Topic Contents
- General Information About Adult Non-Hodgkin Lymphoma
- Cellular Classification of Adult Non-Hodgkin Lymphoma
- Stage Information for Adult NHL
- Treatment Option Overview
- Indolent, Stage I and Contiguous Stage II Adult NHL
- Aggressive, Stage I and Contiguous Stage II Adult Non-Hodgkin Lymphoma
- Indolent, Noncontiguous Stage II / III / IV Adult Non-Hodgkin Lymphoma
- Aggressive, Noncontiguous Stage II / III / IV Adult Non-Hodgkin Lymphoma
- Adult Lymphoblastic Lymphoma
- Diffuse Small Noncleaved-Cell / Burkitt Lymphoma
- Indolent, Recurrent Adult Non-Hodgkin Lymphoma
- Aggressive, Recurrent Adult Non-Hodgkin Lymphoma
- Non-Hodgkin Lymphoma During Pregnancy
- Changes to This Summary (08 / 14 / 2012)
- About This PDQ Summary
- Get More Information From NCI
Adult Non-Hodgkin Lymphoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Adult Non-Hodgkin Lymphoma Treatment
General Information About Adult Non-Hodgkin Lymphoma
Incidence and Mortality
Estimated new cases and deaths from NHL in the United States in 2012:[1]
- New cases: 70,130.
- Deaths: 18,940.
The NHL are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment.[2]
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.
The NHL 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 10 years, but they usually are not curable in advanced clinical stages. 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 approximately 50% to 60%. Of patients with aggressive NHL, 30% to 60% 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 with a divergent histology of both indolent and aggressive disease.[3]
While indolent NHL is responsive to radiation therapy and chemotherapy, a continuous rate of relapse is usually seen in advanced stages. Patients, however, can often be retreated 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.[4,5]
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.
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 treatment.
Aggressive lymphomas are increasingly seen in HIV-positive patients; treatment of these patients requires special consideration. (Refer to the PDQ summary on AIDS-Related Lymphoma Treatment for more information.)
Related Summaries
Other PDQ summaries containing information related to non-Hodgkin lymphoma (NHL) include the following:
- AIDS-Related Lymphoma Treatment
- Childhood Non-Hodgkin Lymphoma Treatment
- Primary CNS Lymphoma Treatment
References:
Cellular Classification of Adult Non-Hodgkin Lymphoma
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.
Table 1. Historical Classification Systems for Non-Hodgkin Lymphoma
| 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 | Diffuse histiocytic |
| 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 neoplasms.[9,10]
Updated REAL/WHO Classification
B-cell neoplasms
| 1. | Precursor B-cell neoplasm: precursor B-acute lymphoblastic leukemia/lymphoblastic lymphoma (LBL). | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2. | Peripheral B-cell neoplasms.
|
T-cell and putative NK-cell neoplasms
| 1. | Precursor T-cell neoplasm: precursor T-acute lymphoblastic leukemia/LBL. | ||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2. | Peripheral T-cell and NK-cell neoplasms.
|
Hodgkin lymphoma
| 1. | Nodular lymphocyte-predominant Hodgkin lymphoma. | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| 2. | Classical Hodgkin lymphoma.
|
The REAL classification encompasses all the lymphoproliferative neoplasms. Refer to the following PDQ summaries for more information:
- Adult Acute Lymphoblastic Leukemia Treatment
- Adult Hodgkin Lymphoma Treatment
- AIDS-Related Lymphoma Treatment
- Chronic Lymphocytic Leukemia Treatment
- Hairy Cell Leukemia Treatment
- Mycosis Fungoides and the Sézary Syndrome Treatment
- Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment
- Primary CNS Lymphoma Treatment
The more than 20 clinicopathologic entities described here can be divided into the more clinically useful indolent or aggressive lymphomas as follows:
PDQ Modification of REAL Classification of Lymphoproliferative Diseases
| 1. | Plasma cell disorders. (Refer to the PDQ summary on Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment for more information.)
|
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|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2. | Hodgkin lymphoma. (Refer to the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.)
|
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| 3. | Indolent lymphoma/leukemia.
|
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| 4. | Aggressive lymphoma/leukemia.
|
Indolent NHL
Follicular lymphoma
Follicular lymphoma comprises 20% of all NHL and as many as 70% of the indolent lymphomas reported in American and European clinical trials.[7,8,10] Most patients with follicular lymphoma are 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.[11]
Despite the advanced stage, the median survival ranges from 8 to 15 years, leading to the designation of being indolent.[12,13,14] Patients with advanced-stage follicular lymphoma are not cured with current therapeutic options.[15] The rate of relapse is fairly consistent over time, even in patients who have achieved complete responses to treatment.[16] Watchful waiting, i.e., the deferring of treatment until the patient becomes symptomatic, is an option for patients with advanced-stage follicular lymphoma.[17] An international index for follicular lymphoma (i.e., the Follicular Lymphoma International Prognostic Index [FLIPI]) [18,19,20] identified five significant risk factors prognostic of overall survival (OS):
| 1. | Age (≤60 years vs. >60 years). |
|---|---|
| 2. | Serum lactate dehydrogenase (LDH) (normal vs. elevated). |
| 3. | Stage (stage I or stage II vs. stage III or stage IV). |
| 4. | Hemoglobin level (≥120 g/L vs. <120 g/L). |
| 5. | Number of nodal areas (≤4 vs. >4). |
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.[18] 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 lactate dehydrogenase and the number of nodal areas.[21] 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).[22]
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.[23] Radiolabeled monoclonal antibodies, vaccines, and autologous or allogeneic bone marrow or peripheral stem cell transplantation are also under clinical evaluation.[23] Currently, no randomized trials 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.[24,25]
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.[26] 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.[27] In this series, high-risk factors for subsequent histologic transformation were advanced stage, high-risk FLIPI, 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 retreatment.[28] Histologic conversions should be treated with the regimens described in the Aggressive, Recurrent Adult Non-Hodgkin Lymphoma section of this summary. The durability of the second remission may be short, and clinical trials should be considered.[28,29,30]
Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia)
Lymphoplasmacytic lymphoma is usually associated with a monoclonal serum paraprotein of immunoglobulin M (IgM) type (Waldenström macroglobulinemia).[31,32,33] 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.
The management of lymphoplasmacytic lymphoma is similar to that of other low-grade lymphomas, especially diffuse small lymphocytic lymphoma/chronic lymphocytic leukemia.[32,33,34,35,36,37] 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.[38] Occasionally, a heated room is required for patients whose cold agglutinins become activated by even minor chilling.
