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Burkitt lymphoma is a fast-growing type of B-cell non-Hodgkin lymphoma that occurs most often in children and young adults. The disease may affect the jaw, central nervous system, bowel, kidneys, ovaries, or other organs. Learn about Burkitt lymphoma and find information on how we support and care for people with Burkitt lymphoma before, during, and after treatment.
The Hematologic Oncology Center provides specialized care for all types of cancers of the blood, including leukemia, lymphoma, multiple myeloma and Waldenström's macroglobulinemia.
The center also includes the hematopoietic stem cell transplantation program, which is one of the largest and most experienced in the world.
To make sure your care is as seamless as possible, a dedicated team of clinicians, who are highly specialized experts in your type of blood cancer, will care for you throughout the treatment process, from diagnosis though long-term follow-up.
Your care team will include oncologists, surgeons, hematologists, physician assistants, nurses, and clinical social workers who are committed to delivering safe, high-quality patient care.
We develop personalized, comprehensive treatment plans for all our patients, offering the latest therapies and supportive resources and taking your individual needs into account.
In addition to conventional treatment approaches, you may have the opportunity to participate in clinical trials that offer access to new, innovative treatments for your type of cancer.
A variety of services and programs also support your care, including nutrition services, emotional support and counseling, pain management, donor services for stem cell transplantation, and support for cancer survivors.
Learn more about treatment and care in the Hematologic Oncology Center
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The lymph system is part of the immune system and is made up of the following:
Because lymph tissue is found throughout the body, adult non-Hodgkin lymphoma can begin in almost any part of the body. Cancer can spread to the liver and many other organs and tissues.
Non-Hodgkin lymphoma in pregnant women is the same as the disease in nonpregnant women of childbearing age. However, treatment is different for pregnant women. This summary includes information on the treatment of non-Hodgkin lymphoma during pregnancy
Non-Hodgkin lymphoma can occur in both adults and children. Treatment for children, however, is different than treatment for adults. (See the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information.)
Lymphomas are divided into two general types: Hodgkin lymphoma and non-Hodgkin lymphoma. This summary is about the treatment of adult non-Hodgkin lymphoma. For information about other types of lymphoma, see the following PDQ summaries:
Waldenström macroglobulinemia begins in a type of white blood cell called B lymphocytes. Certain B lymphocytes multiply out of control and make large amounts of a protein called monoclonal immunoglobulin M (IgM) antibody. High levels of IgM in the blood cause the blood to thicken and leads to many of the symptoms of Waldenström macroglobulinemia. Waldenström macroglobulinemia is also called lymphoplasmacytic lymphoma.
Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn't mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors for adult non-Hodgkin lymphoma include the following:
These and other signs and symptoms may be caused by adult non-Hodgkin lymphoma or by other conditions. Check with your doctor if you have any of the following:
Signs and symptoms of Waldenström macroglobulinemia depend on the part of the body affected. Most patients with Waldenström macroglobulinemia have no signs or symptoms. Check with your doctor if you have any of the following:
The following tests and procedures may be used:
If cancer is found, the following tests may be done to study the cancer cells:
The prognosis (chance of recovery) and treatment options depend on the following:
For non-Hodgkin lymphoma during pregnancy, the treatment options also depend on:
Some types of non-Hodgkin lymphoma spread more quickly than others do. Most non-Hodgkin lymphomas that occur during pregnancy are aggressive. Delaying treatment of aggressive lymphoma until after the baby is born may lessen the mother's chance of survival. Immediate treatment is often recommended, even during pregnancy.
The process used to find out the type of cancer and if cancer cells have spread within the lymph system or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage of the disease in order to plan treatment. The following tests and procedures may be used in the staging process:
For pregnant women with non-Hodgkin lymphoma, staging tests that protect the fetus from the harms of radiation are used. These include MRI, bone marrow aspiration and biopsy, lumbar puncture, and ultrasound, which do not use radiation. An ultrasound exam is a procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.
Cancer can spread through tissue, the lymph system, and the blood:
Adult non-Hodgkin lymphoma may be described as follows:
Stage I adult non-Hodgkin lymphoma is divided into stage I and stage IE.
Stage II adult non-Hodgkin lymphoma is divided into stage II and stage IIE.
Stage III adult non-Hodgkin lymphoma is divided into stage III, stage IIIE, stage IIIS, and stage IIIE+S.
In stage IV adult non-Hodgkin lymphoma, the cancer:
Indolent or aggressive:
Contiguous or noncontiguous:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with Waldenström macroglobulinemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
Recurrent adult non-Hodgkin lymphoma is cancer that has recurred (come back) after it has been treated. The lymphoma may come back in the lymph system or in other parts of the body. Indolent lymphoma may come back as aggressive lymphoma. Aggressive lymphoma may come back as indolent lymphoma.
Different types of treatment are available for patients with non-Hodgkin lymphoma. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
For pregnant women with non-Hodgkin lymphoma, treatment is carefully chosen to protect the fetus. Treatment decisions are based on the mother's wishes, the stage of the non-Hodgkin lymphoma, and the age of the fetus. The treatment plan may change as the signs and symptoms, cancer, and pregnancy change. Choosing the most appropriate cancer treatment is a decision that ideally involves the patient, family, and health care team.
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells and keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.
For pregnant women with non-Hodgkin lymphoma, radiation therapy should be given after delivery, if possible, to avoid any risk to the fetus. If treatment is needed right away, pregnant women may decide to continue the pregnancy and receive radiation therapy. However, lead used to shield the fetus may not protect it from scattered radiation that could possibly cause cancer in the future.
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). To treat certain types of adult non-Hodgkin lymphoma that spread to the brain, CNS prophylaxis (chemotherapy given to kill cancer cells in the brain or spinal cord) may be used. The way the chemotherapy is given depends on the type and stage of the cancer being treated.
Combination chemotherapy is treatment using two or more anticancer drugs. Steroid drugs may be added, to relieve swelling and inflammation.
In pregnant women, the fetus is exposed to chemotherapy when the mother is treated, and some anticancer drugs cause birth defects. Because anticancer drugs are passed to the fetus through the mother, both must be watched closely when chemotherapy is given.
See Drugs Approved for Non-Hodgkin Lymphoma for more information.
Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Monoclonal antibodytherapy and proteasome inhibitor therapy are two types of targeted therapy used to treat adult non-Hodgkin lymphoma.
Monoclonal antibody therapy is a cancer treatment that uses antibodies made in the laboratory from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells. Monoclonal antibodies that have been joined to radioactive material are called radiolabeled monoclonal antibodies.
Proteasome inhibitor therapy blocks the action of proteasomes in cancer cells and may prevent the growth of tumors.
If the blood becomes thick with extra antibody proteins and affects circulation, plasmapheresis is done to remove extra plasma and antibody proteins from the blood. In this procedure, blood is removed from the patient and sent through a machine that separates the plasma (the liquid part of the blood) from the blood cells. The patient's plasma contains the unneeded antibodies and is not returned to the patient. The normal blood cells are returned to the bloodstream along with donated plasma or a plasma replacement. Plasmapheresis does not keep new antibodies from forming.
Biologic therapy is a treatment that uses the patient's immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body's natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.
Interferon is a type of biologic therapy. It affects the division of cancer cells and can slow tumor growth.
Watchful waiting is closely monitoring a patient's condition without giving any treatment until signs or symptoms appear or change.
This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied. Information about clinical trials is available from the NCI Web site.
Vaccine therapy is a type of biologic therapy. Biologic therapy is a treatment that uses the patient's immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body's natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy. Vaccine therapy can also be a type of targeted therapy.
High-dose chemotherapy with stem cell transplant is a method of giving high doses of chemotherapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body's blood cells.
For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.
Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.
Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.
Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's listing of clinical trials.
Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.
Treatment of indolent, stage I and contiguousstage II adult non-Hodgkin lymphoma may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with indolent, stage I adult non-Hodgkin lymphoma and indolent, contiguous stage II adult non-Hodgkin lymphoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
Treatment of aggressive, stage I and contiguousstage II adult non-Hodgkin lymphoma may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with aggressive, stage I adult non-Hodgkin lymphoma and aggressive, contiguous stage II adult non-Hodgkin lymphoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
Treatment of indolent, noncontiguousstage II/III/IV adult non-Hodgkin lymphoma may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with indolent, noncontiguous stage II adult non-Hodgkin lymphoma, indolent, stage III adult non-Hodgkin lymphoma and indolent, stage IV adult non-Hodgkin lymphoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
Treatment of aggressive, noncontiguousstage II/III/IV adult non-Hodgkin lymphoma may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with aggressive, noncontiguous stage II adult non-Hodgkin lymphoma, aggressive, stage III adult non-Hodgkin lymphoma and aggressive, stage IV adult non-Hodgkin lymphoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
Treatment of adult lymphoblastic lymphoma may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult lymphoblastic lymphoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
Treatment of adult diffuse small noncleaved cell/Burkitt lymphoma may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult Burkitt lymphoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
Treatment of Waldenström macroglobulinemia may include the following:
Treatment of indolent, recurrent adult non-Hodgkin lymphoma may include the following:
Treatment of indolent lymphoma that comes back as aggressive lymphoma may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with indolent, recurrent adult non-Hodgkin lymphoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
Treatment of aggressive, recurrent adult non-Hodgkin lymphoma may include the following:
Treatment of aggressive lymphoma that comes back as indolent lymphoma may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with aggressive, recurrent adult non-Hodgkin lymphoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
When aggressivenon-Hodgkin lymphoma is diagnosed in the first trimester of pregnancy, medical oncologists may advise the patient to end her pregnancy so that treatment may begin. Treatment is usually chemotherapy with or without radiation therapy.
When possible, treatment should delayed until after an early delivery, so that the anticancer drugs or radiation therapy will not affect the fetus. However, sometimes the cancer will need to be treated right away to increase the mother's chance of survival.
Women who have indolent (slow-growing) non-Hodgkin lymphoma can usually delay treatment with watchful waiting.
For more information from the National Cancer Institute about adult non-Hodgkin lymphoma, see the following:
For general cancer information and other resources from the National Cancer Institute, see the following:
This information is provided by the National Cancer Institute.
This information was last updated on April 25, 2014.
The NHLs are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment.[1]
Like Hodgkin lymphoma, NHL usually originates in lymphoid tissues and can spread to other organs. NHL, however, is much less predictable than Hodgkin lymphoma and has a far greater predilection to disseminate to extranodal sites. The prognosis depends on the histologic type, stage, and treatment.
Estimated new cases and deaths from NHL in the United States in 2014:[2]
NHL usually originates in lymphoid tissues.
The NHLs can be divided into two prognostic groups: the indolent lymphomas and the aggressive lymphomas.
Indolent NHL types have a relatively good prognosis with a median survival as long as 20 years, but they usually are not curable in advanced clinical stages.[3] Early-stage (stage I and stage II) indolent NHL can be effectively treated with radiation therapy alone. Most of the indolent types are nodular (or follicular) in morphology.
The aggressive type of NHL has a shorter natural history, but a significant number of these patients can be cured with intensive combination chemotherapy regimens.
In general, with modern treatment of patients with NHL, overall survival at 5 years is over 60%. Of patients with aggressive NHL, more than 50% can be cured. The vast majority of relapses occur in the first 2 years after therapy. The risk of late relapse is higher in patients who manifest both indolent and aggressive histologies.[4]
While indolent NHL is responsive to immunotherapy, radiation therapy, and chemotherapy, a continuous rate of relapse is usually seen in advanced stages. Patients, however, can often be re-treated with considerable success as long as the disease histology remains low grade. Patients who present with or convert to aggressive forms of NHL may have sustained complete remissions with combination chemotherapy regimens or aggressive consolidation with marrow or stem cell support.[5][6]
Shankland KR, Armitage JO, Hancock BW: Non-Hodgkin lymphoma. Lancet 380 (9844): 848-57, 2012.
American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed May 21, 2014.
Tan D, Horning SJ, Hoppe RT, et al.: Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience. Blood 122 (6): 981-7, 2013.
Cabanillas F, Velasquez WS, Hagemeister FB, et al.: Clinical, biologic, and histologic features of late relapses in diffuse large cell lymphoma. Blood 79 (4): 1024-8, 1992.
Bastion Y, Sebban C, Berger F, et al.: Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol 15 (4): 1587-94, 1997.
Yuen AR, Kamel OW, Halpern J, et al.: Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 13 (7): 1726-33, 1995.
Late effects of treatment for non-Hodgkin lymphoma
(NHL) have been observed. Pelvic radiation therapy and large cumulative doses of cyclophosphamide have been associated with a high risk of permanent sterility.[1] For as many as three decades after diagnosis, patients are at a significantly elevated risk for second primary cancers, especially the following:[1][2][3]
Left ventricular dysfunction was a significant late effect in long-term survivors of high-grade NHL who received more than 200 mg/m² of doxorubicin.[4][5]
Myelodysplastic syndrome and acute myelogenous leukemia are late complications of myeloablative therapy with autologous bone marrow or peripheral blood stem cell support, as well as conventional chemotherapy-containing alkylating agents.[1][6][7][8][9][10][11][12][13] Most of these patients show clonal hematopoiesis even before the transplantation, suggesting that the hematologic injury usually occurs during induction or reinduction chemotherapy.[8][14][15] With a median 10-year follow-up after autologous bone marrow transplantation (BMT) with conditioning using cyclophosphamide and total-body radiation therapy, in a series of 605 patients, the incidence of a second malignancy was 21%, and 10% of those were solid tumors.[16]
Successful pregnancies with children born free of congenital abnormalities have been reported in young women after autologous BMT.[17]
Some patients have osteopenia or osteoporosis at the start of therapy; bone density may worsen after therapy for lymphoma.[18]
Mudie NY, Swerdlow AJ, Higgins CD, et al.: Risk of second malignancy after non-Hodgkin's lymphoma: a British Cohort Study. J Clin Oncol 24 (10): 1568-74, 2006.
Travis LB, Curtis RE, Glimelius B, et al.: Second cancers among long-term survivors of non-Hodgkin's lymphoma. J Natl Cancer Inst 85 (23): 1932-7, 1993.
Hemminki K, Lenner P, Sundquist J, et al.: Risk of subsequent solid tumors after non-Hodgkin's lymphoma: effect of diagnostic age and time since diagnosis. J Clin Oncol 26 (11): 1850-7, 2008.
Haddy TB, Adde MA, McCalla J, et al.: Late effects in long-term survivors of high-grade non-Hodgkin's lymphomas. J Clin Oncol 16 (6): 2070-9, 1998.
Moser EC, Noordijk EM, van Leeuwen FE, et al.: Long-term risk of cardiovascular disease after treatment for aggressive non-Hodgkin lymphoma. Blood 107 (7): 2912-9, 2006.
Darrington DL, Vose JM, Anderson JR, et al.: Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 12 (12): 2527-34, 1994.
Stone RM, Neuberg D, Soiffer R, et al.: Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 12 (12): 2535-42, 1994.
Armitage JO, Carbone PP, Connors JM, et al.: Treatment-related myelodysplasia and acute leukemia in non-Hodgkin's lymphoma patients. J Clin Oncol 21 (5): 897-906, 2003.
André M, Mounier N, Leleu X, et al.: Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients. Blood 103 (4): 1222-8, 2004.
Oddou S, Vey N, Viens P, et al.: Second neoplasms following high-dose chemotherapy and autologous stem cell transplantation for malignant lymphomas: a report of six cases in a cohort of 171 patients from a single institution. Leuk Lymphoma 31 (1-2): 187-94, 1998.
Lenz G, Dreyling M, Schiegnitz E, et al.: Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 22 (24): 4926-33, 2004.
McLaughlin P, Estey E, Glassman A, et al.: Myelodysplasia and acute myeloid leukemia following therapy for indolent lymphoma with fludarabine, mitoxantrone, and dexamethasone (FND) plus rituximab and interferon alpha. Blood 105 (12): 4573-5, 2005.
Morton LM, Curtis RE, Linet MS, et al.: Second malignancy risks after non-Hodgkin's lymphoma and chronic lymphocytic leukemia: differences by lymphoma subtype. J Clin Oncol 28 (33): 4935-44, 2010.
Mach-Pascual S, Legare RD, Lu D, et al.: Predictive value of clonality assays in patients with non-Hodgkin's lymphoma undergoing autologous bone marrow transplant: a single institution study. Blood 91 (12): 4496-503, 1998.
Lillington DM, Micallef IN, Carpenter E, et al.: Detection of chromosome abnormalities pre-high-dose treatment in patients developing therapy-related myelodysplasia and secondary acute myelogenous leukemia after treatment for non-Hodgkin's lymphoma. J Clin Oncol 19 (9): 2472-81, 2001.
Brown JR, Yeckes H, Friedberg JW, et al.: Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total-body irradiation and autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 23 (10): 2208-14, 2005.
