by Jenny Maxon, Medically reviewed by Dr. C.H. Weaver M.D. 4/2022
Lymphoma is a cancer of the cells of the lymphatic system, which is composed of tissues and organs that produce, store, and carry white blood cells that fight infections and other diseases. The lymphatic system contains lymphoid tissue, which is made up of lymph cells, called lymphocytes. The two main types of lymphocytes are B-cells and T-cells. There are B-cell lymphomas (about 85 percent) and T-cell lymphomas (about 15 percent). The most frequent locations for lymphoma development—the lymph nodes, liver, spleen, and bone marrow—all contain large amounts of lymphoid tissue.
Lymphoma comprises more than 67 subtypes of two closely related cancers: non-Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma,1 named for Thomas Hodgkin, an English physician who described the disease in 1832.
More than 600,000 Americans have lymphoma.2 An estimated 75,000 people in the United States are diagnosed annually with lymphoma (65,540 cases of NHL and 8,490 cases of Hodgkin’s lymphoma), and 22,000 are expected to die of lymphoma (20,210 from NHL and 1,320 from Hodgkin’s lymphoma). Since 1997 death rates for NHL have decreased by 3 percent annually in men and by 3.7 percent annually in women.1
The seventh most common form of cancer, NHL ranges from indolent (slow growing) to highly aggressive (fast growing). Risk increases with age. “While indolent NHL is not curable (unless it is localized to one or two lymph node regions), some patients live for many years,” says Daniel Lebovic, MD, a clinical lecturer in the Division of Hematology-Oncology at the University of Michigan.
Hodgkin’s lymphoma represents about 11 percent of lymphomas and presents mostly during adolescence and early adulthood. It often develops in one lymph node region and spreads to neighboring nodes. It is very curable, even in its advanced stages.
Risk Factors and Symptoms
“Little is known about the causes of lymphoma,” says Anas Younes, MD, a professor at the University of Texas MD Anderson Cancer Center’s Department of Lymphoma/Myeloma. Almost all types contain mutations within DNA, and risk factors include older age, exposure to certain chemicals, immune deficiency (due to immunosuppressive drugs, HIV/AIDS, or congenital immune deficiency), certain infections (H. pylori of the stomach and human T-lymphotropic virus), radiation exposure, and possibly some viruses such as Epstein-Barr virus and hepatitis C virus.
Common signs and symptoms of lymphoma are enlarged lymph nodes, low energy, fevers, night sweats, poor appetite, weight loss, pain, profound fatigue, itching, and abnormal routine blood tests.
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Making a Diagnosis
“Certain observations may raise the suspicion of lymphoma,” Dr. Lebovic says. A physician may feel enlarged lymph nodes during a routine physical exam, or a computed tomography (CT) or positron emission tomography (PET) scan may show an enlarged liver, spleen, or nodes.
“The most accurate diagnosis is made by biopsying an enlarged node,” says Bruce D. Cheson, MD, FACP, head of hematology and deputy chief of the Division of Hematology-Oncology at Georgetown University Hospital, Lombardi Comprehensive Cancer Center. A biopsy involves surgically removing a small tissue sample. By looking under a microscope, a pathologist can confirm lymphoma as well as the type. Lymphoma can also present in bone marrow, and in some instances diagnosis is made by bone marrow biopsy.
Treatment of NHL has evolved a great deal over the past several years and is tailored to the specific type of lymphoma. Some lymphomas require immediate treatment and others can be watched and treatment administered at the time the disease progresses. Recent advances in treatment have focused on increasing the precision of medicines and activating the bodies immune system to enhance the destruction of lymphoma cells.
Systemic therapy is any treatment that can travel throughout the body and attach lymphoma cells where ever they reside. Systemic therapy includes chemotherapy, immunotherapy, and precision cancer medicines. These modalities are the mainstay of treatment for almost all lymphomas.
- Chemotherapy a drug or combination of drugs administered intravenously, kills cancer cells and remains an integral component of treatment. “The more aggressive the lymphoma, the more intense the chemotherapy drugs will be. Chemotherapy is used to treat all Hodgkin’s lymphomas, all aggressive NHLs, and advanced-stage indolent NHLs.
- Precision Cancer Medicines utilizes molecular diagnostic testing, including DNA sequencing, to identify lymphoma-driving abnormalities in the cancer’s genome or biomarker targets on lymphoma cells. Once identified, a medicines can be designed to attack a specific mutation or other related change in the DNA programming of the lymphoma cells. Precision cancer medicine uses targeted drugs and immunotherapy engineered to directly attack lymphoma cells with specific abnormalities with the goal of leaving normal cells largely unharmed.