Asymptomatic patients can be monitored for evidence of disease progression without immediate need for chemotherapy.[17,37,38] Prognostic factors associated with symptoms requiring therapy include age 70 or older, beta-2-microglobulin of 3 mg/dL or more, and increased serum LDH.[37] First-line regimens include rituximab, the nucleoside analogs, and alkylating agents, either as single agents or as part of combination chemotherapy.[39,40,41] 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.[39,42,43][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 of the proteasome inhibitor bortezomib.[38,44] The nucleoside analogues 2-chlorodeoxyadenosine and fludarabine have shown similar response rates for previously untreated patients with lymphoplasmacytic lymphoma.[45,46][Level of evidence: 3iiiDiv] Single-agent alkylators, bortezomib, and combination chemotherapy with or without rituximab also show similar response rates.[44,47,48,49][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.[32,33,39] A combination of bortezomib, dexamethasone, and rituximab has been proposed for its high response rate, rapidity of action, and avoidance of an IgM rebound.[50]
Interferon-alpha also shows activity in this disease, in contrast to poor responses in patients with multiple myeloma.[51] Myeloablative therapy with autologous or allogeneic hematopoietic stem cell support is under clinical evaluation.[52,53,54,55] 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.[39,56] 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 19 months vs. 3 months, P < .01), no difference was observed in OS.[57][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.[58][Level of evidence: 3iiiDiv]
Marginal zone lymphoma
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.[4,59,60,61,62,63,64,65,66]
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.[67,68,69,70] 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.[71] 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 Helicobacter pylori–negative testing, and for poor response to oral alkylator chemotherapy.[72,73,74] Stable asymptomatic patients with persistently positive biopsies have been successfully followed on a watchful waiting approach until disease progression.[68,69] Patients who progress are treated with radiation therapy,[75,76,77,78] rituximab,[79] surgery (total gastrectomy or partial gastrectomy plus radiation therapy),[80] chemotherapy,[64] or combined modality therapy.[81] The use of endoscopic ultrasonography may help clinicians to follow responses in these patients.[82] Three small case series (two retrospective and one prospective) reported durable complete remissions after treatment of Helicobacter pylori in patients with aggressive lymphoma (complete remission rate of 35%–88% and a median duration of 21–60 mo).[83,84,85]
Localized involvement of other sites can be treated with radiation or surgery.[76,77,78,86,87,88] 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.[89] Many of these recurrences involve different MALT sites than the original location.[90] When disseminated to lymph nodes, bone marrow, or blood, this entity behaves like other low-grade lymphomas.[65,91] For patients with ocular adnexal MALT, antibiotic therapy using doxycycline targeting Chlamydia psittaci resulted in durable remissions for half of the patients in a small series of 27 patients.[92][Level of evidence: 3iiiDiv] Large B-cell lymphomas of MALT sites are classified and treated as diffuse large cell lymphomas.[93]
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.[58][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.[94]Campylobacter jejuni has been identified as one of the bacterial species associated with IPSID, and antibiotic therapy may result in remission of the disease.[95]
Splenic marginal zone lymphoma
Splenic marginal zone lymphoma is an indolent lymphoma that is marked by massive splenomegaly and peripheral blood and bone marrow involvement, usually without adenopathy.[96,97,98] This type of lymphoma is otherwise known as splenic lymphoma with villous lymphocytes. Splenectomy may result in prolonged remission.[66,99] 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.[100] Splenic marginal zone lymphoma responds less well to chemotherapy, which would ordinarily be effective for chronic lymphocytic leukemia.[97,98,100] 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.[58,101];[102][Level of evidence: 3iiiDiv] In contrast, no responses to interferon were seen in six HCV-negative patients.
Primary cutaneous anaplastic large cell lymphoma
Primary cutaneous anaplastic large cell lymphoma presents in the skin only with no pre-existing lymphoproliferative disease and no extracutaneous sites of involvement.[103,104,105] 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.[103,104,105]
(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.)
Aggressive NHL
Diffuse large cell lymphoma
Diffuse large B-cell lymphoma is the most common of the NHLs and comprises 30% of newly diagnosed cases.[7] Most patients present with rapidly enlarging masses, often with symptoms both locally and systemically (designated B symptoms with fever, recurrent night sweats, or weight loss). (Refer to the PDQ summary on Fever, Sweats, and Hot Flashes and for more information on weight loss, refer to the Nutrition in Cancer Care summary.) The vast majority of patients with localized disease are curable with combined modality therapy or combination chemotherapy alone.[106] For patients with advanced-stage disease, 50% of presenting patients are cured with doxorubicin-based combination chemotherapy and rituximab.[107,108,109]
An International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of overall survival (OS):[110]
| 1. | Age (≤60 years vs. >60 years). |
|---|---|
| 2. | Serum lactate dehydrogenase (LDH) (normal vs. elevated). |
| 3. | Performance status (0 or 1 vs. 2–4). |
| 4. | Stage (stage I or stage II vs. stage III or stage IV). |
| 5. | Extranodal site involvement (0 or 1 vs. 2–4). |
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.[111] Patients at high risk of relapse may be considered for clinical trials.[112] 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.[113,114,115,116,117,118]
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.[119] CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, others do not.[120,121] 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.[122][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.[123,124] Some cases of large B-cell lymphoma have a prominent background of reactive T-cells and often of histiocytes, so-called T-cell/histocyte-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 diffuse large B-cell lymphoma.[125,126,127] Some patients with diffuse large B-cell lymphoma at diagnosis have a concomitant indolent small B-cell component; while OS appears similar after multidrug chemotherapy, there is a higher risk of indolent relapses.[128]
Mediastinal large B-cell lymphoma (primary mediastinal large B-cell lymphoma)
Primary mediastinal (thymic) large B-cell lymphoma is a subset of diffuse large cell lymphoma characterized by significant fibrosis on histology.[129,130,131,132,133,134,135] Patients are usually female and young (median age 30–40 years). Patients present with a locally invasive anterior mediastinal mass that may cause respiratory symptoms or superior vena cava syndrome. Therapy and prognosis are the same as for other comparably staged patients with diffuse large cell lymphoma, except for advanced-stage patients with a pleural effusion, who have an extremely poor prognosis (progression-free survival is <20%) whether the effusion is cytologically positive or negative. (For information on superior vena cava syndrome and pleural effusion, refer to the Cardiopulmonary Syndromes summary.) High-dose chemotherapy with hematopoietic stem cell rescue has been applied to these poor prognosis patients. Evidence for this approach is anecdotal.[135]
Follicular large cell lymphoma
The natural history of follicular large cell lymphoma remains controversial.[136] 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).[137] Other investigators report a plateau in freedom-from-progression at levels expected for an aggressive lymphoma (40% at 10 years).[138,139] 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.[140] 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 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.[141][Level of evidence: 3iiiA]
Anaplastic large cell lymphoma
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-ALK.[142] 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.[143] Patients with these types of lymphomas are generally treated the same as patients with diffuse large cell lymphomas and have a prognosis that is as good as comparably staged patients, as evidenced in the GER-GPOH-NHL-BFM-90 trial. For patients with relapsed disease, brentuximab vedotin (antitubulin agent attached to a CD30-specific monoclonal antibody) has shown anecdotal responses.[144] ALCL in children is usually characterized by systemic and cutaneous disease and has high response rates and good OS with doxorubicin-based combination chemotherapy.[145]
Extranodal NK-/T-cell lymphoma
Extranodal 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.[146,147,148,149] 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.[150] 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.[151,152,153,154,155,156] 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 allogeneic peripheral stem cell transplantation consolidation.[147,148,149,157,158] An L-asparaginase-containing regimen has shown anecdotal responses for relapsing patients.[159] NK-/T-cell lymphoma that presents only in the skin has a more favorable prognosis, especially in patients with coexpression of CD30 with CD56.[160] A benign NK-cell enteropathy (EBV negative) on endoscopic biopsy should be distinguished from NK-/T-cell lymphoma.[161]