Jackson GH, Wood A, Taylor PR, et al.: Early high dose chemotherapy intensification with autologous bone marrow transplantation in lymphoma associated with retention of fertility and normal pregnancies in females. Scotland and Newcastle Lymphoma Group, UK. Leuk Lymphoma 28 (1-2): 127-32, 1997.
Westin JR, Thompson MA, Cataldo VD, et al.: Zoledronic acid for prevention of bone loss in patients receiving primary therapy for lymphomas: a prospective, randomized controlled phase III trial. Clin Lymphoma Myeloma Leuk 13 (2): 99-105, 2013.
A pathologist should be consulted prior to a biopsy because some studies require special preparation of tissue (e.g., frozen tissue). Knowledge of cell surface markers and immunoglobulin and T-cell receptor gene rearrangements may help with diagnostic and therapeutic decisions. The clonal excess of light-chain immunoglobulin may differentiate malignant from reactive cells. Since the prognosis and the approach to treatment are influenced by histopathology, outside biopsy specimens should be carefully reviewed by a hematopathologist who is experienced in diagnosing lymphomas. Although lymph node biopsies are recommended whenever possible, sometimes immunophenotypic data are sufficient to allow diagnosis of lymphoma when fine-needle aspiration cytology is preferred.[1][2]
Historically, uniform treatment of patients with non-Hodgkin lymphoma (NHL) has been hampered by the lack of a uniform classification system. In 1982, results of a consensus study were published as the Working Formulation.[3] The Working Formulation combined results from six major classification systems into one classification. This allowed comparison of studies from different institutions and countries. The Rappaport classification, which also follows, is no longer in common use.
Working Formulation [3]
Rappaport Classification
Low grade
A. Small lymphocytic, consistent with chronic lymphocytic leukemia
Diffuse lymphocytic, well-differentiated
B. Follicular, predominantly small-cleaved cell
Nodular lymphocytic, poorly differentiated
C. Follicular, mixed small-cleaved, and large cell
Nodular mixed, lymphocytic, and histiocytic
Intermediate grade
D. Follicular, predominantly large cell
Nodular histiocytic
E. Diffuse, small-cleaved cell
Diffuse lymphocytic, poorly differentiated
F. Diffuse mixed, small and large cell
Diffuse mixed, lymphocytic, and histiocytic
G. Diffuse, large cell, cleaved, or noncleaved cell
Diffuse histiocytic
High grade
H. Immunoblastic, large cell
I. Lymphoblastic, convoluted, or nonconvoluted cell
Diffuse lymphoblastic
J. Small noncleaved-cell, Burkitt, or non-Burkitt
Diffuse undifferentiated Burkitt or non-Burkitt
As the understanding of NHL has improved and as the histopathologic diagnosis of NHL has become more sophisticated with the use of immunologic and genetic techniques, a number of new pathologic entities have been described.[4] In addition, the understanding and treatment of many of the previously described pathologic subtypes have changed. As a result, the Working Formulation has become outdated and less useful to clinicians and pathologists. Thus, European and American pathologists have proposed a new classification, the Revised European American Lymphoma (REAL) classification.[5][6][7][8] Since 1995, members of the European and American Hematopathology societies have been collaborating on a new World Health Organization (WHO) classification, which represents an updated version of the REAL system.[9][10]
The WHO modification of the REAL classification recognizes three major categories
of lymphoid malignancies based on morphology and cell lineage: B-cell
neoplasms, T-cell/natural killer (NK)-cell neoplasms, and Hodgkin lymphoma.
Both lymphomas and lymphoid leukemias are included in this classification
because both solid and circulating phases are present in many lymphoid
neoplasms and distinction between them is artificial. For example, B-cell
chronic lymphocytic leukemia and B-cell small lymphocytic lymphoma are simply
different manifestations of the same neoplasm, as are lymphoblastic lymphomas
and acute lymphocytic leukemias. Within the B-cell and T-cell categories, two
subdivisions are recognized: precursor neoplasms, which correspond to the
earliest stages of differentiation, and more mature differentiated
The REAL classification encompasses all the lymphoproliferative neoplasms. Refer to the following PDQ summaries for more information:
Zeppa P, Marino G, Troncone G, et al.: Fine-needle cytology and flow cytometry immunophenotyping and subclassification of non-Hodgkin lymphoma: a critical review of 307 cases with technical suggestions. Cancer 102 (1): 55-65, 2004.
Young NA, Al-Saleem T: Diagnosis of lymphoma by fine-needle aspiration cytology using the revised European-American classification of lymphoid neoplasms. Cancer 87 (6): 325-45, 1999.
National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer 49 (10): 2112-35, 1982.
Pugh WC: Is the working formulation adequate for the classification of the low grade lymphomas? Leuk Lymphoma 10 (Suppl 1): 1-8, 1993.
Harris NL, Jaffe ES, Stein H, et al.: A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84 (5): 1361-92, 1994.
Pittaluga S, Bijnens L, Teodorovic I, et al.: Clinical analysis of 670 cases in two trials of the European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group subtyped according to the Revised European-American Classification of Lymphoid Neoplasms: a comparison with the Working Formulation. Blood 87 (10): 4358-67, 1996.
Armitage JO, Weisenburger DD: New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 16 (8): 2780-95, 1998.
A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 89 (11): 3909-18, 1997.
Pileri SA, Milani M, Fraternali-Orcioni G, et al.: From the R.E.A.L. Classification to the upcoming WHO scheme: a step toward universal categorization of lymphoma entities? Ann Oncol 9 (6): 607-12, 1998.
Society for Hematopathology Program: Society for Hematopathology Program. Am J Surg Pathol 21 (1): 114-121, 1997.
Indolent non-Hodgkin lymphoma (NHL) includes the following subtypes:
Follicular lymphoma comprises 20% of all NHLs and as many as 70% of the indolent lymphomas reported in American and European clinical trials.[1][2][3] Most patients with follicular lymphoma are age 50 years and older and present with widespread disease at diagnosis. Nodal involvement is most common and is often accompanied by splenic and bone marrow disease. Rearrangement of the bcl-2 gene is present in more than 90% of patients with follicular lymphoma; overexpression of the bcl-2 protein is associated with the inability to eradicate the lymphoma by inhibiting apoptosis.[4]
Despite the advanced stage, the median survival ranges from 8 to 15 years, leading to the designation of being indolent.[5][6][7] Patients with advanced-stage follicular lymphoma are not cured with current therapeutic options.[8] The rate of relapse is fairly consistent over time, even in patients who have achieved complete responses to treatment.[9] Watchful waiting, i.e., the deferring of treatment until the patient becomes symptomatic, is an option for patients with advanced-stage follicular lymphoma.[10] An international index for follicular lymphoma (i.e., the Follicular Lymphoma International Prognostic Index [FLIPI]) [11][12][13] identified five significant risk factors prognostic of overall survival (OS):
Patients with none or one risk factor have an 85% 10-year survival rate, while three or more risk factors confer a 40% 10-year survival rate.[11] As a revised FLIPI, an elevated beta-2-microglobulin and lymph node size of more than 6 cm are proposed prognostic factors instead of serum LDH and the number of nodal areas.[14] Gene expression profiles of tumor biopsy specimens suggest that follicular lymphoma that is surrounded by infiltrating T-lymphocytes has a much longer median survival (13.6 years) than follicular lymphoma that is surrounded by dendritic and monocytic cells (3.9 years) (P < .001).[15]
Follicular, small-cleaved cell lymphoma and follicular mixed small-cleaved and large cell lymphoma do not have reproducibly different disease-free survival or OS.
Therapeutic options include watchful waiting; rituximab, an anti-CD20 monoclonal antibody, alone or with purine nucleoside analogs; oral alkylating agents; and combination chemotherapy.[16] Radiolabeled monoclonal antibodies, vaccines, and autologous or allogeneic bone marrow or peripheral stem cell transplantation are also under clinical evaluation.[16][17] Currently, no randomized trials have mature results to guide clinicians about the initial choice of rituximab, nucleoside analogs, alkylating agents, combination chemotherapy, radiolabeled monoclonal antibodies, or combinations of these options. On a comparative basis, it is difficult to prove benefit when relapsing disease is followed with watchful waiting, or when the median survival is more than 10 years. Follicular lymphoma in situ and primary follicular lymphoma of the duodenum are particularly indolent variants that rarely progress and rarely require therapy.[18][19] A so-called pediatric-type nodal follicular lymphoma has indolent behavior and rarely recurs; adult patients with this histologic variant are characterized by a lack of bcl-2 rearrangement in conjunction with a Ki-67 proliferation index greater than 30% and a localized stage I presentation.[20]
Patients with indolent lymphoma may experience a relapse with a more aggressive histology. If the clinical pattern of relapse suggests that the disease is behaving in a more aggressive manner, a biopsy should be performed. Documentation of conversion to a more aggressive histology requires an appropriate change to a therapy applicable to that histologic type.[21] Rapid growth or discordant growth between various disease sites may indicate a histologic conversion. The risk of histologic transformation was 30% by 10 years in a retrospective review of 325 patients from diagnosis between 1972 and 1999.[22] In this series, high-risk factors for subsequent histologic transformation were advanced stage, high-risk FLIPI, and expectant management. The 5-year OS rate was more than 50% for 172 patients who had biopsy-proven, aggressive-histology transformation in a multicenter cohort study employing rituximab plus anthracycline or platinum-based chemotherapy, or similar therapy followed by autologous or allogeneic stem cell transplantation.[23][24]
Lymphoplasmacytic lymphoma is usually associated with a monoclonal serum paraprotein of immunoglobulin M (IgM) type (Waldenström macroglobulinemia).[25][26][27] Most patients have bone marrow, lymph node, and splenic involvement, and some patients may develop hyperviscosity syndrome. Other lymphomas may also be associated with serum paraproteins.
Asymptomatic patients can be monitored for evidence of disease progression without immediate need for chemotherapy.[10][28][29]
Prognostic factors associated with symptoms requiring therapy include the following:
The management of lymphoplasmacytic lymphoma is similar to that of other low-grade lymphomas, especially diffuse, small lymphocytic lymphoma/chronic lymphocytic leukemia.[26][27][28][30][31][32] If the viscosity relative to water is greater than four, the patient may have manifestations of hyperviscosity. Plasmapheresis is useful for temporary, acute symptoms (such as retinopathy, congestive heart failure, and central nervous system dysfunction) but should be combined with chemotherapy for prolonged control of the disease. Symptomatic patients with a serum viscosity of not more than four are usually started directly on chemotherapy. Therapy may be required to correct hemolytic anemia in patients with chronic cold agglutinin disease; rituximab, cyclophosphamide, and steroids are often employed.[29] Occasionally, a heated room is required for patients whose cold agglutinins become activated by even minor chilling.
First-line regimens include rituximab, the nucleoside analogs, and alkylating agents, either as single agents or as part of combination chemotherapy.[33][34][35][36] Rituximab shows 60% to 80% response rates in previously untreated patients, but close monitoring of the serum IgM is required because of a sudden rise in this paraprotein at the start of therapy.[33][37][38][Level of evidence: 3iiiDiv] The rise of IgM after rituximab can be avoided with the concomitant use of an alkylating agent such as cyclophosphamide or the proteosome inhibitor bortezomib.[29][39] The nucleoside analogs 2-chlorodeoxyadenosine and fludarabine have shown similar response rates for previously untreated patients with lymphoplasmacytic lymphoma.[36][40][41][Level of evidence: 3iiiDiv] Single-agent alkylators, bendamustine, bortezomib, and combination chemotherapy with or without rituximab also show similar response rates.[36][39][42][43][44][45][Level of evidence: 3iiiDiv] Currently, no randomized trials guide clinicians about the initial choice of rituximab, nucleoside analogs, alkylating agents, combination chemotherapy, or combinations of these options.[26][27][33] A combination of bortezomib, dexamethasone, and rituximab has been proposed for its high response rate, rapidity of action, and avoidance of an IgM rebound.[46]
Interferon-alpha also shows activity in this disease, in contrast to poor responses in patients with multiple myeloma.[47] Myeloablative therapy with autologous or allogeneic hematopoietic stem cell support is under clinical evaluation.[48][49][50][51] Candidates for this approach should avoid long-term use of alkylating agents or purine nucleoside analogs, which can deplete hematopoietic stem cells or predispose patients to myelodysplasia or acute leukemia.[33][52] After relapse from alkylating-agent therapy, 92 patients with lymphoplasmacytic lymphoma were randomly assigned to either fludarabine or cyclophosphamide, doxorubicin, and prednisone. Although relapse-free survival favored fludarabine (median duration of 19 months vs. 3 months, P < .01), no difference was observed in OS.[53][Level of
evidence: 1iiDii] Among patients with concomitant hepatitis C virus (HCV) infection, some will attain a complete or partial remission after loss of detectable HCV RNA with treatment using interferon-alpha with or without ribavirin.[54][Level of evidence: 3iiiDiv]
Marginal zone lymphomas were previously included among the diffuse, small lymphocytic lymphomas. When marginal zone lymphomas involve the nodes, they are called monocytoid B-cell lymphomas or nodal marginal zone B-cell lymphomas, and when they involve extranodal sites (e.g., gastrointestinal tract, thyroid, lung, breast, orbit, and skin), they are called mucosa-associated lymphatic tissue (MALT) lymphomas.[55][56][57][58][59][60][61][62][63]
Many patients have a history of autoimmune disease, such as Hashimoto thyroiditis or Sjögren syndrome, or of Helicobacter gastritis. Most patients present with stage I or stage II extranodal disease, which is most often in the stomach. Treatment of Helicobacter pylori infection may resolve most cases of localized gastric involvement.[64][65] After standard antibiotic regimens, 50% of patients show resolution of gastric MALT by endoscopy after 3 months. Other patients may show resolution after 12 to 18 months of observation. Of the patients who attain complete remission, 30% demonstrate monoclonality by immunoglobulin heavy chain rearrangement on stomach biopsies with a 5-year median follow-up.[66] The clinical implication of this finding is unknown. Translocation t(11;18) in patients with gastric MALT predicts for poor response to antibiotic therapy, for H. pylori–negative testing, and for poor response to oral alkylator chemotherapy.[67][68][69] Stable asymptomatic patients with persistently positive biopsies have been successfully followed on a watchful waiting approach until disease progression.[65] Patients who progress are treated with radiation therapy,[70][71][72][73] rituximab,[74] surgery (total gastrectomy or partial gastrectomy plus radiation therapy),[75] chemotherapy,[61] or combined–modality therapy.[76] The use of endoscopic ultrasonography may help clinicians to follow responses in these patients.[77] Four case series (encompassing more than 100 patients with stage IE or IIE diffuse, large, B-cell lymphoma with or without associated MALT (but H. pylori-positive) reported durable complete remissions in more than 50% of the patients after treatment of H. pylori.[78][79][80][81]
Localized involvement of other sites can be treated with radiation or surgery.[71][72][73][82][83][84] Patients with extragastric MALT lymphoma have a higher relapse rate than patients with gastric MALT lymphoma in some series, with relapses many years and even decades later.[85] Many of these recurrences involve different MALT sites than the original location.[86] When disseminated to lymph nodes, bone marrow, or blood, this entity behaves like other low-grade lymphomas.[62][87] A prospective, randomized trial of 252 patients with nongastric, extranodal MALT compared chlorambucil with rituximab plus chlorambucil.[88] With a median follow-up of 62 months, the event-free survival was better for the rituximab arm (68% vs. 50%, P = .002), however, the 5-year OS was 89% in both arms.[88][Level of evidence: 1iiDi] This trial was extended with a third arm using rituximab alone, the results of which are not yet available. For patients with ocular adnexal MALT, antibiotic therapy using doxycycline that targeted Chlamydia psittaci resulted in durable remissions for almost half of the patients in a review of the literature that included 131 patients.[89][Level of evidence: 3iiiDiv] Large B-cell lymphomas of MALT sites are classified and treated as diffuse large cell lymphomas.[90]
Patients with nodal marginal zone lymphoma (monocytoid B-cell lymphoma) are treated with the same paradigm of watchful waiting or therapies as described for follicular lymphoma. Among patients with concomitant HCV infection, the majority attain a complete or partial remission after loss of detectable HCV RNA with treatment using interferon-alpha with or without ribavirin.[54][Level of evidence: 3iiiDiv]
The disease variously known as Mediterranean abdominal lymphoma, heavy–chain disease, or immunoproliferative small intestinal disease (IPSID), which occurs in young adults in eastern Mediterranean countries, is another version of MALT lymphoma, which responds to antibiotics in its early stages.[91]Campylobacter jejuni has been identified as one of the bacterial species associated with IPSID, and antibiotic therapy may result in remission of the disease.[92]
Splenic marginal zone lymphoma is an indolent lymphoma that is marked by massive splenomegaly and peripheral blood and bone marrow involvement, usually without adenopathy.[93][94][95] This type of lymphoma is otherwise known as splenic lymphoma with villous lymphocytes. Splenectomy may result in prolonged remission.[63][96]
Management is similar to that of other low-grade lymphomas and usually involves rituximab alone or rituximab in combination with purine analogs or alkylating agent chemotherapy.[97] Splenic marginal zone lymphoma responds less well to chemotherapy, which would ordinarily be effective for chronic lymphocytic leukemia.[94][95][97] Among small numbers of patients with splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes) and infection with HCV, the majority attained a complete or partial remission after loss of detectable HCV RNA with treatment using interferon-alpha with or without ribavirin.[54][98]; [99][Level of evidence: 3iiiDiv] In contrast, no responses to interferon were seen in six HCV-negative patients.
