by Jenny Maxon, Medically reviewed by Dr. C.H. Weaver M.D. 2/2019
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).1 Since 1997 death rates for NHL have decreased by 3 percent annually in men and by 3.7 percent annually in women.3
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.
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.
There are three broad categories of lymphoma treatment: systemic therapy, radiation therapy, and bone marrow (or stem cell) transplant. Treatments are often combined. A watch and wait approach may be recommended in some cases when a patient has a very slow growing form of lymphoma. “Some indolent lymphomas may not need treatment for months to years,” Dr. Cheson says. “Therefore you watch and wait.”
Systemic therapy includes chemotherapy, immunotherapy, and radioimmunotherapy. 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 Medicine The purpose of precision cancer medicine is to define the genomic alterations in a lymphoma's DNA that is driving that specific cancer. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify lymphoma-driving abnormalities in the cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy 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, 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)
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.
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.
Recent Advances in Lymphoma Treatment
Rapid therapeutic advances in lymphoma continue at a gratifying pace, leading to important new treatment options for many patients. “Among these are new applications of existing medications, including very durable disease control for indolent NHL with maintenance therapy using the monoclonal antibody Rituxan® and the high response rates and lower toxicity of the chemotherapy agent Treanda® [bendamustine] for newly diagnosed and relapsed lymphoma,” says Michael E. Williams, MD, Byrd S. Leavell professor of medicine and the chief of the Hematologic Malignancies Section, Hematology/Oncology Division of the University of Virginia Health System.
The precision cancer medicine Adcertris (brentuximab vedotin) has shown dramatic response in patients with otherwise treatment-resistant Hodgkin’s lymphomas as well as certain NHLs,” Dr. Williams continues. “Additional novel monoclonal antibodies and targeted therapeutics are in the advanced stages of clinical testing, and there is every expectation that these dramatic improvements in outcomes, survival, and cure will continue.”
Here are just some of the therapies that exemplify the advances being made:
- 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.
- Keytruda® (pembrolizumab) belongs to a new class of 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.
- Adcetris (brentuximab Vedotin) This antibody-drug conjugate is targeted to CD30, a defining marker of Hodgkin’s lymphoma, and is also a target expressed on 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.
- 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.
- 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
- 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
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.
Two agents used in the engineering process of 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.
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 trial demonstrated an overall anti-cancer response rate in 37%, and a complete disappearance of cancer (complete response) in 30% of patients with recurrent, refractory DLBCL.
The ZUMA-1 trial evaluated Yescart™ (axicabtagene ciloleucel) which is already approved for the treatment of DLBCL, and targets the CD-19 antigen.The trial included108 patients with fast-growing DLBCL, or other aggressive B-cell NHLs, that had stopped responding to prior therapies. Patients were treated with a single infusion of CAR T cell therapy. One year following CAR T cell therapy, 40% of patients have no evidence of cancer
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.
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.govor (800) 422-6237
- US National Institutes of Health, www.clinicaltrials.gov
The Recovery Process
“Once lymphoma patients are in remission, they have laboratory testing and CT or PET scans every three to six months, followed by an oncologist visit,” says Dr. Cheson.
Generally, the more aggressive the lymphoma, the shorter the period between remission and relapse. For that reason, Dr. Lebovic says, “patients with aggressive lymphomas who achieve remission are followed closely for the first couple of years, but then the intensity of monitoring declines.” Patients with indolent lymphomas are followed less frequently, Dr. Lebovic says, though with similar intensity.
The five-year survival for Hodgkin’s lymphoma patients is approximately 85 percent, whereas the 10-year rate is 81 percent. The five-year survival for NHL patients is approximately 67 percent, and the 10-year rate is 56 percent.2
1.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.
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
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