Lymphomatoid granulomatosis
Lymphomatoid granulomatosis is an EBV-positive large B-cell lymphoma with a predominant T-cell background.[162,163] 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
Angioimmunoblastic T-cell lymphoma was formerly called angioimmunoblastic lymphadenopathy with dysproteinemia. Characterized by clonal T-cell receptor gene rearrangement, this entity is managed like diffuse large cell lymphoma.[164,165,166] Patients present with profound lymphadenopathy, fever, night sweats, weight loss, skin rash, a positive Coombs test, and polyclonal hypergammaglobulinemia.[150] (For information on night sweats, weight loss, and skin rash, refer to the PDQ summaries on Fever, Sweats, and Hot Flashes, Nutrition in Cancer Care, and Pruritus, respectively.) Opportunistic infections are frequent because of an underlying immune deficiency. Doxorubicin-based combination chemotherapy is recommended as it is for other aggressive lymphomas.[164] Myeloablative chemotherapy and radiation therapy with autologous or allogeneic peripheral stem cell support has been described in anecdotal reports.[157,167,168] Occasional spontaneous remissions and protracted responses to steroids only have been reported. B-cell EBV genomes are detected in most affected patients.[169]
Peripheral T-cell lymphoma
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.[170] Peripheral T-cell lymphoma encompasses a group of heterogeneous nodal T-cell lymphomas that will require future delineation.[150] 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.[171,172] Therapy involves doxorubicin-based combination chemotherapy, which is also used for B-cell diffuse large cell lymphoma.[173] 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.[171,172]
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. Evidence for this approach is anecdotal.[157,167,174] For relapsing patients, the antifolate pralatrexate has shown a 30% response rate and a median 10-month duration of response for 109 evaluable patients in a prospective trial.[175][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.[176,177] 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.[178,179,180,181,182] Another variant, subcutaneous panniculitis-like T-cell lymphoma, is localized to subcutaneous tissue associated with hemophagocytic syndrome.[183,184,185,186] 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.[187,188,189] 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 with the same paradigm as for the highest-risk groups with diffuse large B-cell lymphoma.[157]
Enteropathy-type intestinal T-cell lymphoma
Enteropathy-type intestinal T-cell lymphoma involves the small bowel of patients with gluten-sensitive enteropathy (celiac sprue).[150,190,191,192] 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.[191,192,193] Complications of treatment include gastrointestinal bleeding, small bowel perforation, and enterocolic fistulae; patients often require parenteral nutrition. (For information on parenteral nutrition, refer to the Gastrointestinal Complications summary and the Nutrition in Cancer Care summary.) 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.[157,191,194][Level of evidence: 3iiiDiii] Evidence for this approach is anecdotal.
Intravascular large B-cell lymphoma (intravascular lymphomatosis)
Intravascular lymphomatosis is characterized by large cell lymphoma confined to the intravascular lumen; with the use of aggressive combination chemotherapy, the prognosis is similar to more conventional presentations.[195,196] The brain, kidneys, lungs, and skin are the organs most likely affected by intravascular lymphomatosis.
Burkitt lymphoma/diffuse small noncleaved-cell lymphoma
Burkitt lymphoma/diffuse small noncleaved-cell lymphoma typically involves younger patients and represents the most common type of pediatric NHL.[197] These types of aggressive extranodal B-cell lymphomas are characterized by translocation and deregulation of the C-myc gene on chromosome 8.[198] A subgroup of patients with dual translocation of C-myc and bcl-2 appear to have an extremely poor outcome despite aggressive therapy (5-mo OS).[199][Level of evidence: 3iiiA] In some patients with larger B cells, there is morphologic overlap with diffuse large B-cell lymphoma. 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.[200,201,202] 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).[203,204,205] Aggressive combination chemotherapy, which is patterned after that used in childhood Burkitt lymphoma, has been described in CLB-9251, for example, and has been very successful for adult patients with more than 60% of advanced-stage patients free of disease at 5 years.[206,207,208,209,210,211] Adverse prognostic factors include bulky abdominal disease and high serum LDH. In some institutions, treatment includes the use of consolidative bone marrow transplantation (BMT).[212,213] 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.[214] (Refer to the PDQ summaries on Primary Central Nervous System Lymphoma Treatment and AIDS-Related Lymphoma Treatment for more information.)
Lymphoblastic lymphoma
Lymphoblastic lymphoma (precursor T-cell) is a very aggressive form of NHL. It often occurs in young patients but not exclusively.[215] 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.[216,217,218] Radiation therapy is sometimes given to areas of bulky tumor masses. Since these forms of NHL tend to progress so 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
Adult T-cell leukemia/lymphoma (ATL) is caused by infection with the retrovirus HTLV-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.[219,220] (Refer to the PDQ summary on Hypercalcemia for more information.) ATL has been divided into four clinical subtypes: acute, lymphoma, chronic, and smoldering.[221,222] The acute and lymphoma types of ATL have done poorly with strategies of combination chemotherapy and allogeneic stem cell transplantation.[223,224] Using combination chemotherapy, only 10% to 20% of patients survived even 3 years in a trial of 118 patients.[225] The combination of zidovudine and interferon-alpha has activity against the leukemic subtype, and sometimes the smoldering and chronic forms of ATL. 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 .[226,227,228,229,230]
Mantle cell lymphoma
Mantle cell lymphoma is found in lymph nodes, the spleen, bone marrow, blood, and sometimes the gastrointestinal system (lymphomatous polyposis).[4,231,232] 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.[233,234] 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.[235] 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.[236,237] 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.[59,238] A high cell proliferation rate (increased Ki-67, mitotic index, beta-2-microglobulin) may be associated with a poorer prognosis.[233,239] It is unclear which chemotherapeutic approach offers the best long-term survival in this clinicopathologic entity; rituximab with CHOP or CHOP-like regimens is the usual first-line induction therapy..[236,240,241,242,243,244,245,246] Patients with low risk on the IPI may do well when initial therapy is deferred.[247][Level of evidence: 3iiiDiv] Many investigators are exploring high-dose chemoradioimmunotherapy with stem cell/marrow support or nonmyeloablative allogeneic stem cell transplantation.[242,243,244,248,249,250,251,252,253,254,255,256,257] Thus far, randomized trials have not shown OS benefits from these newer approaches.[254] 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.[258,259][Level of evidence: 3iiiDiv]
PTLD
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.[260] Pathologists can distinguish a polyclonal B-cell hyperplasia from a monoclonal B-cell lymphoma; both are almost always associated with EBV.[261] Poor performance status, grafted organ involvement, high IPI, elevated LDH, and multiple sites of disease are poor prognostic factors for PTLD.[262,263] In some cases, withdrawal of immunosuppression results in eradication of the lymphoma.[264,265] 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.[265,266] Sometimes, a combination of acyclovir and interferon-alpha has been used.[260,267] If these measures fail, doxorubicin-based combination chemotherapy is recommended, though most patients can avoid cytotoxic therapy.[268] 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.[261] Multifocal, rapidly progressive disease occurs late after transplantation (>1 y) and is usually phenotypically monoclonal and associated with EBV.[269] These patients may have durable remissions using standard chemotherapy regimens for aggressive lymphoma.[269,270,271] Instances of EBV-negative PTLD occur even later (median, 5 y posttransplant) and have particularly poor prognoses.[272] 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).[273] An anti-interleukin-6 monoclonal antibody is also under clinical evaluation.[274]
True histiocytic lymphoma
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.[275,276] 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
Primary effusion lymphoma presents exclusively or mainly in the pleural, pericardial, or abdominal cavities in the absence of an identifiable tumor mass.[277] Patients are usually HIV-seropositive, and the tumor usually contains Kaposi sarcoma-associated herpes virus/human herpes virus 8. Therapy is usually modeled after the treatment of comparably staged diffuse large cell lymphomas, but the prognosis is extremely poor.