Primary cutaneous anaplastic large cell lymphoma presents in the skin only with no pre-existing lymphoproliferative disease and no extracutaneous sites of involvement.[100][101][102] Patients with this type of lymphoma encompass a spectrum ranging from clinically benign lymphomatoid papulosis, marked by localized nodules that may regress spontaneously, to a progressive and systemic disease requiring aggressive doxorubicin-based combination chemotherapy. This spectrum has been called the primary cutaneous CD30-positive T-cell lymphoproliferative disorder.
Patients with localized disease usually undergo radiation therapy. With more disseminated involvement, watchful waiting or doxorubicin-based combination chemotherapy is applied.[100][101][102]
(Refer to the PDQ summaries on Chronic Lymphocytic Leukemia Treatment; Mycosis Fungoides/Sézary Syndrome Treatment; Hairy Cell Leukemia Treatment; and Adult Hodgkin Lymphoma Treatment for more information.)
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Kuo SH, Chen LT, Yeh KH, et al.: Nuclear expression of BCL10 or nuclear factor kappa B predicts Helicobacter pylori-independent status of early-stage, high-grade gastric mucosa-associated lymphoid tissue lymphomas. J Clin Oncol 22 (17): 3491-7, 2004.
Isaacson PG: Gastrointestinal lymphoma. Hum Pathol 25 (10): 1020-9, 1994.
Lecuit M, Abachin E, Martin A, et al.: Immunoproliferative small intestinal disease associated with Campylobacter jejuni. N Engl J Med 350 (3): 239-48, 2004.
Franco V, Florena AM, Iannitto E: Splenic marginal zone lymphoma. Blood 101 (7): 2464-72, 2003.
Iannitto E, Ambrosetti A, Ammatuna E, et al.: Splenic marginal zone lymphoma with or without villous lymphocytes. Hematologic findings and outcomes in a series of 57 patients. Cancer 101 (9): 2050-7, 2004.
Arcaini L, Paulli M, Boveri E, et al.: Splenic and nodal marginal zone lymphomas are indolent disorders at high hepatitis C virus seroprevalence with distinct presenting features but similar morphologic and phenotypic profiles. Cancer 100 (1): 107-15, 2004.
Parry-Jones N, Matutes E, Gruszka-Westwood AM, et al.: Prognostic features of splenic lymphoma with villous lymphocytes: a report on 129 patients. Br J Haematol 120 (5): 759-64, 2003.
Arcaini L, Lazzarino M, Colombo N, et al.: Splenic marginal zone lymphoma: a prognostic model for clinical use. Blood 107 (12): 4643-9, 2006.
Hermine O, Lefrère F, Bronowicki JP, et al.: Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 347 (2): 89-94, 2002.
Kelaidi C, Rollot F, Park S, et al.: Response to antiviral treatment in hepatitis C virus-associated marginal zone lymphomas. Leukemia 18 (10): 1711-6, 2004.
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Kempf W, Pfaltz K, Vermeer MH, et al.: EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Blood 118 (15): 4024-35, 2011.
Aggressive non-Hodgkin lymphoma (NHL) includes the following subtypes:
Diffuse large B-cell lymphoma (DLBCL) is the most common of the NHLs and comprises 30% of newly diagnosed cases.[1] Most patients present with rapidly enlarging masses, often with both local and systemic symptoms (designated B symptoms with fever, recurrent night sweats, or weight loss). (Refer to the PDQ summary on Hot Flashes and Night Sweats and the PDQ summary on Nutrition in Cancer Care for more information on weight loss.)
Some cases of large B-cell lymphoma have a prominent background of reactive T cells and often of histiocytes, so-called T-cell/histiocyte-rich large B-cell lymphoma. This subtype of large cell lymphoma has frequent liver, spleen, and bone marrow involvement; however, the outcome is equivalent to that of similarly staged patients with DLBCL.[2][3][4] Some patients with DLCBL at diagnosis have a concomitant indolent small B-cell component; while overall survival (OS) appears similar after multidrug chemotherapy, there is a higher risk of indolent relapse.[5]
The vast majority of patients with localized disease are curable with combined–modality therapy or combination chemotherapy alone.[6] For patients with advanced-stage disease, 50% of presenting patients are cured with doxorubicin-based combination chemotherapy and rituximab.[7][8][9]
An International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS:[10]
Patients with two or more risk factors have a less than 50% chance of relapse-free survival and OS at 5 years. This study also identifies patients at high risk of relapse based on specific sites of involvement, including bone marrow, central nervous system (CNS), liver, lung, and spleen. Age-adjusted and stage-adjusted modifications of this IPI are used for younger patients with localized disease.[11] The bcl-2 gene and rearrangement of the myc gene or dual overexpression of the myc gene, or both, confer a particularly poor prognosis.[12][13][14][15] Patients at high risk of relapse may be considered for clinical trials.[16] Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.[17][18][19][20][21] Patients who have DLBCL with coexpression of CD20 and CD30 may define a subgroup with a unique molecular signature, a more favorable prognosis, and possible therapeutic implication for the use of anti-CD30–specific therapy, such as brentuximab vedotin.[22]
CNS prophylaxis (usually with four to six injections of methotrexate intrathecally) is recommended for patients with paranasal sinus or testicular involvement. Some clinicians are employing high-dose intravenous methotrexate (usually four doses) as an alternative to intrathecal therapy because drug delivery is improved and patient morbidity is decreased.[23] CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, others do not.[24][25] A retrospective analysis of 605 patients with diffuse large cell lymphoma who did not receive prophylactic intrathecal therapy identified an elevated serum LDH and more than one extranodal site as independent risk factors for CNS recurrence. Patients with both risk factors have a 17% probability of CNS recurrence at 1 year after diagnosis (95% confidence interval [CI], 7%–28%) versus 2.8% (95% CI, 2.7%–2.9%) for the remaining patients.[26][Level of evidence: 3iiiDiii] The addition of rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-based regimens has significantly reduced the risk of CNS relapse in retrospective analyses.[27][28]
Primary mediastinal (thymic) large B-cell lymphoma is a subset of diffuse large cell lymphoma characterized by significant fibrosis on histology.[29][30][31][32][33][34][35] Patients are usually female and young (median age of 30–40 years). Patients present with a locally invasive anterior mediastinal mass that may cause respiratory symptoms or superior vena cava syndrome.
Prognosis and therapy is the same as for other comparably staged patients with DLCBL. Uncontrolled, phase II studies employing dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) plus rituximab or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) show high cure rates while avoiding any mediastinal radiation.[36][37][38][39][Level of evidence: 3iiiA] These results suggest that patients who receive R-CHOP-based regimens may avoid the serious long-term complications of radiation therapy when given with chemotherapy. Posttreatment fluorine-18-fluorodeoxyglucose–positron-emission tomography–computed tomography (FDG-PET-CT) scans appear unreliable with many false positives.[36] The only randomized trial showing an OS advantage for combined modality therapy was retracted. (Refer to the Superior Vena Cava Syndrome section in the PDQ summary on Cardiopulmonary Syndromes for more information.)
The natural history of follicular large cell lymphoma remains controversial.[40] While there is agreement about the significant number of long-term disease-free survivors with early-stage disease, the curability of patients with advanced disease (stage III or stage IV) remains uncertain. Some groups report a continuous relapse rate similar to the other follicular lymphomas (a pattern of indolent lymphoma).[41] Other investigators report a plateau in freedom-from-progression at levels expected for an aggressive lymphoma (40% at 10 years).[42][43] This discrepancy may be caused by variations in histologic classification between institutions and the rarity of patients with follicular large cell lymphoma. A retrospective review of 252 patients, all treated with anthracycline-containing combination chemotherapy, showed that patients with more than 50% diffuse components on biopsy had a worse OS than other patients with follicular large cell lymphoma.[44]
Treatment of these patients is more similar to treatment of aggressive NHL than it is to the treatment of indolent NHL. In support of this approach, treatment with high-dose chemotherapy and autologous hematopoietic peripheral stem cell transplantation (SCT) shows the same curative potential in patients with follicular large cell lymphoma who relapse as it does in patients with diffuse large cell lymphoma who relapse.[45][Level of evidence: 3iiiA]
Anaplastic large cell lymphomas (ALCL) may be confused with carcinomas and are associated with the Ki-1 (CD30) antigen. These lymphomas are usually of T-cell origin, often present with extranodal disease, and are found especially in the skin.
The translocation of chromosomes 2 and 5 creates a unique fusion protein with a nucleophosmin-anaplastic lymphoma kinase (ALK).[46]
Patients whose lymphomas express ALK (immunohistochemistry) are usually younger and may have systemic symptoms, extranodal disease, and advanced-stage disease; however, they have a more favorable survival rate than that of ALK-negative patients.[47][48]
Patients with ALK-positive ALCL are generally treated the same as patients with diffuse large cell lymphomas using the CHOP regimen and have a prognosis that is as good as comparably staged patients.[48] For patients with relapsed disease, anecdotal responses have been reported for brentuximab vedotin (anti-tubulin agent attached to a CD30-specific monoclonal antibody),[49][50] romidepsin,[51] and pralatrexate.[52][Level of evidence: 3iiiDiv] For patients with relapsed disease, autologous stem cell transplantation showed a 50% 3-year progression-free survival (PFS) for 39 patients in a retrospective review.[53][Level of evidence: 3iiiDiii]
ALCL in children is usually characterized by systemic and cutaneous disease and has high response rates and good OS with doxorubicin-based combination chemotherapy.[54]
Extranodal natural killer (NK)-/T-cell lymphoma (nasal type) is an aggressive lymphoma marked by extensive necrosis and angioinvasion, most often presenting in extranodal sites, in particular the nasal or paranasal sinus region.[55][56][57][58] Other extranodal sites include the palate, trachea, skin, and gastrointestinal tract. Hemophagocytic syndrome may occur; historically, these tumors were considered part of lethal midline granuloma.[59] In most cases, Epstein-Barr virus (EBV) genomes are detectable in the tumor cells and immunophenotyping shows CD56 positivity. Cases with blood and marrow involvement are considered NK-cell leukemia.
The increased risk of CNS involvement and of local recurrence has led to recommendations for radiation therapy locally, concurrently, or prior to the start of chemotherapy, and for intrathecal prophylaxis and/or prophylactic cranial radiation therapy.[60][61][62][63][64][65] The highly aggressive course, with poor response and short survival with standard therapies, especially for patients with advanced-stage disease or extranasal presentation, has led some investigators to recommend autologous or allogenic peripheral SCT consolidation.[56][57][58][66][67] L-asparaginase-containing regimens have shown anecdotal response rates greater than 50% for relapsing, refractory, or newly diagnosed stage IV patients.[68][69] NK-/T-cell lymphoma that presents only in the skin has a more favorable prognosis, especially in patients with coexpression of CD30 with CD56.[70] A benign NK-cell enteropathy (EBV negative) on endoscopic biopsy should be distinguished from NK-/T-cell lymphoma.[71]
Lymphomatoid granulomatosis is an EBV-positive large B-cell lymphoma with a predominant T-cell background.[72][73] The histology shows association with angioinvasion and vasculitis, usually manifesting as pulmonary lesions or paranasal sinus involvement.
Patients are managed like others with diffuse large cell lymphoma and require doxorubicin-based combination chemotherapy.
Angioimmunoblastic T-cell lymphoma (AITL) or (ATCL) was formerly called angioimmunoblastic lymphadenopathy with dysproteinemia. Characterized by clonal T-cell receptor gene rearrangement, this entity is managed like diffuse large cell lymphoma.[74][75][76] Patients present with profound lymphadenopathy, fever, night sweats, weight loss, skin rash, a positive Coombs test, and polyclonal hypergammaglobulinemia.[59] (Refer to the information on night sweats in the PDQ summary on Hot Flashes and Night Sweats, information on weight loss in the in the PDQ summary on Nutrition in Cancer Care, and information on skin rash in the PDQ summary on Pruritus.) Opportunistic infections are frequent because of an underlying immune deficiency. B-cell EBV genomes are detected in most affected patients.[77]
Doxorubicin-based combination chemotherapy, such as the CHOP regimen, is recommended as it is for other aggressive lymphomas.[74] The International Peripheral T-Cell Lymphoma Project involving 22 international centers identified 243 patients with AITL or ATCL; the 5-year OS and failure-free survival rates were 33% and 18%.[78] Myeloablative chemotherapy and radiation therapy with autologous or allogeneic peripheral stem cell support has been described in anecdotal reports.[66][79][80] Anecdotal responses have been reported for cyclosporine,[81] pralatrexate,[52] bendamustine,[82] and the histone deacetylase inhibitor romidepsin.[51][Level of evidence: 3iiiDiv] Occasional spontaneous remissions and protracted responses to steroids only have been reported.
Patients with peripheral T-cell lymphoma have diffuse large cell or diffuse mixed lymphoma that expresses a cell surface phenotype of a postthymic (or peripheral) T-cell expressing CD4 or CD8 but not both together.[83] Peripheral T-cell lymphoma encompasses a group of heterogeneous nodal T-cell lymphomas that will require future delineation.[59] This includes the so-called Lennert lymphoma, a T-cell lymphoma admixed with a preponderance of lymphoepithelioid cells.
Most investigators report worse response and survival rates for patients with peripheral T-cell lymphomas than for patients with comparably staged B-cell aggressive lymphomas.[84][85] Most patients present with multiple adverse prognostic factors (i.e., older age, stage IV, multiple extranodal sites, and elevated LDH), and these patients have a low (<20%) failure-free survival and OS at 5 years.[84][85]
Therapy involves doxorubicin-based combination chemotherapy (such as CHOP), which is also used for DLBCL. Consolidation using high-dose chemotherapy with autologous or allogeneic hematopoietic stem cell support has been applied to patients with advanced-stage peripheral T-cell lymphoma after induction therapy with CHOP-based regimens and after response to reinduction therapy at first relapse. Evidence for this approach is anecdotal.[66][79][86][87] For relapsing patients, pralatrexate has shown a 30% response rate and a median 10-month duration of response for 109 evaluable patients in a prospective trial.[51][88][Level of evidence: 3iiiDiv] Also for relapsing patients, similar response rates were seen for romidepsin for 130 evaluable patients in a prospective trial.[51][Level of evidence: 3iiiDiv] Anecdotal responses have been seen with pralatrexate [52] and with bendamustine.[82][Level of evidence: 3iiiDiv] Anecdotal responses have also been seen with alemtuzumab, an anti-CD52 monoclonal antibody, or denileukin diftitox, a toxin-antibody ligand, after relapse from previous chemotherapy.[89][90] The median PFS after first relapse was less than 6 months in one series of 163 patients with peripheral T-cell lymphoma.[91]
An unusual type of peripheral T-cell lymphoma occurring mostly in young men, hepatosplenic T-cell lymphoma, appears to be localized to the hepatic and splenic sinusoids, with cell surface expression of the T-cell receptor gamma/delta.[92][93][94][95][96] Another variant, subcutaneous panniculitis-like T-cell lymphoma, is localized to subcutaneous tissue associated with hemophagocytic syndrome.[97][98][99][100] These patients have cells that express alpha-beta phenotype. Those with gamma-delta phenotype have a more aggressive clinical course and are classified as cutaneous gamma-delta T-cell lymphoma.[101][102][103] These patients may manifest involvement of the epidermis, dermis, subcutaneous region, or mucosa. These entities have extremely poor prognoses with an extremely aggressive clinical course and are treated within the same paradigm as the highest-risk groups with DLBCL.[66]
Enteropathy-type intestinal T-cell lymphoma involves the small bowel of patients with gluten-sensitive enteropathy (celiac sprue).[59][104][105][106] Since a gluten-free diet prevents the development of lymphoma, patients diagnosed with celiac sprue in childhood rarely develop lymphoma. The diagnosis of celiac disease is usually made by finding villous atrophy in the resected intestine. Surgery is often required for diagnosis and to avoid perforation during therapy.
