Verywell Informed


Recent therapy advances with
improved outcomes

By Tom Iarocci, MD | Reviewed by Doru Paul, MD

Treatment Goals

Today, when non-Hodgkin lymphoma (NHL) requires treatment—whether you need treatment for the first time or your lymphoma has returned after prior therapy—there are more options than ever before.

Research has brought about advances and therapies that yield improved outcomes every day. When undergoing treatment, understanding goals and learning how to optimize your therapeutic plan is helpful for both patients and their loved ones.

Treatment goals depend on the specific type of lymphoma, how far the disease has spread in the body, and on many other individual, patient-specific factors such as age, general health, pre-existing chronic medical conditions, and the ability to tolerate a given drug treatment or regimen.

Although it is possible for NHL to arise virtually anywhere in the body, most often it begins in the lymph nodes —those tiny, bean-shaped organs that you have under the skin and all over the body. Lymph nodes are part of the lymphatic system and they are integral to immune health. One of the goals of therapy, then, can be to see an aggressive NHL disappear on imaging scans.

In contrast to the slow growing NHL, more aggressive types of NHL, such as diffuse large B-cell lymphoma (DLBCL), tend to be fast-growing and require prompt treatment. DLBCL is the most common type of NHL in the United States and accounts for about 1 in 3 lymphomas. It often responds well to the initial treatment, with about 75 percent of people having no signs of disease after the first treatment. Many people with DLBCL are cured. However, some cases of DLBCL are more difficult to treat, becoming resistant or refractory to available therapies, in which case a second or third line therapy may be considered.

First, Second, and Third-line Therapies

The defining characteristic of first-line treatment is that it is used first, and therefore first-line or front-line treatments are usually used preferentially to other treatment options.

The optimal choice of a first-line treatment depends on the characteristics of the lymphoma (that is, the type and subtype as well as the stage of disease) but also on your complete medical history, including factors that make you more or less likely to tolerate a given therapy.

Second-line and subsequent therapies are used when there has been an inadequate response to the first-line treatment. How do you know if you have had an inadequate response? That depends, in part, on the NHL type and on the treatment goals. Again, using DLBCL as an example, second-line treatments for DLBCL are used if the first-line treatment did not work, but also if the lymphoma reappears later on.

Targeting the Cancer

Cells that give rise to lymphoma can be targeted by a whole host of differing anti-cancer treatments. DLBCL is a B-cell malignancy, meaning blood-forming cells that would normally produce healthy, mature B-lymphocytes instead give rise to the lymphoma.

Since DLBCL is the most common form of NHL in the United States, let’s use it as an example for understanding the different types of treatment available. They are often used together in combination, but they can also be used individually in some cases or as the need arises in other cases.

  • Chemotherapy

    Chemotherapy kills cancer cells. A commonly used first-line treatment for DLBCL is R-CHOP, followed by radiation therapy. However, an optimal first-line therapy for one patient with DLBCL may not be the best choice for another.

  • Steroids

    Steroids are toxic to lymphoma cells. The ‘P’ in the anti-cancer regimen known as R-CHOP, for instance, stands for prednisone, which is a steroid.

  • Radiation

    This therapy uses high energy radiation to damage the DNA in cancer cells, causing their death or hindering their growth. For people with DLBC, radiation therapy might be used at different points as needed.

  • Targeted Therapies

    These include immunotherapies that trigger the immune system to destroy cancer cells or drugs that block cell signals, stop new blood vessels from feeding cancer cells, or cause controlled cell death.

  • Immunotherapy

    A kind of targeted therapy that works by using the body’s natural ability to find and destroy cancer cells through the immune system.

  • Immunomodulators

    Immunomodulators work by interacting with certain parts of the immune system. Lenalidomide is an immunomodulator used in the treatment of certain cases of DLBCL that have not responded to first-time treatment.

  • Cellular Therapies

    Cellular therapies refer to both hematopoietic stem cell transplants and novel CAR T-cell therapies. These are not first-line treatments•you would not typically begin with such a therapy, but it might be a curative option if the lymphoma has not responded to first and second line agents.