References:
Stage Information for Adult NHL
Stage is important in selecting a treatment for patients with NHL. Chest and abdominal computed tomographic (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. Noncontiguous lymph node involvement, uncommon in Hodgkin lymphoma, is more common among patients with NHL. Involvement of Waldeyer ring, epitrochlear nodes, and the gastrointestinal tract is also more common. Extranodal presentations are more common in NHL. A single extranodal site is occasionally the only site of involvement in patients with diffuse lymphoma. Bone marrow and hepatic involvement are especially common in patients with low-grade lymphomas. 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-E3404 [NCT00274924]) and lack of difference in outcome between PET-negative and PET-positive/biopsy-negative patients in a single-institution trial.[7,8]
Staging Subclassification System
Table 2. Anatomic Stage/Prognostic Groupsa
| Stage | Prognostic Groups |
| a Reprinted with permission from AJCC: 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. | |
| I | Involvement of a single lymphatic site (i.e., nodal region, Waldeyer ring, thymus or spleen) (I). |
| OR | |
| Localized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement (IE) (rare in Hodgkin lymphoma). | |
| II | Involvement of two or more lymph node regions on the same side of the diaphragm (II). |
| OR | |
| 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 | |
| III | 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. |
| IV | Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement. |
| OR | |
| 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. | |
The Ann Arbor staging system is commonly used for patients with NHL.[9,10] 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:
- Unexplained loss of more than 10% of body weight in the 6 months before diagnosis.
- Unexplained fever with temperatures above 38° C.
- Drenching night sweats.
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.
Table 3. Notation for Identification of Sites
| 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:
- Age.
- Performance status.
- Tumor size.
- Lactate dehydrogenase (LDH) values.
- The number of extranodal sites.
To identify subgroups of patients most likely to relapse, an international prognostic index was compiled for 2,031 patients with aggressive NHL.[11] After validation by several cancer centers,[12,13] 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): age (<60 y vs. >60 y), serum LDH (normal vs. elevated), performance status (0 or 1 vs. 2–4), stage (stage I or stage II vs. stage III or stage IV), and extranodal site involvement (0 or 1 vs. 2–4). Patients with two or more risk factors have a less than 50% chance of relapse-free 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. Patients at high risk of relapse may benefit from consolidation therapy or other approaches under clinical evaluation.[11] 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.[14,15]
References:
Treatment Option Overview
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).
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]
Late effects of treatment of NHL have been observed. Pelvic radiation therapy and large cumulative doses of cyclophosphamide have been associated with a high risk of permanent sterility.[2] For as many as 3 decades after diagnosis, patients are at a significantly elevated risk for second primary cancers, especially lung, brain, kidney, and bladder cancers and melanoma, Hodgkin lymphoma, and acute nonlymphocytic leukemia.[3,4,5] 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.[6,7] 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.[4,8,9,10,11,12] Most of these patients show clonal hematopoiesis even before the transplantation, suggesting that the hematologic injury usually occurs during induction or reinduction chemotherapy.[8,13,14] 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.[15] Successful pregnancies with children born free of congenital abnormalities have been reported in young women after autologous BMT.[16]
Aggressive lymphomas are increasingly seen in HIV-positive patients whose treatment 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, prior infection with hepatitis B or hepatitis C should be assessed prior to treatment with rituximab and/or chemotherapy since reactivation of hepatitis may mandate antiviral therapy or discontinuation of rituximab.[17]
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,[18,19,20,21,22,23,24,25,26] thyroid,[27,28] spleen,[29] testis,[30,31] paranasal sinuses,[32,33,34,35] bone,[36,37] orbit,[38,39,40,41,42] and skin.[43,44,45,46,47,48,49,50,51,52]
(Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information.)
References:
Indolent, Stage I and Contiguous Stage II Adult NHL
Although localized presentations are uncommon in NHL, the goal of treatment should be cure of the disease in patients who are shown to have truly localized occurrence after undergoing appropriate staging procedures. 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.[1,2,3,4] Almost half of all patients treated with radiation therapy alone will relapse out-of-field within 10 years.[5] The value of adjuvant treatment with rituximab or chemotherapy in addition to radiation to decrease relapse, has not been confirmed.[6,7]
When radiation therapy is contraindicated, chemotherapy can be employed for symptomatic patients (as outlined below for more advanced-stage patients), or watchful waiting can be considered for asymptomatic patients.[8] A retrospective analysis of the SEER database over 30 years showed improved outcomes for upfront radiation therapy, but one must be very cautious about this type of retrospective analysis. Watchful waiting has never been compared with upfront radiation therapy in a prospective randomized trial.[9]
Patients with involvement not encompassable by radiation therapy are treated as outlined for patients with stage III or stage IV low-grade lymphoma. Follicular large cell and mantle cell NHL are often treated as aggressive lymphomas (nodal and extranodal presentations).
Standard treatment options:
| 1. | Involved-field radiation therapy.[1,2,3,4] |
|---|---|
| 2. | Watchful waiting.[8] |
| 3. | Chemotherapy with radiation therapy.[7] |
| 4. | Extended (regional) radiation therapy as prophylaxis for adjacent nodes.[1,2,3,4,10] |
| 5. | Rituximab, an anti-CD20 monoclonal antibody, either alone or in combination with chemotherapy and extrapolated from trials of patients with advanced-stage disease. |
| 6. | Other therapies as designated for patients with advanced-stage disease. |
Current Clinical Trials
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.