Therapy is with doxorubicin-based combination chemotherapy, but relapse rates appear higher than for comparably staged diffuse large cell lymphoma.[105][106][107] Complications of treatment include gastrointestinal bleeding, small bowel perforation, and enterocolic fistulae; patients often require parenteral nutrition. (Refer to the PDQ summaries on Gastrointestinal Complications and Nutrition in Cancer Care for more information on parenteral nutrition.) Multifocal intestinal perforations and visceral abdominal involvement are seen at the time of relapse. High-dose therapy with hematopoietic stem cell rescue has been applied in first remission or at relapse.[66][105][108][Level of evidence: 3iiiDiii] Evidence for this approach is anecdotal.
Intravascular lymphomatosis is characterized by large cell lymphoma confined to the intravascular lumen. The brain, kidneys, lungs, and skin are the organs most likely affected by intravascular lymphomatosis.
With the use of aggressive combination chemotherapy, the prognosis is similar to more conventional presentations.[109][110]
Burkitt lymphoma/diffuse small noncleaved-cell lymphoma typically involves younger patients and represents the most common type of pediatric NHL.[111] These types of aggressive extranodal B-cell lymphomas are characterized by translocation and deregulation of the C-myc gene on chromosome 8.[112] A subgroup of patients with dual translocation of C-myc and bcl-2 appear to have an extremely poor outcome despite aggressive therapy (5-month OS).[113][Level of evidence: 3iiiA]
In some patients with larger B cells, there is morphologic overlap with DLBCL. These Burkitt-like large cell lymphomas show C-myc deregulation, extremely high proliferation rates, and a gene-expression profile as expected for classic Burkitt lymphoma.[114][115][116] Endemic cases, usually from Africa, involve the facial bones or jaws of children, mostly containing EBV genomes. Sporadic cases usually involve the gastrointestinal system, ovaries, or kidneys. Patients present with rapidly growing masses and a very high LDH but are potentially curable with intensive doxorubicin-based combination chemotherapy.
Treatment of Burkitt lymphoma/diffuse small noncleaved-cell lymphoma involves aggressive multidrug regimens similar to those used for the advanced-stage aggressive lymphomas (diffuse large cell).[117][118][119][120] Aggressive combination chemotherapy, which is patterned after that used in childhood Burkitt lymphoma, has been described in CLB-9251 (NCT00002494), for example, and has been very successful for adult patients with more than 60% of advanced-stage patients free of disease at 5 years.[121][122][123][124][125][126] Adverse prognostic factors include bulky abdominal disease and high serum LDH. In some institutions, treatment includes the use of consolidative bone marrow transplantation (BMT).[127][128] Patients with Burkitt lymphoma have a 20% to 30% lifetime risk of CNS involvement. Prophylaxis with intrathecal chemotherapy is required as part of induction therapy.[129] (Refer to the PDQ summaries on Primary CNS Lymphoma Treatment and AIDS-Related Lymphoma Treatment for more information.)
Lymphoblastic lymphoma (precursor T-cell) is a very aggressive form of NHL. It often occurs in young patients but not exclusively.[130] It is commonly associated with large mediastinal masses and has a high predilection for disseminating to bone marrow and to the CNS.
Treatment is usually patterned after that for acute lymphoblastic leukemia. Intensive combination chemotherapy with or without BMT is the standard treatment of this aggressive histologic type of NHL.[131][132][133] Radiation therapy is sometimes given to areas of bulky tumor masses. Because these forms of NHL tend to progress quickly, combination chemotherapy is instituted rapidly once the diagnosis has been confirmed. Careful review of the pathologic specimens, bone marrow aspirate, biopsy specimen, cerebrospinal fluid cytology, and lymphocyte marker constitute the most important aspects of the pretreatment staging workup. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)
Adult T-cell leukemia/lymphoma (ATL) is caused by infection with the retrovirus human T-lymphotrophic virus 1 and is frequently associated with lymphadenopathy, hypercalcemia, circulating leukemic cells, bone and skin involvement, hepatosplenomegaly, a rapidly progressive course, and poor response to combination chemotherapy.[134][135] ATL has been divided into four clinical subtypes: acute, lymphoma, chronic, and smoldering.[136][137]
The acute and lymphoma types of ATL have done poorly with strategies of combination chemotherapy and allogeneic stem cell transplantation (ASCT) with a median OS under 1 year.[138][139][140] Using combination chemotherapy, less than 10%of 807 patients were alive after 4 years.[140] Anecdotal durable remissions have been reported after ASCT and even after subsequent donor lymphocyte infusion for relapses after transplant.[141][Level of evidence: 3iiiDiv] Among 585 patients who underwent ASCT, the 3-year OS was 36%.[142][Level of evidence: 3iiiA]
The combination of zidovudine and interferon-alpha has activity against ATL, even for patients who failed previous cytotoxic therapy. Durable remissions are seen in the majority of presenting patients with this combination but are not seen in patients with the lymphoma subtype of ATL.[143][144][145][146][147] Symptomatic local progression for all subtypes responds well to palliative radiation therapy.[148]
Mantle cell lymphoma is found in lymph nodes, the spleen, bone marrow, blood, and sometimes the gastrointestinal system (lymphomatous polyposis).[149][150][151] Mantle cell lymphoma is characterized by CD5-positive follicular mantle B cells, a translocation of chromosomes 11 and 14, and an overexpression of the cyclin D1 protein.[152][153]
Like the low-grade lymphomas, mantle cell lymphoma appears incurable with anthracycline-based chemotherapy and occurs in older patients with generally asymptomatic advanced-stage disease.[154] The median survival, however, is significantly shorter (3–5 years) than that of other lymphomas, and this histology is now considered to be an aggressive lymphoma.[155] A diffuse pattern and the blastoid variant have an aggressive course with shorter survival, while the mantle zone type may have a more indolent course.[156][157] A high cell-proliferation rate (increased Ki-67, mitotic index, beta-2-microglobulin) may be associated with a poorer prognosis.[152][158]
It is unclear which chemotherapeutic approach offers the best long-term survival in this clinicopathologic entity; early refractoriness to chemotherapy is a usual feature.[159][160][161][162][163] In a prospective, randomized trial, 532 patients older than 60 years and not eligible for SCT were given either R-CHOP or R-FC (rituximab, fludarabine, cyclophosphamide) for 6 to 8 cycles, followed by maintenance therapy in responders randomly assigned to rituximab or interferon-alpha maintenance therapy.[164] With a median follow-up of 37 months, the OS was significantly shorter after R-FC than after R-CHOP (47% vs. 62%, P = .005; hazard ratio [HR]death, 1.50; 95% CI, 1.13–1.99).[164][Level of evidence: 1iiA] Event-free survival favored rituximab over interferon-alpha (57% PFS at 4 years vs. 34%, P = .01; HR, 0.55; 95% CI, 0.36–0.87), but OS did not differ significantly (79% vs. 67% at 4 years, P = .13).[164][Level of evidence: 1iiDi] However, patients who received R-CHOP induction showed an OS benefit for rituximab maintenance over interferon-alpha maintenance (87% vs. 63% at 4 years, P = .005).[164][Level of evidence: 3iiiA] A randomized trial compared bendamustine plus rituximab with R-CHOP and showed improved PFS (35 vs. 22 months; HR, 0.49; 95% CI, 0.28–0.79; P = .004) but no difference in OS.[165][Level of evidence: 1iiDiii]
Patients with low risk on the IPI may do well when initial therapy is deferred.[166][Level of evidence: 3iiiDiv] Many investigators are exploring high-dose chemoradioimmunotherapy with stem cell/marrow support or nonmyeloablative ASCT.[159][160][163][167][168][169][170][171][172][173][174][175][176] Thus far, randomized trials have not shown OS benefits from these newer approaches.[173] Bortezomib shows response rates close to 50% in relapsed patients, prompting clinical trials combining this proteasome inhibitor with rituximab and cytotoxic agents in first-line therapy.[177][178][Level of evidence: 3iiiDiv] The combination of lenalidomide and rituximab also shows response rates of around 50% in relapsed patients.[179][Level of evidence: 3iiDiv]
Patients who undergo transplantation of the heart, lung, liver, kidney, or pancreas usually require lifelong immunosuppression. This may result in PTLD in 1% to 3% of recipients, which appears as an aggressive lymphoma.[180] Pathologists can distinguish a polyclonal B-cell hyperplasia from a monoclonal B-cell lymphoma; both are almost always associated with EBV.[181]
Poor performance status, grafted organ involvement, high IPI, elevated LDH, and multiple sites of disease are poor prognostic factors for PTLD.[182][183]
In some cases, withdrawal of immunosuppression results in eradication of the lymphoma.[184][185] When this is unsuccessful or not feasible, a trial of rituximab may be considered, because it has shown durable remissions in approximately 60% of patients and a favorable toxicity profile.[185][186] Sometimes, a combination of acyclovir and interferon-alpha has been used.[180][187] If these measures fail, doxorubicin-based combination chemotherapy is recommended, although most patients can avoid cytotoxic therapy.[188] Localized presentations can be controlled with surgery or radiation therapy alone. These localized mass lesions, which may grow over a period of months, are often phenotypically polyclonal and tend to occur within weeks or a few months after transplantation.[181] Multifocal, rapidly progressive disease occurs late after transplantation (>1 year) and is usually phenotypically monoclonal and associated with EBV.[189] These patients may have durable remissions using standard chemotherapy regimens for aggressive lymphoma.[189][190][191] Instances of EBV-negative PTLD occur even later (median, 5 years posttransplant) and have particularly poor prognoses.[192] A sustained clinical response after failure from chemotherapy was attained using an immunotoxin (anti-CD22 B-cell surface antigen antibody linked with ricin, a plant toxin).[193] An anti-interleukin-6 monoclonal antibody is also under clinical evaluation.[194]
True histiocytic lymphomas are very rare tumors that show histiocytic differentiation and express histiocytic markers in the absence of B-cell or T-cell lineage-specific immunologic markers.[195][196] Care must be taken with immunophenotypic tests to exclude ALCL or hemophagocytic syndromes caused by viral infections, especially EBV.
Therapy is modeled after the treatment of comparably staged diffuse large cell lymphomas, but the optimal approach remains to be defined.
Primary effusion lymphoma presents exclusively or mainly in the pleural, pericardial, or abdominal cavities in the absence of an identifiable tumor mass.[197] Patients are usually human immunodeficiency virus seropositive, and the tumor usually contains Kaposi sarcoma–associated herpes virus/human herpes virus 8.
The prognosis of primary effusion lymphoma is extremely poor.
Therapy is usually modeled after the treatment of comparably staged diffuse large cell lymphomas.
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Kluin-Nelemans HC, Hoster E, Hermine O, et al.: Treatment of older patients with mantle-cell lymphoma. N Engl J Med 367 (6): 520-31, 2012.
Martin P, Chadburn A, Christos P, et al.: Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol 27 (8): 1209-13, 2009.
Khouri IF, Lee MS, Saliba RM, et al.: Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma. J Clin Oncol 21 (23): 4407-12, 2003.
Khouri IF, Romaguera J, Kantarjian H, et al.: Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma. J Clin Oncol 16 (12): 3803-9, 1998.
Lefrère F, Delmer A, Suzan F, et al.: Sequential chemotherapy by CHOP and DHAP regimens followed by high-dose therapy with stem cell transplantation induces a high rate of complete response and improves event-free survival in mantle cell lymphoma: a prospective study. Leukemia 16 (4): 587-93, 2002.
Gopal AK, Rajendran JG, Petersdorf SH, et al.: High-dose chemo-radioimmunotherapy with autologous stem cell support for relapsed mantle cell lymphoma. Blood 99 (9): 3158-62, 2002.
Gianni AM, Magni M, Martelli M, et al.: Long-term remission in mantle cell lymphoma following high-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting (R-HDS regimen). Blood 102 (2): 749-55, 2003.
Forstpointner R, Dreyling M, Repp R, et al.: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104 (10): 3064-71, 2004.
Dreyling M, Lenz G, Hoster E, et al.: Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood 105 (7): 2677-84, 2005.
Geisler CH, Kolstad A, Laurell A, et al.: Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood 112 (7): 2687-93, 2008.
Tam CS, Bassett R, Ledesma C, et al.: Mature results of the M. D. Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma. Blood 113 (18): 4144-52, 2009.
Damon LE, Johnson JL, Niedzwiecki D, et al.: Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol 27 (36): 6101-8, 2009.
Fisher RI, Bernstein SH, Kahl BS, et al.: Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 24 (30): 4867-74, 2006.
O'Connor OA, Moskowitz C, Portlock C, et al.: Patients with chemotherapy-refractory mantle cell lymphoma experience high response rates and identical progression-free survivals compared with patients with relapsed disease following treatment with single agent bortezomib: results of a multicentre Phase 2 clinical trial. Br J Haematol 145 (1): 34-9, 2009.
Wang M, Fayad L, Wagner-Bartak N, et al.: Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol 13 (7): 716-23, 2012.
Morrison VA, Dunn DL, Manivel JC, et al.: Clinical characteristics of post-transplant lymphoproliferative disorders. Am J Med 97 (1): 14-24, 1994.
Knowles DM, Cesarman E, Chadburn A, et al.: Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. Blood 85 (2): 552-65, 1995.
Leblond V, Dhedin N, Mamzer Bruneel MF, et al.: Identification of prognostic factors in 61 patients with posttransplantation lymphoproliferative disorders. J Clin Oncol 19 (3): 772-8, 2001.
Ghobrial IM, Habermann TM, Maurer MJ, et al.: Prognostic analysis for survival in adult solid organ transplant recipients with post-transplantation lymphoproliferative disorders. J Clin Oncol 23 (30): 7574-82, 2005.
Armitage JM, Kormos RL, Stuart RS, et al.: Posttransplant lymphoproliferative disease in thoracic organ transplant patients: ten years of cyclosporine-based immunosuppression. J Heart Lung Transplant 10 (6): 877-86; discussion 886-7, 1991 Nov-Dec.
Evens AM, David KA, Helenowski I, et al.: Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era. J Clin Oncol 28 (6): 1038-46, 2010.
Kuehnle I, Huls MH, Liu Z, et al.: CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation. Blood 95 (4): 1502-5, 2000.
Shapiro RS, Chauvenet A, McGuire W, et al.: Treatment of B-cell lymphoproliferative disorders with interferon alfa and intravenous gamma globulin. N Engl J Med 318 (20): 1334, 1988.
Leblond V, Sutton L, Dorent R, et al.: Lymphoproliferative disorders after organ transplantation: a report of 24 cases observed in a single center. J Clin Oncol 13 (4): 961-8, 1995.
Mamzer-Bruneel MF, Lomé C, Morelon E, et al.: Durable remission after aggressive chemotherapy for very late post-kidney transplant lymphoproliferation: A report of 16 cases observed in a single center. J Clin Oncol 18 (21): 3622-32, 2000.
Swinnen LJ: Durable remission after aggressive chemotherapy for post-cardiac transplant lymphoproliferation. Leuk Lymphoma 28 (1-2): 89-101, 1997.
McCarthy M, Ramage J, McNair A, et al.: The clinical diversity and role of chemotherapy in lymphoproliferative disorder in liver transplant recipients. J Hepatol 27 (6): 1015-21, 1997.
Leblond V, Davi F, Charlotte F, et al.: Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity? J Clin Oncol 16 (6): 2052-9, 1998.
Senderowicz AM, Vitetta E, Headlee D, et al.: Complete sustained response of a refractory, post-transplantation, large B-cell lymphoma to an anti-CD22 immunotoxin. Ann Intern Med 126 (11): 882-5, 1997.
Haddad E, Paczesny S, Leblond V, et al.: Treatment of B-lymphoproliferative disorder with a monoclonal anti-interleukin-6 antibody in 12 patients: a multicenter phase 1-2 clinical trial. Blood 97 (6): 1590-7, 2001.
Soslow RA, Davis RE, Warnke RA, et al.: True histiocytic lymphoma following therapy for lymphoblastic neoplasms. Blood 87 (12): 5207-12, 1996.
Kamel OW, Gocke CD, Kell DL, et al.: True histiocytic lymphoma: a study of 12 cases based on current definition. Leuk Lymphoma 18 (1-2): 81-6, 1995.
Nador RG, Cesarman E, Chadburn A, et al.: Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood 88 (2): 645-56, 1996.
Stage is important in selecting a treatment for patients with non-Hodgkin lymphoma (NHL). Chest and abdominal computed tomography (CT) scans are usually part of the staging evaluation for all lymphoma patients. The staging system is similar to the staging system used for Hodgkin lymphoma.
Common among patients with NHL is involvement of the following:
Cytologic examination of cerebrospinal fluid may be positive in patients with aggressive NHL. Involvement of hilar and mediastinal lymph nodes is less common than in Hodgkin lymphoma. Mediastinal adenopathy, however, is a prominent feature of lymphoblastic lymphoma and primary mediastinal B-cell lymphoma, entities primarily found in young adults.