  • Stem Cell Transplant

    Stem cell transplant involves replacing damaged or destroyed stem cells in the bone marrow with healthy new ones. The transplanted, healthy stem cells form the new bone marrow and the new mature blood cells.

  • CAR T-Cell Therapy

    CAR T-cell therapy augments the immune cells’ ability to “see” cancer. It involves engineering your own immune cells to recognize and attack cancer cells. There is no need to search for a donor match, which is a rate-limiting step in some stem cell transplants.

  • Investigational Therapies

    Investigational therapies seem promising but have not yet been proven. They may work better than what is currently available and could ultimately become a new, FDA-approved therapy for your disease, but this is not always the case.

Treatment Response Assessment

Whether or not the goals of therapy were achieved—in other words, finding out if a therapy worked—is determined by testing. The whole process is known as treatment response assessment.

A combination of imaging scans are used to see shrinkage or disappearance of the disease. These results are used in conjunction with other clinical factors to evaluate whether or not the response to treatment has been robust.

Today, PET/CT scans are used for many types of NHL, including many cases of DLBCL. The results of such tests are used to advise next steps. With DLBCL, the ultimate desired outcome would be to see the disease sites disappear from the lymph nodes and/or other areas of involvement; shrinkage of the disease is also a good sign.

The options for second and third-line treatment of DLBCL depend on several factors, including the response to initial treatment and whether you plan to have a stem cell transplant. If the cancer appears to be gone or is smaller, that generally steers the discussion toward one set of options for second-line treatment; if the cancer looks the same or is larger, other options are discussed and considered, and/or some patients choose to join a clinical trial.

Treatment Advances

Innovative second-and third-line treatments for NHL have been emerging in recent years, drawing upon a growing scientific knowledge-base with respect to cancer genetics and the key molecular pathways of cancer.

These novel therapies include gene therapies and targeted therapies that provide much-needed treatment options for second- and third-line use when a first-line treatment fails.

Gene Therapy

The term gene therapy refers to a wide range of treatments that all use genetic material to modify cells. The modification occurs in a laboratory (in vitro) or in the patient (in vivo) to help fight cancer.

Over the last few decades, gene therapy has grown from a merely promising concept to a practical treatment for deadly and difficult-to-treat forms of cancer, now including certain types of NHL.

Recent treatment advances drawing on gene therapy include the use of genetically modified T-cells as immunotherapy to target lymphoma cells that carry the CD19 marker.


In October 2017, the FDA approved YESCARTA (axicabtagene ciloleucel), a chimeric antigen receptor (CAR) T-cell therapy, to treat adults with certain types of large B-cell lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment.

Your own T-cells are collected and sent to “boot camp.” During the training process, chimeric receptor (CAR) genes are introduced in your very own T-cells, enabling them to specifically recognize cancer cells. Then the T-cells are infused back into your body, where they will recognize and attack the cancer cells. In this way, each dose of YESCARTA uses a patient’s own immune system to help fight the lymphoma.

YESCARTA is now available at authorized treatment centers across the United States. It does have the potential to cause severe side effects which doctors will discuss with you and weigh out whether the therapy is right for your specific situation.


In May 2018, the FDA approved KYMRIAH (tisagenlecleucel), a therapy in the same category as YESCARTA, for use in adult patients with certain types of relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.

Kymriah is available at select centers throughout the United States. Its prior approval was for pediatric patients up to 25 years old with acute lymphoblastic leukemia (ALL) that is relapsing or refractory to treatment, thus many centers where Kymriah has been established are currently children’s medical centers.

Watch the video to learn more about how YESCARTA and KYMRIAH work.

Future Outlooks

Both CAR-T cell therapies are perceived as valuable additions to the treatment armamentarium for certain types of NHL. They use CAR-T cell technology to direct the immunotherapy to CD-19, a marker that is expressed in many cases of NHL. However, the CAR T-cell technology is not restricted to this marker, and other targets are being investigated and developed.

Other advances to look out for can be gleaned by looking at the “pipeline” of new agents and combinations being tested in clinical trials. Emerging treatments have tried to leverage knowledge about cell signals that are specific to B-cell receptors on B-lymphocytes. Other research focuses on specific subtypes of DLBCL and how they might differ in response to available therapies.