References:
Aggressive, Stage I and Contiguous Stage II Adult Non-Hodgkin Lymphoma
Patients with stage I or contiguous stage II diffuse large B-cell lymphoma are candidates for combination chemotherapy with or without radiation therapy. Four prospective randomized trials have evaluated the comparison of CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone) or more intensive CHOP-based chemotherapy alone versus combined modality therapy with CHOP and involved-field radiation therapy (IF-XRT).[1,2,3,4,5]
With 7 years' median follow-up, 576 patients older than 60 years with early-stage disease received four cycles of CHOP with or without IF-XRT; there was no difference in 5-year event-free survival (EFS) (61% vs. 64%, P = .5) or overall survival (OS) (72% vs. 68%, P = .6).[1][Level of evidence: 1iiA] A randomized trial of 401 patients comparing eight cycles of CHOP to three cycles of CHOP with IF-XRT was initially reported as having an OS advantage for the combined modality arm at 5 years, [2] but a re-evaluation for OS at 9 years showed no difference in either arm of the study.[3][Level of evidence: 1iiA] A randomized study (EST-1484) of 210 patients who attained a radiologic complete remission after eight cycles of CHOP compared IF-XRT with no further therapy; there was no difference in OS at 10 years (68% vs. 65%, P = .24).[4][Level of evidence: 1iiA]
A randomized trial of 631 patients younger than 60 years compared more intensive CHOP-based chemotherapy versus three cycles of CHOP with IF-XRT; with 4 years' median follow-up, the intensive chemotherapy was superior in 5-year EFS (82% vs. 74%, P > .001) and 5-year OS (90% vs. 81%, P = .001).[5][Level of evidence: 1iiA]
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 only on the basis of historical comparison to prior studies.[6][Level of evidence: 3iiiDiii] A preliminary study using CHOP with or without etoposide for patients older than 60 years suggested improvement in EFS and OS for treatment delivered every 2 weeks versus the standard 3-week regimen.[7]
A randomized study (DSHNHL-1999-1A) of 1,222 patients older than 60 years compared R-CHOP given every 2 weeks for six or eight cycles to CHOP given every 2 weeks for six or eight cycles.[8] With a median follow-up of 35 months, the EFS favored R-CHOP given every 2 weeks for six or eight cycles (EFS, relative risk [RR], 0.5 [0.40–0.65], P < .001). The OS favored R-CHOP for only six cycles because of increased toxicity in the eight-cycle arm (RR of death, 0.63 [0.46–0.85], P = .003).[8][Level of evidence: 1iiA] There has been no comparison to standard R-CHOP or CHOP given every 3 weeks.
Standard treatment options:
- Chemotherapy with or without IF-XRT.
- R-CHOP (four to eight cycles).
- R-CHOP (three to eight cycles) plus IF-XRT.
There are no comparative studies to establish an optimal number of chemotherapy cycles for patients with early stage disease.
Treatment options under clinical evaluation:
- R-ACVBP (rituximab + doxorubicin + cyclophosphamide + vindesine + bleomycin + prednisone).[5]
Current Clinical Trials
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.
General information about clinical trials is also available from the NCI Web site.
References:
Indolent, Noncontiguous Stage II / III / IV Adult Non-Hodgkin Lymphoma
Optimal treatment of advanced stages of low-grade lymphoma 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 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 given consideration.[1,2,3] Three randomized trials compared watchful waiting to immediate chemotherapy. All three trials showed no difference in cause-specific or overall survival (OS). For patients randomly assigned to watchful waiting, the median time to require therapy was 2 to 3 years and one-third of patients never required treatment with watchful waiting (half died of other causes and half remained progression-free after 10 y).[2,4];[5][Level of evidence: 1iiA] The PRIMA trial compared watchful waiting to immediate rituximab, the anti-CD20 monoclonal antibody, with or without maintenance doses. 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.[6,7,8,9,10,11,12,13,14,15,16,17]
Standard therapy includes rituximab, an anti-CD20 monoclonal antibody, either alone or in combination with purine nucleoside analogs such as fludarabine or 2-chlorodeoxyadenosine, oral alkylating agents (with or without steroids), or combination chemotherapy. However, none of these therapies are curative for advanced-stage disease, but 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, and the use of idiotype vaccines and radiolabeled monoclonal antibodies. 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.[18];[3] [Level of evidence: 1iiDiii]
Four randomized, prospective studies of previously untreated patients (involving more than 1,300 patients) and one Cochrane meta-analysis including both untreated and previously treated patients (involving almost 1,000 patients) have compared rituximab plus combination chemotherapy with chemotherapy alone. Rituximab plus chemotherapy was superior in terms of event-free or progression-free survival (ranging from 2–3 years) in all of the studies and in terms of OS in all but one study (absolute benefit ranging from 6%–13% at 4 years, P < .04 and hazard ratio [HR], 0.63 [0.51–0.79] for the meta-analysis).[19,20,21,22];[23][Level of evidence: 1iiA] All of these trials were performed in symptomatic patients who required therapy. These results do not negate watchful waiting when appropriate.
Maintenance Rituximab
In three randomized, prospective studies involving previously treated patients with relapsed indolent lymphoma, patients were randomly assigned to rituximab maintenance after retreatment with combination chemotherapy (with or without rituximab during induction) or observation alone; all trials showed prolongation of response duration,[24,25,26] and one trial demonstrated improvement in median progression-free survival (3.7 years vs. 1.3 years, P < .001) and overall survival (OS) (74% vs. 64%, P = .07) at 5 years with a median follow-up of 39 months favoring maintenance rituximab.[25][Level of evidence: 1iiDiii]
In the PRIMA study, 1,019 previously untreated high-risk patients who required treatment achieved complete or partial response after induction therapy with immunochemotherapy (usually R-CHOP) and were then randomly assigned to 2 years of maintenance rituximab versus no maintenance.[27] With a median follow-up of 36 months, progression-free survival favored rituximab maintenance 74.9% to 57.6% (HR, 0.56; 95% confidence interval, 0.44–0.68, P< .0001), but with no difference in overall survival.[27][Level of evidence: 1iiDiii]
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.[28]
Standard treatment options:
| 1. | For asymptomatic patients, deferred therapy with careful observation.[2,29] |
|---|---|
| 2. | Rituximab may be considered as first-line therapy.
|
| 3. | Purine nucleoside analog: |
| 4. | Oral alkylating agents (with or without steroids): |
| 5. | Combination chemotherapy alone:
|
| 6. | 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, as was shown in the SWOG-9911 trial, for example.[54,55] Randomized prospective studies are required to determine the optimal utilization of this modality.[56] |
| 7. | Intensive therapy with chemotherapy with or without TBI or high-dose radioimmunotherapy followed by autologous or allogeneic BMT or peripheral stem cell transplantation is under clinical evaluation.[57,58,59,60,61,62,63,64,65,66,67] |
| 8. | Phase III trials comparing chemotherapy alone versus chemotherapy followed by anti-idiotype vaccine.[68,69,70] |
| 9. | Extended-field radiation therapy (noncontiguous stage II and stage III patients).[71,72,73] |
Current Clinical Trials
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.
General information about clinical trials is also available from the NCI Web site.
References:
Aggressive, Noncontiguous Stage II / III / IV Adult Non-Hodgkin Lymphoma
Drug combinations described in this section:
- ACVBP: doxorubicin plus cyclophosphamide plus vindesine plus bleomycin plus prednisone.
- CHOP: cyclophosphamide plus doxorubicin plus vincristine plus prednisone.
- CNOP: cyclophosphamide plus mitoxantrone plus vincristine plus prednisone.
- m-BACOD: methotrexate plus bleomycin plus doxorubicin plus cyclophosphamide plus vincristine plus dexamethasone plus leucovorin.
- MACOP-B: methotrexate plus doxorubicin plus cyclophosphamide plus vincristine plus prednisone fixed dose plus bleomycin plus leucovorin.
- ProMACE CytaBOM: prednisone plus doxorubicin plus cyclophosphamide plus etoposide plus cytarabine plus bleomycin plus vincristine plus methotrexate plus leucovorin.
- R-CHOP: Rituximab, an anti-CD20 monoclonal antibody, plus cyclophosphamide plus doxorubicin plus vincristine plus prednisone.