The majority of patients with NHL present with advanced (stage III or stage IV) disease that can often be identified with limited staging procedures such as CT scanning and biopsies of the bone marrow and other accessible sites of involvement. Laparoscopic biopsy or laparotomy is not required for staging but may be necessary to establish a diagnosis or histologic type.[1] Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose can be used for initial staging and for follow-up after therapy as a supplement to CT scanning.[2][3][4][5][6] Interim PET scans after two to four cycles of therapy did not provide reliable prognostic information because of problems of interobserver reproducibility in a large cooperative group trial (ECOG-E344 [NCT00274924]) and lack of difference in outcome between PET-negative and PET-positive/biopsy-negative patients in two prospective trials.[7][8][9]
Prognostic Groups
Involvement of a single lymphatic site (i.e., nodal region, Waldeyer ring, thymus or spleen) (I).
Localized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement (IE) (rare in Hodgkin lymphoma).
Involvement of two or more lymph node regions on the same side of the diaphragm (II).
Localized involvement of a single extralymphatic organ or site in association with regional lymph node involvement with or without involvement of other lymph node regions on the same side of the diaphragm (IIE). The number of regions involved may be indicated by a subscript Arabic numeral, for example, II3.
Involvement of lymph node regions on both sides of the diaphragm (III), which also may be accompanied by extralymphatic extension in association with adjacent lymph node involvement (IIIE) or by involvement of the spleen (IIIS) or both (IIIE, IIIS). Splenic involvement is designated by the letter S.
Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement.
Isolated extralymphatic organ involvement in the absence of adjacent regional lymph node involvement, but in conjunction with disease in distant site(s). Stage IV includes any involvement of the liver or bone marrow, lungs (other than by direct extension from another site), or cerebrospinal fluid.
aReprinted with permission from American Joint Committee on Cancer: Hodgkin and non-Hodgkin lymphomas. In Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 607–11.
The Ann Arbor staging system is commonly used for patients with NHL.[10][11] In this system, stage I, stage II, stage III, and stage IV adult NHL can be subclassified into A and B categories: B for those with well-defined generalized symptoms and A for those without such symptoms. The B designation is given to patients with any of the following symptoms:
Occasionally, specialized staging systems are used. The physician should be aware of the system used in a specific report.
The E designation is used when extranodal lymphoid malignancies arise in tissues separate from, but near, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver. If pathologic proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed.
N = nodes
H = liver
L = lung
M = bone marrow
S = spleen
P = pleura
O = bone
D = skin
Current practice assigns a clinical stage (CS) based on the findings of the clinical evaluation and a pathologic stage (PS) based on the findings made as a result of invasive procedures beyond the initial biopsy.
For example, on percutaneous biopsy, a patient with inguinal adenopathy and a positive lymphangiogram without systemic symptoms might be found to have involvement of the liver and bone marrow. The precise stage of such a patient would be CS IIA, PS IVA(H+)(M+).
A number of other factors that are not included in the above staging system are important for the staging and prognosis of patients with NHL. These factors include the following:
To identify subgroups of patients most likely to relapse, an international prognostic index was compiled for 2,031 patients with aggressive NHL.[12] After validation by several cancer centers,[13][14] the major cooperative groups have used this index in the design of new clinical trials. The model is simple to apply, reproducible, and predicts outcome even after patients have achieved a complete remission. The model identifies five significant risk factors prognostic of overall survival (OS):
Patients with two or more risk factors have a less than 50% chance of relapse-free survival and OS at 5 years. This study also identifies patients at high risk of relapse based on specific sites of involvement, including bone marrow, central nervous system, liver, lung, and spleen. The bcl-2 gene and rearrangement of the myc gene or dual overexpression of the myc gene, or both, confer a particularly poor prognosis.[15][16][17][18] Patients at high risk of relapse may benefit from consolidation therapy or other approaches under clinical evaluation.[12] Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.[19][20]
Mann GB, Conlon KC, LaQuaglia M, et al.: Emerging role of laparoscopy in the diagnosis of lymphoma. J Clin Oncol 16 (5): 1909-15, 1998.
Zijlstra JM, Hoekstra OS, Raijmakers PG, et al.: 18FDG positron emission tomography versus 67Ga scintigraphy as prognostic test during chemotherapy for non-Hodgkin's lymphoma. Br J Haematol 123 (3): 454-62, 2003.
Juweid ME, Cheson BD: Role of positron emission tomography in lymphoma. J Clin Oncol 23 (21): 4577-80, 2005.
Juweid ME, Stroobants S, Hoekstra OS, et al.: Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 25 (5): 571-8, 2007.
Cheson BD, Pfistner B, Juweid ME, et al.: Revised response criteria for malignant lymphoma. J Clin Oncol 25 (5): 579-86, 2007.
Terasawa T, Lau J, Bardet S, et al.: Fluorine-18-fluorodeoxyglucose positron emission tomography for interim response assessment of advanced-stage Hodgkin's lymphoma and diffuse large B-cell lymphoma: a systematic review. J Clin Oncol 27 (11): 1906-14, 2009.
Horning SJ, Juweid ME, Schöder H, et al.: Interim positron emission tomography scans in diffuse large B-cell lymphoma: an independent expert nuclear medicine evaluation of the Eastern Cooperative Oncology Group E3404 study. Blood 115 (4): 775-7; quiz 918, 2010.
Moskowitz CH, Schöder H, Teruya-Feldstein J, et al.: Risk-adapted dose-dense immunochemotherapy determined by interim FDG-PET in Advanced-stage diffuse large B-Cell lymphoma. J Clin Oncol 28 (11): 1896-903, 2010.
Pregno P, Chiappella A, Bellò M, et al.: Interim 18-FDG-PET/CT failed to predict the outcome in diffuse large B-cell lymphoma patients treated at the diagnosis with rituximab-CHOP. Blood 119 (9): 2066-73, 2012.
Lymphoid neoplasms. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 599-628.
Salles G, de Jong D, Xie W, et al.: Prognostic significance of immunohistochemical biomarkers in diffuse large B-cell lymphoma: a study from the Lunenburg Lymphoma Biomarker Consortium. Blood 117 (26): 7070-8, 2011.
Advani RH, Chen H, Habermann TM, et al.: Comparison of conventional prognostic indices in patients older than 60 years with diffuse large B-cell lymphoma treated with R-CHOP in the US Intergroup Study (ECOG 4494, CALGB 9793): consideration of age greater than 70 years in an elderly prognostic index (E-IPI). Br J Haematol 151 (2): 143-51, 2010.
Rosenwald A, Wright G, Chan WC, et al.: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346 (25): 1937-47, 2002.
Treatment of non-Hodgkin lymphoma (NHL) depends on the histologic type and stage. Many of the improvements in survival have been made using clinical trials (experimental therapy) that have attempted to improve on the best available accepted therapy (conventional or standard therapy).
In asymptomatic patients with indolent forms of advanced NHL, treatment may be
deferred until the patient becomes symptomatic as the disease progresses. When
treatment is deferred, the clinical course of patients with indolent NHL
varies; frequent and careful observation is required so that effective
treatment can be initiated when the clinical course of the disease accelerates.
Some patients have a prolonged indolent course, but others have disease that
rapidly evolves into more aggressive types of NHL that require immediate
Radiation techniques differ somewhat from those used in the treatment of
Hodgkin lymphoma. The dose of radiation therapy usually varies from 25 Gy to
50 Gy and is dependent on factors that include the histologic type of
lymphoma, the patient's stage and overall condition, the goal of treatment
(curative or palliative), the proximity of sensitive surrounding organs, and
whether the patient is being treated with radiation therapy alone or in
combination with chemotherapy. Given the patterns of
disease presentations and relapse, treatment may need to include unusual sites
such as Waldeyer ring, epitrochlear, or mesenteric nodes. The
associated morbidity of the treatment must be considered carefully. The
majority of patients who receive radiation are usually treated on only one side
of the diaphragm. Localized presentations of extranodal NHL may be treated
with involved-field techniques with significant (>50%) success.
Standard Treatment Options
Indolent, Stage I and Contiguous Stage II Adult NHL
Radiation therapy
Rituximab with or without chemotherapy
Watchful waiting
Other therapies as designated for patients with advanced-stage disease
Indolent, Noncontiguous Stage II/III/IV Adult NHL
Watchful waiting for asymptomatic patients
Purine nucleoside analogs
Alkylating agents (with or without steroids)
Combination chemotherapy
Yttrium-90 labeled ibritumomab tiuxetan and iodine-131-labeled tositumomab
Maintenance rituximab
Indolent, Recurrent Adult NHL
Chemotherapy (single agent or combination)
Radiolabeled anti-CD20 monoclonal antibodies
Palliative radiation therapy
Aggressive, Stage I and Contiguous Stage II Adult NHL
R-CHOP with or without IF-XRT
Aggressive, Noncontiguous Stage II/III/IV Adult NHL
Other combination chemotherapy
Adult Lymphoblastic Lymphoma
Intensive therapy
Diffuse, Small, Noncleaved-Cell/Burkitt Lymphoma
Aggressive multidrug regimens
Central nervous system (CNS) prophylaxis
Aggressive, Recurrent Adult NHL
Bone marrow or stem cell transplantation
Re-treatment with standard agents
CNS = central nervous system; CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone; IF-XRT = involved-field radiation therapy; NHL = non-Hodgkin lymphoma; R-CHOP = rituximab, an anti-CD20 monoclonal antibody, cyclophosphamide, doxorubicin, vincristine, and prednisone.
Even though standard treatment in patients with lymphomas can cure a significant fraction, numerous clinical trials that explore improvements in treatment are in progress. If possible, patients should be included in these studies. Standardized guidelines for response assessment have been suggested for use in clinical trials.[1]
Aggressive lymphomas are increasingly seen in human immunodeficiency virus (HIV)-positive patients; treatment
of these patients requires special consideration. (Refer to the PDQ summary on
AIDS-Related Lymphoma Treatment for more information.)
In addition to screening for HIV among patients with aggressive lymphomas, active hepatitis B or hepatitis C should be assessed prior to treatment with rituximab and/or chemotherapy.[2][3] Even patients with undetectable hepatitis B viral loads after remote past infection benefit from prophylaxis with entecavir in the context of rituximab therapy.[4] Similarly, prophylaxis for herpes zoster with acyclovir or valcyclovir and prophylaxis for pneumocystis with trimethoprim/sulfamethoxazole or dapsone are usually applied with rituximab with or without combination chemotherapy.
Several unusual presentations of lymphoma occur that often require somewhat modified approaches to staging and therapy. The reader is referred to reviews for a more detailed description of extranodal presentations in the gastrointestinal system,[5][6][7][8][9][10][11][12][13] thyroid,[14][15] spleen,[16] testis,[17][18][19] paranasal sinuses,[20][21][22][23] bone,[24][25] orbit,[26][27][28][29][30] and skin.[31][32][33][34][35][36][37][38][39][40]
(Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information.)
Cheson BD, Horning SJ, Coiffier B, et al.: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17 (4): 1244, 1999.
Niitsu N, Hagiwara Y, Tanae K, et al.: Prospective analysis of hepatitis B virus reactivation in patients with diffuse large B-cell lymphoma after rituximab combination chemotherapy. J Clin Oncol 28 (34): 5097-100, 2010.
Dong HJ, Ni LN, Sheng GF, et al.: Risk of hepatitis B virus (HBV) reactivation in non-Hodgkin lymphoma patients receiving rituximab-chemotherapy: a meta-analysis. J Clin Virol 57 (3): 209-14, 2013.
Huang YH, Hsiao LT, Hong YC, et al.: Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol 31 (22): 2765-72, 2013.
Maor MH, Velasquez WS, Fuller LM, et al.: Stomach conservation in stages IE and IIE gastric non-Hodgkin's lymphoma. J Clin Oncol 8 (2): 266-71, 1990.
Salles G, Herbrecht R, Tilly H, et al.: Aggressive primary gastrointestinal lymphomas: review of 91 patients treated with the LNH-84 regimen. A study of the Groupe d'Etude des Lymphomes Agressifs. Am J Med 90 (1): 77-84, 1991.
Taal BG, Burgers JM, van Heerde P, et al.: The clinical spectrum and treatment of primary non-Hodgkin's lymphoma of the stomach. Ann Oncol 4 (10): 839-46, 1993.
Tondini C, Giardini R, Bozzetti F, et al.: Combined modality treatment for primary gastrointestinal non-Hodgkin's lymphoma: the Milan Cancer Institute experience. Ann Oncol 4 (10): 831-7, 1993.
d'Amore F, Brincker H, Grønbaek K, et al.: Non-Hodgkin's lymphoma of the gastrointestinal tract: a population-based analysis of incidence, geographic distribution, clinicopathologic presentation features, and prognosis. Danish Lymphoma Study Group. J Clin Oncol 12 (8): 1673-84, 1994.
Haim N, Leviov M, Ben-Arieh Y, et al.: Intermediate and high-grade gastric non-Hodgkin's lymphoma: a prospective study of non-surgical treatment with primary chemotherapy, with or without radiotherapy. Leuk Lymphoma 17 (3-4): 321-6, 1995.
Koch P, del Valle F, Berdel WE, et al.: Primary gastrointestinal non-Hodgkin's lymphoma: I. Anatomic and histologic distribution, clinical features, and survival data of 371 patients registered in the German Multicenter Study GIT NHL 01/92. J Clin Oncol 19 (18): 3861-73, 2001.
Koch P, del Valle F, Berdel WE, et al.: Primary gastrointestinal non-Hodgkin's lymphoma: II. Combined surgical and conservative or conservative management only in localized gastric lymphoma--results of the prospective German Multicenter Study GIT NHL 01/92. J Clin Oncol 19 (18): 3874-83, 2001.
Koch P, Probst A, Berdel WE, et al.: Treatment results in localized primary gastric lymphoma: data of patients registered within the German multicenter study (GIT NHL 02/96). J Clin Oncol 23 (28): 7050-9, 2005.
Blair TJ, Evans RG, Buskirk SJ, et al.: Radiotherapeutic management of primary thyroid lymphoma. Int J Radiat Oncol Biol Phys 11 (2): 365-70, 1985.
Junor EJ, Paul J, Reed NS: Primary non-Hodgkin's lymphoma of the thyroid. Eur J Surg Oncol 18 (4): 313-21, 1992.
Morel P, Dupriez B, Gosselin B, et al.: Role of early splenectomy in malignant lymphomas with prominent splenic involvement (primary lymphomas of the spleen). A study of 59 cases. Cancer 71 (1): 207-15, 1993.
Zucca E, Conconi A, Mughal TI, et al.: Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the International Extranodal Lymphoma Study Group. J Clin Oncol 21 (1): 20-7, 2003.
Vitolo U, Chiappella A, Ferreri AJ, et al.: First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial. J Clin Oncol 29 (20): 2766-72, 2011.
Cheah CY, Wirth A, Seymour JF: Primary testicular lymphoma. Blood 123 (4): 486-93, 2014.
Sasai K, Yamabe H, Kokubo M, et al.: Head-and-neck stages I and II extranodal non-Hodgkin's lymphomas: real classification and selection for treatment modality. Int J Radiat Oncol Biol Phys 48 (1): 153-60, 2000.
Ferreri AJ, Reni M, Ceresoli GL, et al.: Therapeutic management with adriamycin-containing chemotherapy and radiotherapy of monostotic and polyostotic primary non-Hodgkin's lymphoma of bone in adults. Cancer Invest 16 (8): 554-61, 1998.
Dubey P, Ha CS, Besa PC, et al.: Localized primary malignant lymphoma of bone. Int J Radiat Oncol Biol Phys 37 (5): 1087-93, 1997.
Martinet S, Ozsahin M, Belkacémi Y, et al.: Outcome and prognostic factors in orbital lymphoma: a Rare Cancer Network study on 90 consecutive patients treated with radiotherapy. Int J Radiat Oncol Biol Phys 55 (4): 892-8, 2003.
Sjö LD, Ralfkiaer E, Juhl BR, et al.: Primary lymphoma of the lacrimal sac: an EORTC ophthalmic oncology task force study. Br J Ophthalmol 90 (8): 1004-9, 2006.
Sjö LD: Ophthalmic lymphoma: epidemiology and pathogenesis. Acta Ophthalmol 87 Thesis 1: 1-20, 2009.
Geelen FA, Vermeer MH, Meijer CJ, et al.: bcl-2 protein expression in primary cutaneous large B-cell lymphoma is site-related. J Clin Oncol 16 (6): 2080-5, 1998.
Pandolfino TL, Siegel RS, Kuzel TM, et al.: Primary cutaneous B-cell lymphoma: review and current concepts. J Clin Oncol 18 (10): 2152-68, 2000.
Sarris AH, Braunschweig I, Medeiros LJ, et al.: Primary cutaneous non-Hodgkin's lymphoma of Ann Arbor stage I: preferential cutaneous relapses but high cure rate with doxorubicin-based therapy. J Clin Oncol 19 (2): 398-405, 2001.