One promising avenue has to deal with another receptor that may be expressed by lymphoma cells. Brentuximab vedotin is an anti-CD30 antibody-drug conjugate with proven efficacy in patients with CD30+ malignancies, including classical Hodgkin lymphoma and anaplastic large cell lymphoma. Promising activity has also been seen in other lymphomas that express CD30. Several NHL subtypes, including cases of DLBCL, are known to express CD30, even though the extent to which they do this is variable.

Brentuximab vedotin has safely been combined with chemotherapy and is now being compared with standard treatments in clinical trials. In patients with high-intermediate–risk/high-risk DLBCL, there is a study of brentuximab vedotin (Adcetris) with R-CHOP that has been yielding positive results, especially in patients with CD30-expressing disease.

Optimizing Treatment

Being diagnosed with lymphoma can be a life-changing event, and being diagnosed with a fast-growing cancer such as DLBCL can be very unexpected and even life-shattering.

Survivors often cite an increased level of comfort with becoming educated enough to understand the basics of the disease and its treatment—enough, at least, to ask the doctor questions about your illness and the treatment options that might be best for you as an individual.

There is more than one treatment for lymphoma, and part of the new normal is working with your doctor to understand your options and plot the course for your future and identifying ways that you can feel better while receiving treatment.

What to Expect

Chemotherapy is given in cycles of treatment days followed by days of rest to allow your body to recover before the next cycle. Side effects can be different in different people, even for the same drug. Fast growing cells affected by chemotherapy include the hair follicles, gut, mouth, and blood cells, and so chemo can result in side effects such as nausea, lack of appetite, hair loss, and low blood counts. Radiation has side effects such as fatigue and skin changes.

Both radiation and chemotherapy can have side effects that emerge long after your treatment. Not all possible side effects are discussed here, so ask your medical team to go over the complete list and help you identify strategies for coping with them.

Supportive Care

Supportive care consists of treatment for the symptoms or health conditions caused by cancer or cancer treatment, but not treatment to kill the cancer cells themselves.

The aim of supportive care (also known as palliative care) is to improve your quality of life as a patient. It can include treatment for physical and emotional symptoms that you may encounter along your cancer journey. For anyone facing an aggressive lymphoma, it is important to talk to your treatment team to plan the best supportive care for you.

Complementary and alternative medicine (CAM) may be an option. Acupuncture for pain management and yoga for relaxation, for example, help with comfort and wellbeing.

Talking to Your Doctor

At the end of the day, the best way to optimize your treatment is to keep an open dialogue with your doctor. Deciding on a treatment can be one of the most stressful times during your journey. Getting answers to your questions can help dissolve fears and concerns.

There are some questions that you should always ask. Use this guide to help start a discussion with your doctor and learn answers that will help you feel empowered and know what to expect. Every option has both benefits and drawbacks, so be sure to consider both when you decide what is best for you.

  • Now that I am diagnosed, are there additional tests I need to have that will help us decide on a treatment?

  • Who will talk with me about the next steps for treatment and when?

  • How does my stage and disease status impact what is available for my treatment?

  • How will you determine if my treatment is working?

  • At what point would we consider cellular therapies? Would I be a candidate for such therapies?

  • Are there any clinical trials that you would recommend for me?

  • How might the various available treatments affect my quality of life during and after treatment?

Article Sources:

  • Bartlett NL, Smith MR, Siddiqi T, et al. Brentuximab vedotin activity in diffuse large B-cell lymphoma with CD30 undetectable by visual assessment of conventional immunohistochemistry. Leuk Lymphoma. 2017;58(7):1607-1616.

  • Hitz F, Connors JM, Gascoyne RD, et al. Outcome of patients with primary refractory diffuse large B cell lymphoma after R-CHOP treatment. Ann Hematol. 2015;94:1839-1843.

  • National Comprehensive Cancer Care Network. NCCN Guidelines Version 4.2018 B-Cell Lymphomas.

  • Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544.

  • Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378(15):1396-1407.

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