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]
Doxorubicin-based combination chemotherapy produces long-term disease-free survival in 35% to 45% of patients.[2,3,4] Higher cure rates have been reported in single-institution studies than in cooperative group trials.
A prospective, randomized trial of four regimens (CHOP, ProMACE CytaBOM, m-BACOD, and MACOP-B) for patients with diffuse large B-cell lymphoma showed no difference in overall survival (OS) or time-to-treatment failure at 3 years.[4][Level of evidence: 1iiA] Other randomized trials have confirmed no advantage among the standard doxorubicin-based combinations versus CHOP.[5];[6][Level of evidence: 1iiA] A randomized clinical trial failed to demonstrate a beneficial effect of adjuvant radiation therapy in advanced-stage aggressive NHL.[7]
The combination of rituximab and CHOP (R-CHOP) showed improvement in event-free survival (EFS) and OS compared with CHOP alone in 399 advanced-stage patients with diffuse large B-cell lymphoma older than 60 years (EFS = 57% vs. 38%, P = .002, and OS = 70% vs. 57%, P = .007 at 2 y).[8][Level of evidence: 1iiA] At 10-years' median follow-up, the OS of patients who received R-CHOP compared with patients who received CHOP was 44% versus 28%, P < .0001.[9] Similarly, for 326 evaluable patients younger than 61 years, R-CHOP showed improvement in EFS and OS compared to CHOP alone (EFS = 79% vs. 59%, P = .001, and OS = 93% vs. 84%, P = .001 at 3 years).[10][Level of evidence: 1iiA] These two studies established R-CHOP as the standard regimen for newly diagnosed patients with diffuse large B-cell lymphoma.[11]
A preliminary study using CHOP with or without etoposide for patients older than 60 years suggested improvement in EFS and OS for treatment delivered every 2 weeks versus the standard 3-week regimen.[12] A randomized study (DSHNHL-1999-1A) of 1,222 patients older than 60 years compared R-CHOP given every 2 weeks for six or eight cycles to CHOP given every 2 weeks for six or eight cycles.[13] With a median follow-up of 35 months, the EFS favored R-CHOP given every 2 weeks for six or eight cycles (EFS, relative risk [RR], 0.5 [0.40–0.65], P < .001). The OS favored R-CHOP for only six cycles because of increased toxicity in the eight-cycle arm (RR of death, 0.63 [0.46–0.85], P = .003).[13][Level of evidence: 1iiA] There was no comparison to standard R-CHOP or CHOP given every 3 weeks.
A trial of 635 patients, aged 61 to 69 years, with stage III and stage IV disease, elevated lactate dehydrogenase (LDH), or performance status of 2 to 4, randomly assigned patients to receive CHOP or ACVBP. With a median follow-up of 68 months, patients who received ACVBP had superior EFS and OS (EFS = 39% vs. 29% at 5 years, P = .005 and OS = 46% vs. 38% at 5 years, P = .036).[14][Level of evidence: 1iiA] Two prospective randomized trials that compared CHOP with CNOP for patients aged 60 years and older with diffuse large cell lymphoma showed a significant advantage for CHOP in terms of disease-free survival and OS.[15];[16][Level of evidence: 1iiA] Two other randomized trials of patients aged 70 years and older confirm the superiority of CHOP over other less toxic regimens in progression-free survival and OS.[17];[18][Level of evidence: 1iiA] Although infusion regimens have been proposed, a randomized trial of infusional CHOP versus standard CHOP therapy showed no improvement in relapse-free survival or OS.[19][Level of evidence: 1iiA] 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.[14,20,21,22]
An International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS:[23]
| 1. | Age (≤60 years vs. >60 years). |
|---|---|
| 2. | Serum LDH (normal vs. elevated). |
| 3. | Performance status (0 or 1 vs. 2–4). |
| 4. | Stage (stage I or stage II vs. stage III or stage IV). |
| 5. | Extranodal site involvement (0 or 1 vs. 2–4). |
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. Patients at high risk of relapse may be considered for clinical trials.[24] 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.[25,26]
Several randomized, prospective trials evaluated the role of autologous bone marrow transplantation (BMT) or stem cell transplantation consolidation versus chemotherapy alone in patients in first remission with diffuse large cell lymphoma.[27,28,29,30,31,32,33,34];[35][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.[28,34] 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.[36] Whether autologous BMT, or peripheral stem cell transplantation, or allogeneic BMT have definitive roles in the treatment of high-risk patients in first remission awaits the results of ongoing randomized trials such as SWOG-S0016 (NCT00006721), for example, that employed R-CHOP or other rituximab-based chemotherapy regimens.
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.[4,38] 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.[39][Level of evidence: 3iiiDiii] The addition of rituximab to CHOP-based regimens has significantly reduced the risk of CNS relapse in retrospective analyses.[40,41] 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.
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.[42] Treatment options include: alkaline hydration; allopurinol; and rasburicase, a recombinant urate oxidase.[43]
Standard treatment options:
| 1. | CHOP plus rituximab.[8] |
|---|---|
| 2. | Autologous BMT or peripheral stem cell transplantation or allogeneic BMT for patients at high risk of relapse is under clinical evaluation. |
Current Clinical Trials
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.
General information about clinical trials is also available from the NCI Web site.
References:
Adult Lymphoblastic Lymphoma
Lymphoblastic lymphoma is a very aggressive form of 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), much like acute lymphocytic leukemia (ALL). 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. Careful review of the pathologic specimens, bone marrow aspirate and biopsy specimen, cerebrospinal fluid cytology, and lymphocyte marker constitute the most important aspects of the pretreatment staging workup. 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.)
Current Clinical Trials
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.
General information about clinical trials is also available from the NCI Web site.
Diffuse Small Noncleaved-Cell / Burkitt Lymphoma
Treatment of these lymphomas is usually with aggressive multidrug regimens similar to those used for the advanced-stage aggressive lymphomas (diffuse large cell).[1,2,3] An intensive clinical trial, CLB-9251 (NCT00002494), has been described. It used aggressive combination chemotherapy patterned after that used in childhood Burkitt lymphoma and has been very successful for adult patients.[4,5,6,7,8] Adverse prognostic factors include bulky abdominal disease and high serum lactate dehydrogenase. In some institutions, treatment includes the use of consolidative bone marrow transplantation.[9,10]
Patients with diffuse small noncleaved-cell/Burkitt lymphoma have a 20% to 30% lifetime risk of CNS involvement. CNS prophylaxis (usually with four to six injections of methotrexate intrathecally) is recommended for all patients.[11] In a series of 41 patients treated with systemic and intrathecal chemotherapy, 44% of those who presented with CNS disease and 13% of those who relapsed with CNS involvement became long-term disease-free survivors.[12] CNS relapse patterns were similar whether or not patients received radiation therapy, but increased neurologic deficits were noted among those patients who received radiation therapy.
Current Clinical Trials
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.
General information about clinical trials is also available from the NCI Web site.