Grange F, Bekkenk MW, Wechsler J, et al.: Prognostic factors in primary cutaneous large B-cell lymphomas: a European multicenter study. J Clin Oncol 19 (16): 3602-10, 2001.
Mirza I, Macpherson N, Paproski S, et al.: Primary cutaneous follicular lymphoma: an assessment of clinical, histopathologic, immunophenotypic, and molecular features. J Clin Oncol 20 (3): 647-55, 2002.
Smith BD, Glusac EJ, McNiff JM, et al.: Primary cutaneous B-cell lymphoma treated with radiotherapy: a comparison of the European Organization for Research and Treatment of Cancer and the WHO classification systems. J Clin Oncol 22 (4): 634-9, 2004.
Willemze R, Jaffe ES, Burg G, et al.: WHO-EORTC classification for cutaneous lymphomas. Blood 105 (10): 3768-85, 2005.
El-Helw L, Goodwin S, Slater D, et al.: Primary B-cell lymphoma of the skin: the Sheffield Lymphoma Group Experience (1984-2003). Int J Oncol 25 (5): 1453-8, 2004.
Zinzani PL, Quaglino P, Pimpinelli N, et al.: Prognostic factors in primary cutaneous B-cell lymphoma: the Italian Study Group for Cutaneous Lymphomas. J Clin Oncol 24 (9): 1376-82, 2006.
Senff NJ, Noordijk EM, Kim YH, et al.: European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas. Blood 112 (5): 1600-9, 2008.
Although localized presentations are uncommon in non-Hodgkin lymphoma (NHL), the goal of treatment should be to cure the disease in patients who are shown to have truly localized occurrence after undergoing appropriate staging procedures.
Standard treatment options for indolent, stage I and contiguous stage II adult NHL include the following:
The National Lymphocare Study identified 471 patients with stage I follicular lymphoma. Of those patients, 206 were rigorously staged with a bone marrow aspirate and biopsy, and computed tomography (CT) scans or positive-emission tomography (PET-CT) scans.[1] Nonrandomized treatments included radiation therapy (27%), rituximab-chemotherapy (R-chemotherapy) (28%), watchful waiting (17%), R-chemotherapy plus radiation therapy (13%), and rituximab alone (12%), although more than one-third of the patients started with expectant therapy. With a median follow-up of 57 months, progression-free survival favored R-chemotherapy or R-chemotherapy plus radiation therapy, but overall survival was nearly identical, all over 90%.[1][Level of evidence: 3iiiD] Clinical trials are required to answer questions such as:[2]
Long-term disease control within radiation fields can be achieved in a significant number of patients with indolent stage I or stage II NHL by using dosages of radiation that usually range from 25 Gy to 40 Gy to involved sites or to extended fields that cover adjacent nodal sites.[3][4][5][6][7] Almost half of all patients treated with radiation therapy alone will relapse out-of-field within 10 years.[8]
For symptomatic patients who require therapy, when radiation therapy is contraindicated or when an alternative treatment is preferred, rituximab with or without chemotherapy can be employed (as outlined below for more advanced-stage patients). The value of adjuvant treatment with radiation to decrease relapse, plus rituximab (an anti-CD20 monoclonal antibody) either alone or in combination with chemotherapy, has been extrapolated from trials of patients with advanced-stage disease and has not been confirmed.[9][10]
Watchful waiting can be considered for asymptomatic patients.[11] Watchful waiting has never been compared with upfront radiation therapy in a prospective, randomized trial; a retrospective analysis of the Surveillance, Epidemiology and End Results Program (SEER) database over 30 years showed improved outcomes for upfront radiation therapy.[12]
Patients with involvement not encompassable by radiation therapy are treated as outlined for patients with stage III or stage IV low-grade lymphoma.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with indolent, stage I adult non-Hodgkin lymphoma and indolent, contiguous stage II adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Friedberg JW, Byrtek M, Link BK, et al.: Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study. J Clin Oncol 30 (27): 3368-75, 2012.
Montoto S: Management of localized-stage follicular lymphoma: changing the paradigm? J Clin Oncol 30 (27): 3328-9, 2012.
Mac Manus MP, Hoppe RT: Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol 14 (4): 1282-90, 1996.
Vaughan Hudson B, Vaughan Hudson G, MacLennan KA, et al.: Clinical stage 1 non-Hodgkin's lymphoma: long-term follow-up of patients treated by the British National Lymphoma Investigation with radiotherapy alone as initial therapy. Br J Cancer 69 (6): 1088-93, 1994.
Denham JW, Denham E, Dear KB, et al.: The follicular non-Hodgkin's lymphomas--I. The possibility of cure. Eur J Cancer 32A (3): 470-9, 1996.
Haas RL, Poortmans P, de Jong D, et al.: High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas. J Clin Oncol 21 (13): 2474-80, 2003.
Guckenberger M, Alexandrow N, Flentje M: Radiotherapy alone for stage I-III low grade follicular lymphoma: long-term outcome and comparison of extended field and total nodal irradiation. Radiat Oncol 7: 103, 2012.
Guadagnolo BA, Li S, Neuberg D, et al.: Long-term outcome and mortality trends in early-stage, Grade 1-2 follicular lymphoma treated with radiation therapy. Int J Radiat Oncol Biol Phys 64 (3): 928-34, 2006.
Kelsey SM, Newland AC, Hudson GV, et al.: A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade, localised non-Hodgkins lymphoma. Med Oncol 11 (1): 19-25, 1994.
Seymour JF, Pro B, Fuller LM, et al.: Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent non-Hodgkin's lymphoma. J Clin Oncol 21 (11): 2115-22, 2003.
Advani R, Rosenberg SA, Horning SJ: Stage I and II follicular non-Hodgkin's lymphoma: long-term follow-up of no initial therapy. J Clin Oncol 22 (8): 1454-9, 2004.
Pugh TJ, Ballonoff A, Newman F, et al.: Improved survival in patients with early stage low-grade follicular lymphoma treated with radiation: a Surveillance, Epidemiology, and End Results database analysis. Cancer 116 (16): 3843-51, 2010.
Optimal treatment of advanced stages of low-grade non-Hodgkin lymphoma (NHL) is controversial because of low cure rates with the current therapeutic options. Numerous clinical trials are in progress to settle treatment issues, and patients should be urged to participate. The rate of relapse is fairly constant over time, even in patients who have achieved complete response to treatment. Indeed, relapse may occur many years after treatment. Currently, no randomized trials guide clinicians about the initial choice of watchful waiting, rituximab, nucleoside analogs, alkylating agents, combination chemotherapy, radiolabeled monoclonal antibodies, or combinations of these options.[1]; [2][Level of evidence: 1iiDiii]
For patients with indolent, noncontiguous stage II and stage III non-Hodgkin lymphoma, central lymphatic radiation therapy has been proposed but is not usually recommended as a form of treatment.[3][4]
Numerous prospective clinical trials of interferon-alpha, including SWOG-8809, have shown no consistent benefit; the role of interferon in patients with indolent lymphoma remains controversial.[5][6][7][8][9][10][11][12][13][14][15][16]
Standard treatment options for indolent, noncontiguous stage II/III/IV adult NHL include the following:
The rate of relapse is fairly constant over time, even in patients who have achieved complete responses to treatment. Indeed, relapse may occur many years after treatment. In this category, deferred treatment (i.e., watchful waiting until the patient becomes symptomatic before initiating treatment) should be considered.[2][17][18][19]
Evidence (watchful waiting):
Rituximab may be considered as first-line therapy, either alone or in combination with other agents.
Standard therapy includes rituximab, an anti-CD20 monoclonal antibody, either alone or in combination with purine nucleoside analogs such as fludarabine or 2-chlorodeoxyadenosine, alkylating agents (with or without steroids), or combination chemotherapy.
A prospective, randomized trial of 534 patients with previously untreated, advanced-stage follicular lymphoma compared R-CHOP, R-FM, and R-CVP. With a median follow-up of 34 months, there was no difference in OS, but the 3-year PFS favored R-CHOP (68%) and R-FM (63%) over R-CVP (52%) (P for the three regimens = .011).[39][Level of evidence: 1iiDiii]
Evidence (rituximab):
Obinutuzumab is an alternative CD20-binding monoclonal antibody with alternative epitope binding and is being studied in patients with recurrent follicular lymphoma. This agent has shown responses in 20% to 30% of patients when used alone and in 80% of patients when combined with CHOP or FC (fludarabine and cyclophosphamide) in relapsed follicular lymphoma patients.[45][46][Level of evidence: 3iiiDiv]
Evidence (bendamustine):
Yttrium-90-labeled ibritumomab tiuxetan and iodine-131–labeled tositumomab are available for previously untreated and relapsing patients with minimal (<25%) or no marrow involvement with lymphoma.[59][60][61] In a randomized, prospective trial, 554 patients with previously untreated advanced-stage follicular lymphoma received either R-CHOP times six cycles or CHOP times six cycles followed by I-131 tositumomab radioimmunotherapy (RIT); with a median follow-up of 4.9 years, there was no significant difference between the PFS and OS (2-year OS, R-CHOP, 97%; CHOP-RIT, 93%; P = .08).[62][Level of evidence: 1iiD] Because a significant prolongation of PFS was seen for R-CHOP followed by rituximab maintenance compared with R-CHOP alone,[63] this lack of benefit for CHOP-RIT was particularly disappointing. Iodine-131–labeled tositumomab became commercially unavailable in 2013.
In a randomized trial of 409 patients with stage III or IV follicular lymphoma who achieved a complete or partial response, yttrium-90 ibritumomab tiuxetan consolidation versus no consolidation was evaluated. The radiolabelled antibody consolidation improved median PFS by 3 years (P < .001), and median time to next treatment was improved by 5.1 years (P < .001); however, there was no change in OS.[64][Level of evidence: 1iiDiii]
Evidence (maintenance rituximab):
Many questions remain about rituximab maintenance, particularly about truncating therapy at 2 years and long-term safety and efficacy. The most salient question is whether a strategy of observation after induction with rituximab therapy at time of symptomatic progression is equivalent or superior to mandated rituximab maintenance.[68]
Since none of the standard therapies listed above are curative for advanced-stage disease, innovative approaches are under clinical evaluation. The approaches include intensive therapy with chemotherapy and total-body irradiation (TBI) followed by autologous or allogeneic bone marrow transplantation (BMT) or peripheral stem cell transplantation (PSCT), and the use of idiotype vaccines and radiolabeled monoclonal antibodies.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with indolent, noncontiguous stage II adult non-Hodgkin lymphoma, indolent, stage III adult non-Hodgkin lymphoma and indolent, stage IV adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Hagenbeek A, Eghbali H, Monfardini S, et al.: Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage III and IV low-grade malignant Non-Hodgkin's lymphoma. J Clin Oncol 24 (10): 1590-6, 2006.
Gribben JG: How I treat indolent lymphoma. Blood 109 (11): 4617-26, 2007.
Jacobs JP, Murray KJ, Schultz CJ, et al.: Central lymphatic irradiation for stage III nodular malignant lymphoma: long-term results. J Clin Oncol 11 (2): 233-8, 1993.
Mendenhall NP, Million RR: Comprehensive lymphatic irradiation for stage II-III non-Hodgkin's lymphoma. Am J Clin Oncol 12 (3): 190-4, 1989.
Smalley RV, Andersen JW, Hawkins MJ, et al.: Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin's lymphoma. N Engl J Med 327 (19): 1336-41, 1992.
Solal-Céligny P, Lepage E, Brousse N, et al.: Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: final analysis of survival and toxicity in the Groupe d'Etude des Lymphomes Folliculaires 86 Trial. J Clin Oncol 16 (7): 2332-8, 1998.
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Fisher RI, Dana BW, LeBlanc M, et al.: Interferon alpha consolidation after intensive chemotherapy does not prolong the progression-free survival of patients with low-grade non-Hodgkin's lymphoma: results of the Southwest Oncology Group randomized phase III study 8809. J Clin Oncol 18 (10): 2010-6, 2000.
Cole BF, Solal-Céligny P, Gelber RD, et al.: Quality-of-life-adjusted survival analysis of interferon alfa-2b treatment for advanced follicular lymphoma: an aid to clinical decision making. J Clin Oncol 16 (7): 2339-44, 1998.
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Hainsworth JD, Litchy S, Morrissey LH, et al.: Rituximab plus short-duration chemotherapy as first-line treatment for follicular non-Hodgkin's lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23 (7): 1500-6, 2005.
Hiddemann W, Kneba M, Dreyling M, et al.: Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106 (12): 3725-32, 2005.
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Press OW, Unger JM, Rimsza LM, et al.: Phase III randomized intergroup trial of CHOP plus rituximab compared with CHOP chemotherapy plus (131)iodine-tositumomab for previously untreated follicular non-Hodgkin lymphoma: SWOG S0016. J Clin Oncol 31 (3): 314-20, 2013.
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Sebban C, Mounier N, Brousse N, et al.: Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 108 (8): 2540-4, 2006.
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Ha CS, Kong JS, Tucker SL, et al.: Central lymphatic irradiation for stage I-III follicular lymphoma: report from a single-institutional prospective study. Int J Radiat Oncol Biol Phys 57 (2): 316-20, 2003.
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Rossier C, Schick U, Miralbell R, et al.: Low-dose radiotherapy in indolent lymphoma. Int J Radiat Oncol Biol Phys 81 (3): e1-6, 2011.
In general, treatment with standard agents rarely produces a cure in patients whose disease has relapsed. Sustained remissions after relapse can often be obtained in patients with indolent lymphomas, but relapse will usually ensue. Favorable survival after relapse has been associated with an age younger than 60 years, complete remission rather than partial remission, and duration of response longer than 1 year. Even the most favorable subset, however, has a tenfold greater mortality compared with age-adjusted U.S. population rates.[1] Patients who experience a relapse with indolent lymphoma can often have their disease controlled with single agent or combination chemotherapy, rituximab (an anti-CD20 monoclonal antibody), lenalidomide, radiolabeled anti-CD20 monoclonal antibodies, or palliative radiation therapy.[2][3] Long-term freedom from second relapse, however, is uncommon and multiple relapses will usually occur. Patients with indolent lymphoma may experience a relapse with a more aggressive histology. If the clinical pattern of relapse suggests that the disease is behaving in a more aggressive manner, a biopsy should be performed. Documentation of conversion to a more aggressive histology requires an appropriate change to therapy applicable to that histologic type.[4] Rapid growth or discordant growth between various disease sites may indicate a histologic conversion.
In a retrospective review of 325 patients between 1972 and 1999, the risk of histologic transformation was 30% by 10 years from diagnosis.[5] In this series, high risk factors for subsequent histologic transformation were advanced stage, high-risk Follicular Lymphoma International Prognostic Index, and expectant management. The median survival after transformation was 1 to 2 years, with 25% of patients alive at 5 years and with approximately 10% to 20% of patients alive 10 years after re-treatment.[6]
A prospective trial of 631 patients with follicular lymphoma and with a median follow-up of 60 months in the rituximab era (2002–2009) found a 5-year transformation rate (11%) to a higher-grade histology.[7] The median overall survival (OS) after transformation was 50 months, and the 5-year OS rate was 66%, if the transformation occurred more than 18 months after a diagnosis of follicular lymphoma. This series describes a better prognosis for patients with transformation than was experienced by patients in the prerituximab era.
(Refer to the Treatment for Aggressive, Recurrent Adult NHL section of this summary for descriptions of the regimens used to treat histologic conversions.) The durability of the second remission may be short, and clinical trials should be considered.
Standard treatment options for indolent, recurrent adult NHL include the following:
Significant activity for fludarabine and 2-chlorodeoxyadenosine has been demonstrated in relapsed low-grade lymphomas, both as single agents and in combination with other drugs.[8][9][10][11][12][13] Patients may respond to the original induction regimen again, especially if the duration of remission exceeds one year. For relapsing patients, rituximab alone or in combination with agents not previously used may induce remissions.
Rituximab results in a 40% to 50% response rate in patients who relapse with indolent B-cell lymphomas.[14][15][16][17] Rituximab can also be combined with combination chemotherapy.[18]
Responses of 20% to 30% have been reported for lenalidomide, especially for follicular lymphoma and small lymphocytic lymphoma.[22][Level of evidence: 3iiiDiv]
Durable responses to radiolabeled monoclonal antibodies, such as yttrium-90 ibritumomab (commercially available) and iodine-131 tositumomab, have also been reported before and after cytotoxic chemotherapy.[23][24][25][26][27][28][Level of evidence: 1iiDiii]
A prospective trial of 409 patients with follicular lymphoma who responded to induction chemotherapy were randomly assigned to yttrium-90 ibritumomab or no further consolidation; with a median follow-up of 7.3 years, the 8-year PFS favored ibritumomab (41% vs. 22% [HR, 0.47; P < .001), but there was no difference in OS.[29][Level of evidence: 1iiDiii]
Palliation may be achieved with very low-dose (4 Gy) involved-field radiation therapy for patients with indolent and aggressive relapsed disease.[30]
Treatment options under clinical evaluation include the following:
Evidence (stem cell transplant):
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with indolent, recurrent adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Weisdorf DJ, Andersen JW, Glick JH, et al.: Survival after relapse of low-grade non-Hodgkin's lymphoma: implications for marrow transplantation. J Clin Oncol 10 (6): 942-7, 1992.