- Immunotherapy is used to fight B-cell NHL by either stimulating a patient’s immune system to work harder or by giving patients man made versions of immune system components.4
Recent Advances in Lymphoma Treatment
Here are just some of the therapies that exemplify the advances being made:
- Monjuvi (tafasitamab-cxix) is a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody, it is indicated for use in combination with Revlimid. The combination produced a 60% response rate and a median response duration of 21.7 months in NHL patients refractory to other therapies.16,17
- Zynlonta is an antibody drug conjugate (ADC), a type of precision cancer medicine that targets the CD19 antigen on B cells. The antibody is attached to pyrrolobenzodiazeprine dimer, a cytotoxic (cancer cell killing) agent that is is internalized following attachment to the CD19 antigen where it blocks cancer cells’ division and causes the cells to die. DNA - cross linking agents are significantly more potent than systemic chemotherapy.
- Polivy (polatuzumab vedotin-piiq) is an antibody drug conjugate that targets CD79b and delivers chemotherapy directly to b-cells. The NCCN guidelines note that bendamustine, Rituxan (rituximab), and Polivy is indicated for patients with translocations of MYC and BCL2 and/or BCL6.18,19
- Parsaclisib is a phosphatidylinositol 3-kinase-δ inhibitor (PI3K), that is being developed for the treatment of different types of B-cell malignancies and systemic lupus erythematosus, the initial focus is advanced B cell lymphomas. The PI3K pathway promotes cancer cell proliferation, growth, motility, metabolism and survival and the disruption of this pathway with precision cancer medicines can prevent certain cancers from growing and spreading.
- Xpovio (selinexor) is an orally available, small molecule inhibitor of CRM1 (chromosome region maintenance 1 protein, exportin 1 or XPO1)20,21
- Keytruda® (pembrolizumab) belongs to a class of immunotherapy medicines called PD-1 inhibitors that help the immune system recognize and attack cancer. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1 may enhance the ability of the immune system to fight cancer. Keytruda® works by blocking PD-1. Early studies show significant activity when used alone or in combination with Rituxan.31
- Adcetris (brentuximab Vedotin) This antibody-drug conjugate is targeted to CD30, a defining marker of Hodgkin’s lymphoma, NHL and various T-cell cancers and other hematologic malignancies.1 Adcetris is a type of immunotherapy/chemotherapy, administered intravenously, and FDA approved for the treatment of several types of Hodgkin and non-Hodgkin lymphomas.
- Revlimid® (lenalidomide) This oral immunomodulatory therapy is being evaluated as a single agent for patients with mantle cell lymphoma and T-cell lymphoma, as well as in combination with Rituxan in patients with follicular NHL and following Rituxan plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment in patients with diffuse large B-cell lymphoma.2
- Rituxan® (rituximab) Studies show that in patients with advanced indolent NHL, maintenance Rituxan (a type of immunotherapy administered intravenously) after chemotherapy significantly prolongs progression-free survival to a far greater extent than has been achieved by any previous strategy and with minimum toxicity.3
- Calquence (acalabrutinib) is a kinase inhibitor that works by blocking an enzyme needed by the cancer to multiply and spread. Calquence has been approved for the treatment of Mantle Cell Lymphoma based on a reported overall response rate of 81 percent.
- Venclexta (ventoclax) The BCL-2 protein is a type of protein that contributes to a cancer cell’s survival. Over expression of the BCL-2 protein in lymphoma cells is associated with increased survival time of the cancer cells as well as resistance to standard chemotherapy. Venclexta is an agent that binds to the BCL-2 protein, thereby disabling its ability to keep cancer cells alive.
- Gazyva (obinutuzumab) Gazyva is an engineered monoclonal antibody designed to attach to CD20, a protein found on certain types of B-cells. It is thought to work by attacking targeted cells both directly and together with the body’s immune system. The FDA approved Gazyva based on a clinical trial comparing chemotherapy with Rituxan or Gazyva. The progression-free survival was significantly improved with Gazyva compared to Rituxan.
- About Aliqopa (copanlisib) Aliqopa is a precision cancer medicine that inhibits several key cell-signaling pathways in lymphoma cell lines resulting in cancer cell death by apoptosis and inhibition of the growth of primary malignant B cell lymphoma cell lines.
- Imbruvica (ibrutinib) Imbruvica is a targeted agent that works by inhibiting the enzyme needed by the cancer to multiply and spread. The drug’s approval was based on the results of a study that included 111 patients with MCL who were given Imbruvica daily until their disease progressed or side effects became intolerable. Results of the study indicated that nearly 66 percent of patients experienced an objective response—meaning their cancer shrank or disappeared after treatment.