References:
Indolent, Recurrent Adult Non-Hodgkin Lymphoma
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 palliative radiation therapy, chemotherapy, or rituximab, an anti-CD20 monoclonal antibody.[2,3] Long-term freedom from second relapse, however, is uncommon and multiple relapses will usually occur. 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.[4,5,6,7,8,9] Rituximab results in a 40% to 50% response rate in patients who relapse with indolent B-cell lymphomas.[10,11,12,13] Rituximab can also be combined with combination chemotherapy.[14] Responses of 20% to 30% have been reported for lenalidomide, especially for follicular lymphoma and small lymphocytic lymphoma.[15][Level of evidence: 3iiiDiv] Durable responses to radiolabeled monoclonal antibodies before and after cytotoxic chemotherapy, such as yttrium-90 ibritumomab (commercially available) and iodine-131 tositumomab, have also been reported.[16,17,18,19,20,21,22] In three randomized, prospective studies involving previously treated patients with relapsed indolent lymphoma, patients were randomly assigned to rituximab maintenance after retreatment with combination chemotherapy (with or without rituximab during induction) or observation alone; all trials showed prolongation of response duration,[23,24,25] and one trial demonstrated improvement in median progression-free survival (3.7 years vs. 1.3 years, P < .001) and overall survival (OS) (74% vs. 64%, P = .07) at 5 years with a median follow-up of 39 months favoring maintenance rituximab.[24][Level of evidence: 1iiDiii]
In many institutions, autologous or allogeneic stem cell transplantations are being used for patients whose disease has relapsed. Such an approach is still under evaluation but should be considered in the context of a clinical trial.[26,27,28,29,30] The German Low-Grade Lymphoma Study Group treated 307 patients with follicular lymphoma with two cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)-like induction chemotherapy and then randomly assigned them to autologous stem cell transplantation versus interferon maintenance.[31] With a median follow-up of 4.2 years, the 5-year progression-free survival was 65% for transplantation versus 33% for interferon (P < .001), but with no difference in OS.[31][Level of evidence: 1iiDiii]
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.[32] 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.[33] 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 retreatment.[34] (Refer to the Aggressive, Recurrent Adult Non-Hodgkin Lymphoma 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.[34,35,36]
Palliation may be achieved with very low-dose (4 Gy) involved-field radiation therapy for patients with indolent and aggressive relapsed disease.[37]
Current Clinical Trials
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.
General information about clinical trials is also available from the NCI Web site.
References:
Aggressive, Recurrent Adult Non-Hodgkin Lymphoma
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]
In a prospective, randomized study, known as the EORTC-PARMA trial, 215 patients in first or second relapse of aggressive lymphoma, younger than 60 years, and with no bone marrow or central nervous system involvement, were given two cycles of intensive combination chemotherapy. The 109 patients who responded were randomly assigned to receive four more cycles of chemotherapy and involved-field radiation therapy (IF-XRT) versus autologous BMT followed by IF-XRT. With a 5-year median follow-up, the event-free survival (EFS) was significantly improved with transplantation (46% vs. 12%). Overall survival (OS) was also significantly better with transplantation (53% vs. 32%).[7][Level of evidence: 1iiA] Salvage BMT was unsuccessful for patients on the nontransplant arm whose disease relapsed.
In general, patients who responded to initial therapy and who have responded to conventional therapy for relapse prior to the BMT have had the best results.[8] In a prospective trial, patients who relapsed late (>12 months after diagnosis) had better OS than patients who relapsed earlier (8-year survival was 29% vs. 13%, P = .001).[9][Level of evidence: 3iiiA] Peripheral stem cell transplantation 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 stem cell transplantation 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 stem cell transplantation.[13,14];[13,15][Level of evidence: 3iiiDiv] In a randomized, prospective trial, 396 patients with diffuse large B-cell lymphoma in first relapse, or who were refractory to first-line therapy, received either R-ICE (rituximab, ifosfamide, etoposide, and carboplatin) or R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin) followed by autologous stem cell transplantation; there was no difference in 3-year EFS or OS.[16][Level of evidence: 1iiA]
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] Rituximab alone can induce responses in 33% of patients with relapsing aggressive lymphoma of appropriate phenotype (CD20-positive).[21];[22][Level of evidence: 3iiiDiv] Radiolabeled anti-CD20 monoclonal antibodies, such as iodine-131 tositumomab and yttrium-90 ibritumomab, induce 60% to 80% response rates in patients with relapsed or refractory B-cell lymphoma.[23,24];[25][Level of evidence: 3iiiDiv] Denileukin diftitox, a fusion protein combining diphtheria toxin and interleukin-2, resulted in a 25% objective response rate in 45 heavily pretreated patients, as evidenced in E-1497, for example, with aggressive B-cell NHL (CD25, i.e., interleukin-2 receptor, expression was not correlated with response).[26][Level of evidence: 3iiiDiv]
The indolent lymphomas may relapse with an aggressive histology (i.e., histologic conversion). The durability of the second remission may be short, and clinical trials, such as autologous or allogeneic peripheral stem cell transplantation, should be considered.[27,28,29,30] 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.[31]
Palliation may be achieved with very low-dose (4 Gy) IF-XRT for patients with indolent and aggressive relapsed disease.[32]
Current Clinical Trials
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.
General information about clinical trials is also available from the NCI Web site.
References:
Non-Hodgkin Lymphoma During Pregnancy
Introduction
Since non-Hodgkin lymphomas (NHL) occur in an older patient population than Hodgkin lymphomas, this may account for fewer reports of NHL patients with coexisting pregnancy.[1]
Stage Information for NHL During Pregnancy
To avoid exposure to ionizing radiation, magnetic resonance imaging is the preferred tool for staging evaluation.[2] (Refer to the Stage Information for Adult Non-Hodgkin Lymphoma section of this summary for more information.)
Treatment Option Overview for NHL During Pregnancy
According to anecdotal case series, most NHL 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]
With follow-up ranging from several months to 11 years, children who were exposed to high-dose doxorubicin-containing combination chemotherapy in utero (especially during the second and third trimester) have been found to be normal.[5,6,7,8] For most of the chemotherapeutic agents used for the treatment of NHL, there are no data regarding long-term effects on children exposed in utero.
Termination of pregnancy in the first trimester may be an option that allows therapy for women with aggressive NHL. For some women, early delivery, when feasible, may minimize or avoid exposure to chemotherapy or radiation therapy. Treatment may be delayed for those women with an indolent NHL
References:
Changes to This Summary (08 / 14 / 2012)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Adult Non-Hodgkin Lymphoma
Updated statistics with estimated new cancer cases and deaths for 2012 (cited American Cancer Society as reference 1).
Cellular Classification of Adult Non-Hodgkin Lymphoma
Added text to state that follicular lymphoma in situ and primary follicular lymphoma of the duodenum are particularly indolent variants that rarely progress and rarely require therapy (cited Schmatz et al. and Jegalian et al. as references 24 and 25, respectively).
Revised text to state that therapy may be required to correct hemolytic anemia in patients with chronic cold agglutinin disease and rituximab, cyclophosphamide, and steroids are often employed.
Added text to state that the rise of IgM after rituximab can be avoided with the concomitant use of an alkylating agent such as cyclophosphamide or of the proteasome inhibitor bortezomib (cited Dimopoulos et al. as reference 44).
Added Laszlo et al. as reference 46.
Revised text to state that myeloablative therapy with autologous or allogeneic hematopoietic stem cell support is under clinical evaluation (cited Kyriakou et al. as reference 55).
Added Bayraktar et al. as reference 87.