Link BK, Maurer MJ, Nowakowski GS, et al.: Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: a report from the University of Iowa/MayoClinic Specialized Program of Research Excellence Molecular Epidemiology Resource. J Clin Oncol 31 (26): 3272-8, 2013.
Hochster HS, Kim KM, Green MD, et al.: Activity of fludarabine in previously treated non-Hodgkin's low-grade lymphoma: results of an Eastern Cooperative Oncology Group study. J Clin Oncol 10 (1): 28-32, 1992.
Kay AC, Saven A, Carrera CJ, et al.: 2-Chlorodeoxyadenosine treatment of low-grade lymphomas. J Clin Oncol 10 (3): 371-7, 1992.
Redman JR, Cabanillas F, Velasquez WS, et al.: Phase II trial of fludarabine phosphate in lymphoma: an effective new agent in low-grade lymphoma. J Clin Oncol 10 (5): 790-4, 1992.
Tulpule A, Schiller G, Harvey-Buchanan LA, et al.: Cladribine in the treatment of advanced relapsed or refractory low and intermediate grade non-Hodgkin's lymphoma. Cancer 83 (11): 2370-6, 1998.
Klasa RJ, Meyer RM, Shustik C, et al.: Randomized phase III study of fludarabine phosphate versus cyclophosphamide, vincristine, and prednisone in patients with recurrent low-grade non-Hodgkin's lymphoma previously treated with an alkylating agent or alkylator-containing regimen. J Clin Oncol 20 (24): 4649-54, 2002.
Davis TA, White CA, Grillo-López AJ, et al.: Single-agent monoclonal antibody efficacy in bulky non-Hodgkin's lymphoma: results of a phase II trial of rituximab. J Clin Oncol 17 (6): 1851-7, 1999.
Piro LD, White CA, Grillo-López AJ, et al.: Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol 10 (6): 655-61, 1999.
Davis TA, Grillo-López AJ, White CA, et al.: Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment. J Clin Oncol 18 (17): 3135-43, 2000.
van Oers MH, Van Glabbeke M, Giurgea L, et al.: Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 28 (17): 2853-8, 2010.
van Oers MH, Klasa R, Marcus RE, et al.: Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 108 (10): 3295-301, 2006.
Martinelli G, Schmitz SF, Utiger U, et al.: Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol 28 (29): 4480-4, 2010.
Witzig TE, Wiernik PH, Moore T, et al.: Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma. J Clin Oncol 27 (32): 5404-9, 2009.
Witzig TE, Gordon LI, Cabanillas F, et al.: Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 20 (10): 2453-63, 2002.
Witzig TE, Flinn IW, Gordon LI, et al.: Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. J Clin Oncol 20 (15): 3262-9, 2002.
Ansell SM, Ristow KM, Habermann TM, et al.: Subsequent chemotherapy regimens are well tolerated after radioimmunotherapy with yttrium-90 ibritumomab tiuxetan for non-Hodgkin's lymphoma. J Clin Oncol 20 (18): 3885-90, 2002.
Davies AJ, Rohatiner AZ, Howell S, et al.: Tositumomab and iodine I 131 tositumomab for recurrent indolent and transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 22 (8): 1469-79, 2004.
Fisher RI, Kaminski MS, Wahl RL, et al.: Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas. J Clin Oncol 23 (30): 7565-73, 2005.
Leahy MF, Seymour JF, Hicks RJ, et al.: Multicenter phase II clinical study of iodine-131-rituximab radioimmunotherapy in relapsed or refractory indolent non-Hodgkin's lymphoma. J Clin Oncol 24 (27): 4418-25, 2006.
Haas RL, Poortmans P, de Jong D, et al.: Effective palliation by low dose local radiotherapy for recurrent and/or chemotherapy refractory non-follicular lymphoma patients. Eur J Cancer 41 (12): 1724-30, 2005.
Freedman A, Friedberg JW, Gribben J: High-dose therapy for follicular lymphoma. Oncology (Huntingt) 14 (3): 321-6, 329; discussion 330-2, 338, 2000.
Brice P, Simon D, Bouabdallah R, et al.: High-dose therapy with autologous stem-cell transplantation (ASCT) after first progression prolonged survival of follicular lymphoma patients included in the prospective GELF 86 protocol. Ann Oncol 11 (12): 1585-90, 2000.
Khouri IF, McLaughlin P, Saliba RM, et al.: Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood 111 (12): 5530-6, 2008.
Sebban C, Brice P, Delarue R, et al.: Impact of rituximab and/or high-dose therapy with autotransplant at time of relapse in patients with follicular lymphoma: a GELA study. J Clin Oncol 26 (21): 3614-20, 2008.
Thomson KJ, Morris EC, Milligan D, et al.: T-cell-depleted reduced-intensity transplantation followed by donor leukocyte infusions to promote graft-versus-lymphoma activity results in excellent long-term survival in patients with multiply relapsed follicular lymphoma. J Clin Oncol 28 (23): 3695-700, 2010.
Patients with stage I or contiguous stage II diffuse large B-cell lymphoma are candidates for combination chemotherapy with or without involved-field radiation therapy (IF-XRT).
The following drug combinations are referred to in this section:
Standard treatment options for aggressive, stage I and contiguous stage II adult NHL include the following:
Four prospective randomized trials have evaluated the comparison of CHOP or more intensive CHOP-based chemotherapy alone versus combined–modality therapy with CHOP and IF-XRT.[1][2][3][4][5]
Evidence (CHOP vs. CHOP with IF-XRT):
The confirmation of efficacy for rituximab in advanced-stage disease as evidenced in SWOG-S0014 (NCT00005089), for example, has suggested the use of R-CHOP with or without radiation therapy but its use is only supported by retrospective comparisons.[6][Level of evidence: 3iiiDiii]
Evidence (R-CHOP vs. CHOP):
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with aggressive, stage I adult non-Hodgkin lymphoma and aggressive, contiguous stage II adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Bonnet C, Fillet G, Mounier N, et al.: CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 25 (7): 787-92, 2007.
Miller TP, Leblanc M, Spier C, et al.: CHOP alone compared to CHOP plus radiotherapy for early stage aggressive non-Hodgkin's lymphomas: update of the Southwest Oncology Group (SWOG) randomized trial. [Abstract] Blood 98 (11): A-3024, 2001.
Horning SJ, Weller E, Kim K, et al.: Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin's lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol 22 (15): 3032-8, 2004.
Reyes F, Lepage E, Ganem G, et al.: ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 352 (12): 1197-205, 2005.
Persky DO, Unger JM, Spier CM, et al.: Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. J Clin Oncol 26 (14): 2258-63, 2008.
Pfreundschuh M, Schubert J, Ziepert M, et al.: Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 9 (2): 105-16, 2008.
Pfreundschuh M, Kuhnt E, Trümper L, et al.: CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol 12 (11): 1013-22, 2011.
Ketterer N, Coiffier B, Thieblemont C, et al.: Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol 24 (4): 1032-7, 2013.
The treatment of choice for patients with advanced stages of aggressive non-Hodgkin lymphoma (NHL) is combination chemotherapy, either alone or supplemented by local-field radiation therapy.[1]
Standard treatment options for Aggressive, Noncontiguous Stage II/III/IV Adult NHL include the following:
The following studies established R-CHOP as the standard regimen for newly diagnosed patients with DLBCL.[2] Dose intensification of R-CHOP by a 14-day versus a 21-day cycle did not result in improved outcomes.[3]
Evidence (R-CHOP):
Evidence (CHOP with or without other therapies):
As SWOG-9349 did, clinical trials continue to explore modifications of CHOP and rituximab with CHOP by increasing doses, reducing intervals between cycles, and combining new drugs with new mechanisms of action.[3][13][14][15][16][17][18] None of these trials establishes a survival advantage for reduced intervals between cycles or for increasing doses of the chemotherapy.
Doxorubicin-based combination chemotherapy produces long-term DFS in 35% to 45% of patients.[2][4][5] Higher cure rates have been reported in single-institution studies than in cooperative group trials.
Evidence (other combination chemotherapy):
A randomized clinical trial failed to demonstrate a beneficial effect of adjuvant radiation therapy in advanced-stage aggressive NHL.[22]
Four case series involving more than 100 patients with stage IE or IIE disease (with or without associated mucosa-associated lymphatic tissue) and with positive Helicobacter pylori infection reported that more than 50% of patients attained a durable complete remission after appropriate antibiotic therapy to eradicate H. pylori.[23][24][25][26][Level of evidence: 3iiiDiv]
An IPI for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS:[27]
Patients with two or more risk factors have a less than 50% chance of relapse-free survival and OS at 5 years. This study also identifies patients at high risk of relapse based on specific sites of involvement, including bone marrow, central nervous system (CNS), liver, lung, and spleen. The bcl-2 gene and rearrangement of the myc gene or dual overexpression of the myc gene, or both, confer a particularly poor prognosis.[28][29][30][31] Patients at high risk of relapse may be considered for clinical trials.[32] Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.[33][34]
Patients with bulky and extensive lymphadenopathy and elevations of serum uric acid and LDH are at increased risk of tumor lysis syndrome resulting in metabolic derangements such as hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and subsequent acute renal failure.[35] Treatment options include: alkaline hydration, allopurinol, and rasburicase, a recombinant urate oxidase.[36]
CNS prophylaxis (usually with four to six injections of methotrexate intrathecally) is recommended for patients with paranasal sinus or testicular involvement. Some clinicians are employing high-dose intravenous methotrexate (usually four doses) as an alternative to intrathecal therapy because drug delivery is improved and patient morbidity is decreased.[37] CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, and others do not.[19][38]
Patients with diffuse, small, noncleaved-cell/Burkitt's lymphoma or lymphoblastic lymphoma have a 20% to 30% lifetime risk of CNS involvement. CNS prophylaxis is recommended for these histologies.
Several randomized, prospective trials evaluated the role of autologous BMT or SCT consolidation versus chemotherapy alone in patients in first remission with diffuse large cell lymphoma.[40][41][42][43][44][45][46][47]; [48][49][Level of evidence: 1iiA] Although some of these trials demonstrated significant increases in EFS (by 10% to 20%) among patients who received high-dose therapy, significant differences in OS could not be demonstrated prospectively in any of the series.
Retrospective analyses of high-intermediate (two risk factors) or high-risk (more than three risk factors) patients as defined by IPI suggest improved survival with BMT in two of the trials.[41][47] These studies do not establish that high-dose consolidation is of value to patients with aggressive lymphoma who are truly at high risk of relapse, and they also demonstrate that EFS may be a poor surrogate for OS for these patients.[50]
After R-CHOP induction chemotherapy (or similar regimens), the addition of involved-field radiation therapy to sites of initial bulky disease (≥5–10 cm) or to extralymphatic sites remains controversial.[51][52][53] Increased risks, such as long-term toxicities (e.g., second malignancies), must be considered.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with aggressive, noncontiguous stage II adult non-Hodgkin lymphoma, aggressive, stage III adult non-Hodgkin lymphoma and aggressive, stage IV adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Cunningham D, Hawkes EA, Jack A, et al.: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 381 (9880): 1817-26, 2013.
Coiffier B, Thieblemont C, Van Den Neste E, et al.: Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 116 (12): 2040-5, 2010.
Pfreundschuh M, Trümper L, Osterborg A, et al.: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7 (5): 379-91, 2006.
Récher C, Coiffier B, Haioun C, et al.: Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet 378 (9806): 1858-67, 2011.
Bastion Y, Blay JY, Divine M, et al.: Elderly patients with aggressive non-Hodgkin's lymphoma: disease presentation, response to treatment, and survival--a Groupe d'Etude des Lymphomes de l'Adulte study on 453 patients older than 69 years. J Clin Oncol 15 (8): 2945-53, 1997.
Tirelli U, Errante D, Van Glabbeke M, et al.: CHOP is the standard regimen in patients > or = 70 years of age with intermediate-grade and high-grade non-Hodgkin's lymphoma: results of a randomized study of the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Study Group. J Clin Oncol 16 (1): 27-34, 1998.
Gaynor ER, Unger JM, Miller TP, et al.: Infusional CHOP chemotherapy (CVAD) with or without chemosensitizers offers no advantage over standard CHOP therapy in the treatment of lymphoma: a Southwest Oncology Group Study. J Clin Oncol 19 (3): 750-5, 2001.
Pfreundschuh M, Trümper L, Kloess M, et al.: Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 104 (3): 634-41, 2004.
Blayney DW, LeBlanc ML, Grogan T, et al.: Dose-intense chemotherapy every 2 weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and prednisone may improve survival in intermediate- and high-grade lymphoma: a phase II study of the Southwest Oncology Group (SWOG 9349). J Clin Oncol 21 (13): 2466-73, 2003.
Coiffier B: Increasing chemotherapy intensity in aggressive lymphomas: a renewal? J Clin Oncol 21 (13): 2457-9, 2003.
Tilly H, Lepage E, Coiffier B, et al.: Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood 102 (13): 4284-9, 2003.
Pfreundschuh M, Trümper L, Kloess M, et al.: Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood 104 (3): 626-33, 2004.
Schmitz N, Nickelsen M, Ziepert M, et al.: Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol 13 (12): 1250-9, 2012.
Delarue R, Tilly H, Mounier N, et al.: Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol 14 (6): 525-33, 2013.
Gordon LI, Harrington D, Andersen J, et al.: Comparison of a second-generation combination chemotherapeutic regimen (m-BACOD) with a standard regimen (CHOP) for advanced diffuse non-Hodgkin's lymphoma. N Engl J Med 327 (19): 1342-9, 1992.
Cooper IA, Wolf MM, Robertson TI, et al.: Randomized comparison of MACOP-B with CHOP in patients with intermediate-grade non-Hodgkin's lymphoma. The Australian and New Zealand Lymphoma Group. J Clin Oncol 12 (4): 769-78, 1994.
O'Connell MJ, Harrington DP, Earle JD, et al.: Prospectively randomized clinical trial of three intensive chemotherapy regimens for the treatment of advanced unfavorable histology non-Hodgkin's lymphoma. J Clin Oncol 5 (9): 1329-39, 1987.
Ziepert M, Hasenclever D, Kuhnt E, et al.: Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J Clin Oncol 28 (14): 2373-80, 2010.
Coiffier B, Altman A, Pui CH, et al.: Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 26 (16): 2767-78, 2008.
Cortes J, Moore JO, Maziarz RT, et al.: Control of plasma uric acid in adults at risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone--results of a multicenter phase III study. J Clin Oncol 28 (27): 4207-13, 2010.
Haioun C, Lepage E, Gisselbrecht C, et al.: Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol--a groupe d'Etude des lymphomes de l'Adulte study. J Clin Oncol 18 (16): 3025-30, 2000.
Haioun C, Lepage E, Gisselbrecht C, et al.: Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87-2. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 15 (3): 1131-7, 1997.
Santini G, Salvagno L, Leoni P, et al.: VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 16 (8): 2796-802, 1998.
Gianni AM, Bregni M, Siena S, et al.: High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 336 (18): 1290-7, 1997.
Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al.: Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study. J Natl Cancer Inst 93 (1): 22-30, 2001.
Gisselbrecht C, Lepage E, Molina T, et al.: Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 20 (10): 2472-9, 2002.
Martelli M, Gherlinzoni F, De Renzo A, et al.: Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin's lymphoma: an Italian multicenter randomized trial. J Clin Oncol 21 (7): 1255-62, 2003.
Milpied N, Deconinck E, Gaillard F, et al.: Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 350 (13): 1287-95, 2004.
Betticher DC, Martinelli G, Radford JA, et al.: Sequential high dose chemotherapy as initial treatment for aggressive sub-types of non-Hodgkin lymphoma: results of the international randomized phase III trial (MISTRAL). Ann Oncol 17 (10): 1546-52, 2006.
Stiff PJ, Unger JM, Cook JR, et al.: Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med 369 (18): 1681-90, 2013.
Shipp MA, Abeloff MD, Antman KH, et al.: International Consensus Conference on high-dose therapy with hematopoietic stem-cell transplantation in aggressive non-Hodgkin's lymphomas: report of the jury. Ann Oncol 10 (1): 13-9, 1999.
Held G, Murawski N, Ziepert M, et al.: Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol 32 (11): 1112-8, 2014.