- Treanda® (bendamustine) The simpler two-drug regimen of Treanda plus Rituxan could become the new standard first-line therapy for indolent NHL, in place of the current standard regimen of R-CHOP. A study showed that this chemotherapy regimen improved progression-free survival and complete remission rates while showing a better tolerability.4
Bispecific antibodies represent an innovative precision immunotherapy approach that helps the body’s immune system target lymphoma cells and appears very promising. Bispecific antibodies have two arms. One arm of the drug attaches to a specific protein on the lymphoma cell. The other arm activates immune cells in the patient to kill the lymphoma cells. Several bispecific antibodies are in development for the treatment of non-Hodgkin lymphoma.
Bispecifics appear capable of inducing complete remissions in patients with refractory or resistant NHL including patients that have failed multiple therapies, stem cell transplantation or CAR T cell therapy. Despite recent advances in the treatment of NHL some patients still succumb to NHL and new treatments are needed.
Understanding DNA Damage Response or DDR and Cancer Treatment
What is DNA Damage Response or DDR?
Chimeric Antigen Receptor (CAR) T-cell Therapy
CAR-T is a new type of treatment that utilizes a patient’s own T-cells (a type of immune cell) to fight certain types of blood cancers. The T-cells are removed from the patient and engineered to recognize specific proteins found on the surface of cancer cells. The T-cells are then infused back into the patient to fight the cancer in their body. CAR T-cells have already been approved by the United States Food and Drug Administration (FDA) for the treatment of specific types of leukemia and lymphoma.10,11
One of the two CAR T cell therapies approved by the FDA, Kymria ™ (tisagenlecleucal), is being evaluated for treatment of DLBCL that has stopped responding to prior therapies. Kymria is an important component in engineering the T cells to recognize and bind to the CD-19 antigen, a protein that is found on B cells – which are the cancerous cells in DLBCL.
The JULIET clinical trial evaluated Kymria in patients with relapsed/refractory DLBCL who had received 2 or more lines of therapy and who were ineligible for or had disease progression after ASCT. The best overall response rate was 52% and at 12 months following the initial response, the rate of relapse-free survival was estimated to be 65%; it was even higher (79%) among patients who had achieved a complete response.10
The ZUMA-1 clinical trial evaluated Yescart™ (axicabtagene ciloleucel) in patients with refractory DLBCL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma, which was defined as progressive or stable disease as the best response to the most recent chemotherapy regimen or disease progression/relapse within 12 months of ASCT. The objective response rate was 82%, and the complete response rate was 54%. At a median follow-up of 15.4 months, 42% of patients continued to have a response, with 40% maintaining a complete response. At 18 months, the overall rate of survival was 52%.11
A clinical trial directly CAR T cell therapy to the standard stem cell transplant among patients whose NHL has stopped responding to prior therapy will be initiated shortly to further clarify the role of CAR T cell therapy in this group of patients.
Bone Marrow (or Stem Cell) Transplant
High-dose chemotherapy and a blood stem cell, or bone marrow, transplant is the best treatment available for certain lymphomas. Higher doses of chemotherapy (known as dose-intensive or high-dose therapy) kill more cancer cells than do lower doses in certain types of cancer. These higher doses also damage normal cells, however, particularly the blood-producing stem cells in the bone marrow.
To help bone marrow make healthy new blood cells, some stem cells (early, blood-forming cells that grow and mature in the bone marrow but can circulate in the blood) may be extracted before chemotherapy is given. These cells are then transplanted back into the body, where they restore bone marrow so that it can build healthy new blood cells.5
Stem cell transplants are classified based on which individual donates the stem cells and the source from which they are collected (bone marrow, peripheral blood, or umbilical cord). Each of these variables presents important advantages and disadvantages.
When the stem cells come from the patient, the transplant is referred to as an autologous transplant. This type is recommended for patients with aggressive lymphoma who initially responded to chemotherapy but relapsed after their first-line regimen. Because a transplant is most successful when it’s performed with as little active lymphoma as possible, patients receive two or three additional chemotherapy cycles prior to transplant. Autologous transplants are generally performed only in patients in relatively good health (aside from their lymphoma) who are under 70 years of age.
In an allogeneic transplant, the patient receives bone marrow cells from a bone marrow donor (someone with certain immune system similarities), often a sibling. Ideally, the donor bone marrow cells view the cancer as “foreign” and attack it. In some cases, however, the donor bone marrow cells view some of the patient’s normal tissue as foreign and attack them, a response called graft versus host disease. Allogeneic transplants contain far greater risks and are generally reserved for patients younger than 65.