Added Stefanovic et al. as reference 88.
Added Stretenovic et al. as reference 90.
Added Kempf et al. as reference 105.
Added Barrans et al. as reference 118.
Added text to state that the addition of rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-based regimens has significantly reduced the risk of central nervous system (CNS) relapse in retrospective analyses (cited Villa et al. and Boehme et al. as references 123 and 124, respectively).
Added text to state for patients with relapse disease, brentuximab vedotin has shown anecdotal responses (cited Younes et al. as reference 144).
Revised text to state that the highly aggressive course has led some investigators to recommend autologous or allogeneic peripheral stem cell transplantation consolidation.
Added text to state that an L-asparaginase-containing regimen has shown anecdotal responses for relapsing patients (cited Jaccard et al. as reference 159).
Added text to state that a benign natural killer (NK)-cell enteropathy on endoscopic biopsy should be distinguished from NK-/T-cell lymphoma (cited Mansoor et al. as reference 161).
Added Weisenburger et al. as and Simon et al. as references 171 and 173, respectively.
Revised text to state that 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.
Added text to state that for relapsing patients, the use of antifolate pralatrexate has shown a 30% response rate and a median 10-month duration of response for 109 evaluable patients in a prospective trial (cited O'Connor et al. as reference 175 and level of evidence 3iiiDiv).
Added Di Sabatino et al. as reference 192.
Added Salaverria et al. as reference 202.
Added text to state that adult T-cell leukemia/lymphoma (ATL) has been divided into four clinical subtypes: acute, lymphoma, chronic, and smoldering (cited Shimoyama et al. and Takasaki et al. as references 221 and 222, respectively). Also added that the acute and lymphoma types of ATL have done poorly with strategies of combination chemotherapy and allogeneic stem cell transplantation (cited Yamada et al. and Fukushima et al. as references 223 and 224, respectively).
Revised text to state that the combination of zidovudine and interferon-alpha, which has activity against the leukemic subtype, and sometimes the smoldering and chronic forms of ATL; added that 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 (cited 2010 Bazarbachi et al. and 2011 Bazarbachi et al. as references 229 and 230, respectively).
Added Pérez-Galán et al. as reference 234; also revised text to state that it is unclear which chemotherapeutic approach offers the best long-term survival in this clinicopathologic entity and that rituximab with CHOP or CHOP-like regimens is the usual first-line induction therapy; also added Griffiths et al. as reference 246.
Stage Information for Adult Non-Hodgkin Lymphoma
Added Salles et al. and Advani et al. as references 12 and 13, respectively.
Treatment Option Overview
Added Morton et al. as reference 12.
Added text to state that in addition to screening for human immunodeficiency virus among patients with aggressive lymphomas, prior infection with hepatitis B or hepatitis C should be assessed prior to treatment with rituximab and/or chemotherapy since reactivation of hepatitis may mandate antiviral therapy or discontinuation of rituximab (cited Niitsu et al. as reference 17).
Added Vitolo et al. as reference 31.
Indolent, Stage I and Contiguous Stage II Adult Non-Hodgkin Lymphoma
Added text to state that almost half of all patients treated with radiation therapy alone will relapse out-of-field within 10 years (cited Guadagnolo et al. as reference 5). Also revised text to state that the value of adjuvant treatment with rituximab or chemotherapy in addition to radiation to decrease relapse, has not been confirmed.
Added text to state that a retrospective analysis of the SEER database over 30 years showed improved outcomes for upfront radiation therapy, but one must be very cautious about this type of retrospective analysis. Watchful waiting has never been compared with upfront radiation therapy in a prospective randomized trial (cited Pugh et al. as reference 9).
Indolent, Noncontiguous Stage II/III/IV Adult Non-Hodgkin Lymphoma
Revised text to state that in three randomized prospective studies involving previously treated patients with relapsed indolent lymphoma, patients were randomly assigned to rituximab maintenance after retreatment with combination chemotherapy or observation alone; all trials showed prolongation of response duration (cited van Oers et al. and Martinelli et al. as references 24 and 26, respectively); also updated statistics of one trial that demonstrated improvement in median progression-free survival favoring maintenance rituximab (van Oers, level of evidence 1iiDiii).
Added text to state that in the PRIMA study, 1,019 previously untreated high-risk patients who required treatment achieved complete or partial response after induction therapy with immunochemotherapy and were then randomly assigned to 2 years of maintenance rituximab versus no maintenance (cited Salles et al. as reference 27 and level of evidence 1iiDiii); also added that at a median follow-up, progression-free survival favored rituximab maintenance with no difference in overall survival (OS).
Added text to state that many questions remain about rituximab maintenance, and 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 (cited Friedberg et al. as reference 28).
Revised text of the ninth standard treatment option to include noncontiguous stage II patients (cited Jacobs et al. and Mendenhall et al. as references 72 and 73, respectively).
Aggressive, Noncontiguous Stage II/III/IV Adult Non-Hodgkin Lymphoma
Revised text to include statistics for a 10-year median follow-up (cited 2010 Coiffier et al. as reference 9).
Added Ziepert et al. as reference 23.
Added text to state that the addition of rituximab to CHOP-based regimens has significantly reduced the risk of CNS relapse in retrospective analyses (cited Villa et al. and Boehme et al. as references 40 and 41, respectively).
Added text to state that patients with bulky and extensive lymphadenopathy and elevations of serum uric acid and lactate dehydrogenase are at increased risk of tumor lysis syndrome resulting in metabolic derangements such as hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and subsequent acute renal failure (cited 2008 Coiffier et al. as reference 42). Also added that treatment options include: alkaline hydration; allopurinol; and rasburicase, a recombinant urate oxidase (cited Cortes et al. as reference 43).
Indolent, Recurrent Adult Non-Hodgkin Lymphoma
Revised text to state that durable responses to radiolabeled monoclonal antibodies before and after cytotoxic chemotherapy have also been reported (cited Link et al. as reference 22).
Revised text to state that in three randomized prospective studies involving previously treated patients with relapsed indolent lymphoma, patients were randomly assigned to rituximab maintenance after retreatment with combination chemotherapy or observation alone; all trials showed prolongation of response duration (cited van Oers et al. and Martinelli et al. as references 24 and 26, respectively); also updated statistics of one trial that demonstrated improvement in median progression-free survival favoring maintenance rituximab (van Oers, level of evidence 1iiDiii).
Aggressive, Recurrent Adult Non-Hodgkin Lymphoma
Added van Kampen et al. as reference 13.
Added text to state that in a randomized, prospective trial, 396 patients with diffuse large B-cell lymphoma in first relapse, or who were refractory to first-line therapy, received either R-ICE (rituximab, ifosfamide, etoposide, and carboplatin) or R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin) followed by autologous stem cell transplantation; there was no difference in 3-year event-free survival or OS (cited Gisselbrecht et al. as reference 16 and level of evidence 1iiA).
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult non-Hodgkin lymphoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
- be discussed at a meeting,
- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Adult Non-Hodgkin Lymphoma Treatment are:
- Mark J. Levis, MD, PhD (Johns Hopkins University)
- Eric J. Seifter, MD (Johns Hopkins University)
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National Cancer Institute: PDQ® Adult Non-Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2012-08-14
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