Kahl BS: Bulky aggressive B-cell lymphoma: to radiate or not to radiate--that is the question. J Clin Oncol 32 (11): 1097-8, 2014.
Phan J, Mazloom A, Medeiros LJ, et al.: Benefit of consolidative radiation therapy in patients with diffuse large B-cell lymphoma treated with R-CHOP chemotherapy. J Clin Oncol 28 (27): 4170-6, 2010.
Lymphoblastic lymphoma is a very aggressive form of non-Hodgkin lymphoma (NHL), which often occurs in young patients, but not exclusively. Lymphoblastic lymphoma is commonly associated with large mediastinal masses and has a high predilection for disseminating to bone marrow and the central nervous system (CNS). The treatment paradigms are based on trials for acute lymphoblastic leukemia (ALL) since lymphoblastic lymphoma and ALL are considered different manifestations of the same biologic disease. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)
Treatment is usually patterned after ALL. Intensive combination chemotherapy with CNS prophylaxis is the standard treatment of this aggressive histologic type of NHL. Radiation therapy is sometimes given to areas of bulky tumor masses. Since these forms of NHL tend to progress quickly, combination chemotherapy is instituted rapidly once the diagnosis has been confirmed.
The most important aspects of the pretreatment staging workup include careful review of the following pathological specimens:
Standard Treatment Options for Adult Lymphoblastic Lymphoma include the following:
(Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)
Standard treatment is intensive combination chemotherapy with CNS prophylaxis.
Radiation therapy is sometimes given to areas of bulky tumor masses.
New treatment approaches are being developed by the national cooperative groups. Other approaches include the use of bone marrow transplantation for consolidation. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult lymphoblastic lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Diffuse, small, noncleaved-cell/Burkitt lymphoma typically involves younger patients and represents the most common type of pediatric NHL.[1]
Standard treatment options for diffuse, small, noncleaved-cell/Burkitt lymphoma include the following:
Standard treatment for diffuse, small, noncleaved-cell/Burkitt lymphoma is usually with aggressive multidrug regimens similar to those used for the advanced-stage aggressive lymphomas (such as diffuse large cell).[2][3][4] In some institutions, treatment includes the use of consolidative bone marrow transplantation.[5][6] Adverse prognostic factors include bulky abdominal disease and high serum lactate dehydrogenase.
Evidence (aggressive multidrug regimens):
Patients with diffuse, small, noncleaved-cell/Burkitt lymphoma have a 20% to 30% lifetime risk of CNS involvement. CNS prophylaxis with methotrexate is recommended for all patients, usually given as four to six intrathecal injections.[13] (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information).
Evidence (CNS prophylaxis):
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult Burkitt lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Magrath IT, Haddy TB, Adde MA: Treatment of patients with high grade non-Hodgkin's lymphomas and central nervous system involvement: is radiation an essential component of therapy? Leuk Lymphoma 21 (1-2): 99-105, 1996.
Standard treatment options for aggressive, recurrent adult non-Hodgkin lymphoma (NHL) include the following:
Bone marrow transplantation (BMT) is the treatment of choice for patients whose lymphoma has relapsed.[1] Preliminary studies indicate that approximately 20% to 40% of patients will have a long-term disease-free status, but the precise percentage depends on patient selection and the specific treatment used. Preparative drug regimens have varied; some investigators also use total-body irradiation. Similar success has been achieved using autologous marrow, with or without marrow purging, and allogeneic marrow.[2][3][4][5][6]
Evidence (BMT):
In general, patients who responded to initial therapy and who responded to conventional therapy for relapse prior to the BMT have had the best results.[8]
Peripheral stem cell transplantation (SCT) has yielded results equivalent to standard autologous transplantation.[10][11] Even patients who never experienced complete remission with conventional chemotherapy may have prolonged progression-free survival (31% at 5 years) after high-dose chemotherapy and hematopoietic SCT if they retain chemosensitivity to reinduction therapy.[12][Level of evidence: 3iiiDiii] Some patients who relapse after a previous autologous transplantation can have durable remissions after myeloablative or nonmyeloablative allogeneic SCT.[13][14]; [15][Level of evidence: 3iiiDiv]
Evidence (peripheral SCT):
In general, re-treatment with standard agents rarely produces a cure in patients whose lymphomas relapse.[17] Several salvage chemotherapy regimens are available.[18][19][20]
Durable responses to radiolabeled monoclonal antibodies have been reported for transformed low-grade B-cell lymphoma.[23][24] Not infrequently, an aggressive lymphoma may relapse as a small cell (indolent) lymphoma. Such a situation occurs with indolent lymphoma in the bone marrow and aggressive lymphoma in a nodal site. Patients may present in such a manner, and chemotherapy might successfully eradicate the peripheral disease while failing to eliminate the small cell component from the bone marrow. The clinical significance and natural history of this pattern of disease is not well defined.
In general, patients with aggressive lymphoma who relapse with indolent histology will benefit from palliative therapy.[29] Palliation may be achieved with very low-dose (4 Gy) IF-XRT for patients with indolent and aggressive relapsed disease.[30]
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with aggressive, recurrent adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Phillips GL, Fay JW, Herzig RH, et al.: The treatment of progressive non-Hodgkin's lymphoma with intensive chemoradiotherapy and autologous marrow transplantation. Blood 75 (4): 831-8, 1990.
Chopra R, Goldstone AH, Pearce R, et al.: Autologous versus allogeneic bone marrow transplantation for non-Hodgkin's lymphoma: a case-controlled analysis of the European Bone Marrow Transplant Group Registry data. J Clin Oncol 10 (11): 1690-5, 1992.
Ratanatharathorn V, Uberti J, Karanes C, et al.: Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma. Blood 84 (4): 1050-5, 1994.
Mills W, Chopra R, McMillan A, et al.: BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma. J Clin Oncol 13 (3): 588-95, 1995.
Philip T, Guglielmi C, Hagenbeek A, et al.: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 333 (23): 1540-5, 1995.
Vellenga E, van Putten WL, van 't Veer MB, et al.: Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood 111 (2): 537-43, 2008.
Guglielmi C, Gomez F, Philip T, et al.: Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial. J Clin Oncol 16 (10): 3264-9, 1998.
Vose JM, Anderson JR, Kessinger A, et al.: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma. J Clin Oncol 11 (10): 1846-51, 1993.
Liberti G, Pearce R, Taghipour G, et al.: Comparison of peripheral blood stem-cell and autologous bone marrow transplantation for lymphoma patients: a case-controlled analysis of the EBMT Registry data. Lymphoma Working Party of the EBMT. Ann Oncol 5 (Suppl 2): 151-3, 1994.
Vose JM, Zhang MJ, Rowlings PA, et al.: Autologous transplantation for diffuse aggressive non-Hodgkin's lymphoma in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 19 (2): 406-13, 2001.
van Kampen RJ, Canals C, Schouten HC, et al.: Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin's lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry. J Clin Oncol 29 (10): 1342-8, 2011.
Freytes CO, Loberiza FR, Rizzo JD, et al.: Myeloablative allogeneic hematopoietic stem cell transplantation in patients who experience relapse after autologous stem cell transplantation for lymphoma: a report of the International Bone Marrow Transplant Registry. Blood 104 (12): 3797-803, 2004.
Rezvani AR, Norasetthada L, Gooley T, et al.: Non-myeloablative allogeneic haematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: a multicentre experience. Br J Haematol 143 (3): 395-403, 2008.
Gisselbrecht C, Glass B, Mounier N, et al.: Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 28 (27): 4184-90, 2010.
Larouche JF, Berger F, Chassagne-Clément C, et al.: Lymphoma recurrence 5 years or later following diffuse large B-cell lymphoma: clinical characteristics and outcome. J Clin Oncol 28 (12): 2094-100, 2010.
Rodriguez MA, Cabanillas FC, Velasquez W, et al.: Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP. J Clin Oncol 13 (7): 1734-41, 1995.
Rizzieri DA, Sand GJ, McGaughey D, et al.: Low-dose weekly paclitaxel for recurrent or refractory aggressive non-Hodgkin lymphoma. Cancer 100 (11): 2408-14, 2004.
Kewalramani T, Zelenetz AD, Nimer SD, et al.: Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood 103 (10): 3684-8, 2004.
Coiffier B, Haioun C, Ketterer N, et al.: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 92 (6): 1927-32, 1998.
Tobinai K, Igarashi T, Itoh K, et al.: Japanese multicenter phase II and pharmacokinetic study of rituximab in relapsed or refractory patients with aggressive B-cell lymphoma. Ann Oncol 15 (5): 821-30, 2004.
Wiseman GA, Gordon LI, Multani PS, et al.: Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: a phase II multicenter trial. Blood 99 (12): 4336-42, 2002.
Dang NH, Hagemeister FB, Pro B, et al.: Phase II study of denileukin diftitox for relapsed/refractory B-Cell non-Hodgkin's lymphoma. J Clin Oncol 22 (20): 4095-102, 2004.
Zinzani PL, Pellegrini C, Gandolfi L, et al.: Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. Clin Lymphoma Myeloma Leuk 11 (6): 462-6, 2011.
Wiernik PH, Lossos IS, Tuscano JM, et al.: Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol 26 (30): 4952-7, 2008.
Lee AY, Connors JM, Klimo P, et al.: Late relapse in patients with diffuse large-cell lymphoma treated with MACOP-B. J Clin Oncol 15 (5): 1745-53, 1997.
Non-Hodgkin lymphomas (NHLs) occur more frequently than Hodgkin lymphoma in an older population. This age difference may account for fewer reports of NHL in pregnant patients.[1]
To avoid exposure to ionizing radiation, magnetic resonance imaging is the preferred tool for staging evaluation.[2] (Refer to the Stage Information for Adult NHL section of this summary for more information.)
Indolent NHL During Pregnancy
Delay treatment until after delivery
Aggressive NHL During Pregnancy
Immediate therapy
Early delivery, when feasible
Termination of pregnancy
Treatment may be delayed for those women with an indolent NHL.
According to anecdotal case series, most NHLs in pregnant patients are aggressive, and delay of therapy until after delivery appears to have poor outcomes.[1][3][4][5] Consequently, some investigators favor immediate therapy, even during pregnancy.[5] In a review of 121 patient case reports from 74 papers, one-half of the patients had very aggressive lymphomas, such as Burkitt lymphoma, and one-half of the patients had involvement of the breast, ovaries, uterus, or placenta.[6] One-half of the patients received therapy antepartum, and the 6-month survival was reported at 53%, with a live-birth rate of 83%.[6][Level of evidence: 3iiiDiv]
For some women, early delivery, when feasible, may minimize or avoid exposure to chemotherapy or radiation therapy.
Termination of pregnancy in the first trimester may be an option that allows immediate therapy for women with aggressive NHL.
Evidence (treatment effect on children exposed in utero):
Ward FT, Weiss RB: Lymphoma and pregnancy. Semin Oncol 16 (5): 397-409, 1989.
Nicklas AH, Baker ME: Imaging strategies in the pregnant cancer patient. Semin Oncol 27 (6): 623-32, 2000.
Steiner-Salz D, Yahalom J, Samuelov A, et al.: Non-Hodgkin's lymphoma associated with pregnancy. A report of six cases, with a review of the literature. Cancer 56 (8): 2087-91, 1985.
Spitzer M, Citron M, Ilardi CF, et al.: Non-Hodgkin's lymphoma during pregnancy. Gynecol Oncol 43 (3): 309-12, 1991.
Gelb AB, van de Rijn M, Warnke RA, et al.: Pregnancy-associated lymphomas. A clinicopathologic study. Cancer 78 (2): 304-10, 1996.
Horowitz NA, Benyamini N, Wohlfart K, et al.: Reproductive organ involvement in non-Hodgkin lymphoma during pregnancy: a systematic review. Lancet Oncol 14 (7): e275-82, 2013.
Avilés A, Díaz-Maqueo JC, Torras V, et al.: Non-Hodgkin's lymphomas and pregnancy: presentation of 16 cases. Gynecol Oncol 37 (3): 335-7, 1990.
Moore DT, Taslimi MM: Multi-agent chemotherapy in a case of non-Hodgkin's lymphoma in second trimester of pregnancy. J Tenn Med Assoc 84 (9): 435-6, 1991.
Nantel S, Parboosingh J, Poon MC: Treatment of an aggressive non-Hodgkin's lymphoma during pregnancy with MACOP-B chemotherapy. Med Pediatr Oncol 18 (2): 143-5, 1990.
This information was last updated on August 22, 2014.
Our licensed social workers are here to help adult patients and their loved ones face the many new concerns and anxieties following a cancer diagnosis, offering emotional support and assistance with obtaining needed resources.
Our support groups are geared to specific cancers and methods of treatment. They give patients the opportunity to meet and share information and moral support. Our experienced, compassionate staff facilitates and guides discussion.
If you are dealing with the death of a loved one, grief can be a lonely and isolating experience. The Bereavement Program provides support to bereaved family members and friends following the death of a patient.
Concierge Services is your one-stop place to learn about Dana-Farber programs, services and resources, as well as information on getting around Boston, finding lodging or restaurants, and activities in the area.
The Expressive Arts Therapy program, sponsored by the Leonard P. Zakim Center for Integrative Therapies, provides adult patients, family members, and caregivers with a variety of options to support well-being during cancer treatment. From live music meditation to painting technique workshops, the program offers a range of creative outlets to suit every interest.
Dana-Farber and Brigham and Women's Hospital, including parking facilities, are fully accessible to people with disabilities. There are wheelchairs at the main entrance, and security staff can provide personal assistance. We also have many educational materials available in large print and audiotape formats.
The Ethics Consultation Service is available for patients and families who may be facing difficult decisions and choices regarding care. Our goal is to bring together patients, families and health care providers to talk about ethical concerns and help everyone involved arrive at a resolution that is right for all.
This comprehensive resource offers guidance, information and resources to support the entire family, including how to talk to children about cancer, advice for the well partner, and creating a support network.
Find practical tips and suggestions for individuals caring for a family member or friend with cancer, including creating a caregiving plan, finding community resources, and looking after your own well-being.
Friends' Place provides personal consultations to help cancer patients of all ages cope with changes in physical appearance that result from cancer treatment. Our experienced, compassionate team provides fittings for compression garments or breast prostheses, helps with wigs and other head coverings, and offers make-up and skincare advice.
The Friends' Corner Gift Shop, located on the first floor of the Yawkey Center for Cancer Care, offers a wide selection of unique gifts and everyday items for patients, families and staff.
Dana-Farber offers several services to help you and your family manage the financial side of cancer treatment. From creating bill payment schedules and estate planning advice to debt management and resource assistance for patients in need, our team is here for you.
Every year, thousands of patients with cancer from around the world come to Dana-Farber for their care. We provide a wide array of logistical and other services for individuals who live outside the United States.
Dana-Farber provides interpreting services for patients whose first language is not English. Interpreters may be requested for any activity, including registration, booking appointments, attending treatments and exams, support groups, and meetings with doctors and other members of your health care team.
Our nutritionists are registered dietitians who can assist you in planning an optimal diet during any stage of your cancer journey, cope with any side effects you may experience, and answer your questions about the latest findings on cancer and nutrition.
One-to-One connects adult patients, family members and caregivers with individuals who have gone through cancer themselves, providing an experienced and reassuring perspective for those facing a cancer diagnosis, treatment and recovery.
The Eleanor and Maxwell Blum Patient and Family Resource Center and its satellite resource rooms are staffed by health care professionals and provide computer stations, books, brochures, videos, and CDs to help you find information and support on a variety of issues about cancer treatment and care.
Patients websites help friends and family members stay up-to-date on their loved ones' condition and write messages of support and encouragement.
The Dana-Farber pharmacy fills prescriptions for all pediatric and adult patients. Our pharmacists are an extension of the patient care team and work closely with your physicians to provide seamless, convenient, safe care.
More than 1,200 Dana-Farber patients and their families have enjoyed free trips to baseball games, theater shows, museums, and other attractions this year through the Recreational Resources program.
The Sexual Health Program provides education, consultation and personalized rehabilitation for patients and their partners who have experienced changes in sexual health during and after cancer treatment.
Through all stages of cancer treatment and survivorship, our Spiritual Care staff is available 24 hours a day to provide emotional and spiritual support for adults and pediatric patients and family members.
Young adults with cancer face very different challenges than patients who were diagnosed earlier in childhood or later in adulthood. The Young Adult Program can help you to find the resources and expertise available at Dana-Farber to help support your cancer experience.
Integrative therapies, also known as complementary therapies, range from acupuncture and massage to nutritional guidance and music therapy. Patients treated at the Zakim Center credit its services with easing nausea, improving circulation, and reducing pain, stress, and anxiety associated with cancer treatment.
In this video, Dr. Ann LaCasce talks about her work in the Hematologic Oncology Treatment Center at Dana-Farber/Brigham and Women's Cancer Center.