An allogeneic transplant can benefit patients who relapse after an autologous transplant or who cannot receive an autologous transplant because their disease is not sensitive to chemotherapy.
RIT delivers radiation therapy directly to tumor sites. Radioimmunotherapy agents are therapies like Rituxan, which have a radioisotope attached to them. These “guided missiles” are able to destroy cancer cells because they attach to the lymphoma and deliver small doses of medicine to the cells.5 A treatment for advanced-stage indolent B-cell NHL, radioimmunotherapy is used as a single agent and requires only one treatment.
Radiation therapy is occasionally used as an adjunct to chemotherapy, as it destroys localized lymphoma cells that may have survived chemotherapy by damaging their DNA. Radiation is also an alternative for patients who cannot tolerate chemotherapy, and it can be used to manage pain or swelling.
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An Alternative Treatment Option: Clinical Trials
Clinical trials are research studies that are conducted to answer questions about a promising treatment or a new way of using an old treatment. Daniel Lebovic, MD, a clinical lecturer in the Division of Hematology-Oncology at the University of Michigan, recommends that patients volunteer for clinical trials if they have a lymphoma subtype that doesn’t have good treatment options or if they haven’t adequately responded to typical treatments.
Patients can learn about clinical trials through their treatment center or through the following organizations:
- Leukemia & Lymphoma Society, www.leukemia-lymphoma.org or (800) 955-4572
- Lymphoma Research Foundation, www.lymphoma.orgor (800) 500-9976
- National Cancer Institute, www.cancer.gov or (800) 422-6237
- US National Institutes of Health, www.clinicaltrials.gov
- Jaffe ES, Harris NL, Stein H, Isaacson PG. Classification of lymphoid neoplasms: the microscope as a tool for disease discovery. Blood. 2008;112(12):4384-99.
- Altekruse SF, Kosary CL, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975-2007. National Cancer Institute website. Available at: https://seer.cancer.gov/archive/csr/1975_2007.
- Cancer Facts & Figures 2010. American Cancer Society website. Available at:
- Immunotherapy. American Cancer Society website. Available at:
- Lymphoma Treatments. Lymphoma Research Foundation website. Available at:
- Brentuximab Vedotin (SGN-35). Seattle Genetics website. Available at:
- Clinical Data from Two Phase II Studies Evaluating Revlimid Plus Rituximab in Indolent Non-Hodgkin’s Lymphomas Presented at ASH. Celgene website. Available at:
- Rituximab Maintenance Improves Progression-Free Survival in Indolent Lymphoma. Medscape Today website. Available at:
- Bendamustine Plus Rituximab Could Replace R-CHOP in Indolent Lymphomas. Medscape Today website. Available at:
- Schuster, Bishop, Tam, et al. Primary analysis of Juliet: A global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Proceedings from the 59th annual meeting and exhibition of the American Society of Hematology; Atlanta, GA; December 9-12, 2017; Abstract #577. Retrieved from
- United States Food and Drug Administration. FDA News Release. . Accessed April 13, 2016.
- Ribas A, Hodi FS, Kefford R, et al. Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL). J Clin Oncol 32:5s, 2014.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) B-Cell Lymphomas Version 4.2020 — August 13, 2020. . Accessed September 10, 2020.
- Jacobsen ED, Sharman JP, Oki Y, et al. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood 2015;125(9):1394-1402. doi:10.1182/blood-2014-09-598763
- Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45–56. doi:10.1056/NEJMoa1804980
- 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. doi:10.1056/NEJMoa1707447
- US Food and Drug Administration. FDA approves polatuzumab vedotin-piiq for diffuse large B-cell lymphoma. . Published June 10, 2019. Accessed August 28, 2020.
- Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-Cell lymphoma. J Clin Oncol. 2020;38(2):155-165. doi:10.1200/JCO.19.00172.
- US Food and Drug Administration. FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma. . Published June 22, 2020. Accessed August 28, 2020.
- Kalakonda N, Maerevoet M, Cavallo F, et al. [Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial](https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(20%2930120-4/fulltext). Lancet Haematol. 2020;7(7):e511-e522. doi:10.1016/S2352-3026(20)30120-4
- US Food and Drug Administration. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. . Published August 3, 2020. Accessed August 28, 2020.
- Salles G, Duell J, González Barca E, et al. [Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study](https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20%2930225-4/fulltext). Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4PolivyTM [package insert]. South San Francisco, CA: Genentech, Inc; 2019.
- astoupil L, Chin C, Westin J, et al. Safety and activity of pembrolizumab in combination with rituximab in relapsed or refractory follicular lymphoma. Blood Adv. 2022 Feb 22;6(4):1143-1151