, M.D., a lymphoma specialist at the Dana-Farber Cancer Institute who was not involved in the research. “This has not been the case in adult studies, and the Children’s Oncology Group should be applauded for their efforts.”

In the pediatric trial, brentuximab vedotin plus chemotherapy “resulted in the best outcomes we have ever seen in patients with Hodgkin lymphoma and high-risk disease,” Dr. LaCasce added.

Longer follow-up is needed to determine for each group whether there are late relapses of Hodgkin lymphoma or development of second cancers.

Reducing the amount of radiation used to treat young patients

More than half of the participants in both groups received radiation therapy after completion of chemotherapy for tumors that, based on PET imaging performed part way through their treatments, were slow to respond, or shrink.

The radiation was tailored for individual patients and involved smaller areas and lower doses than have been used in previous pediatric trials, noted Dr. Castellino.

“In general, we are all trying to limit the use of radiation given the risk of long-term side effects,” said Dr. LaCasce. “Recent studies have demonstrated that we can significantly reduce the use of radiation by using PET scans to measure early responses to treatment.”

As the authors of an accompanying editorial in NEJM wrote, “Limiting the radiation dose, reducing exposure to normal tissue, and omitting radiation therapy altogether remain important goals.”

Adding brentuximab vedotin to the chemotherapy-based regimen did not increase side effects, the researchers found. A side effect that has been reported in adult trials involving brentuximab vedotin—severe peripheral neuropathy, which can cause pain and tingling in parts of the body—was less common in the Children’s Oncology Group trial, noted Dr. Castellino.

The most common side effects in the brentuximab vedotin group included low white and blood cell counts, inflammation or irritation in the mucous membranes in the mouth (stomatitis), and infection.

During the treatment phase of the clinical trial, less than 10% of patients who received brentuximab vedotin needed a dose reduction because of side effects, according to Kara Kelly, M.D., of Roswell Park Comprehensive Cancer Center and University of Buffalo School of Medicine and Biomedical Science and a leader of the trial.

“The FDA approval is a win for children”

The findings from the Children’s Oncology Group trial are consistent with the results of a smaller study published last year. In that study, which did not include a control group, brentuximab vedotin plus chemotherapy showed promise as an initial treatment for children and adolescents with high-risk Hodgkin lymphoma.

But experts agreed that those study results were not conclusive. “The new [Children’s Oncology Group] findings provide definitive evidence that brentuximab vedotin can improve outcomes for children with high-risk Hodgkin lymphoma,” said Dr. Smith.

Dr. Castellino agreed. “The FDA approval is a win for children who now have access to a targeted therapy for Hodgkin lymphoma for the first time.”