Lymphoma, non-Hodgkin's, adult: Treatment - Health Professional Information [NCI PDQ]

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Adult Non-Hodgkin Lymphoma Treatment (PDQ®)

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult non-Hodgkin lymphoma. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

  • Prognostic factors.
  • Cellular classification.
  • Staging.
  • Pregnancy-related considerations.
  • Treatment options by cancer stage.

This summary 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.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

General Information About Adult Non-Hodgkin Lymphoma

Related Summaries

Other PDQ summaries containing information related to non-Hodgkin lymphoma include:

  • AIDS-Related Lymphoma Treatment
  • Primary Central Nervous System Lymphoma Treatment
  • Childhood Non-Hodgkin Lymphoma Treatment

Statistics

Note: Estimated new cases and deaths from non-Hodgkin lymphoma (NHL) in the United States in 2008:[1]

  • New cases: 66,120.
  • Deaths: 19,160.

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 re-treated with considerable success as long as the disease histology remains low grade. Patients who present with or convert to aggressive forms of NHL may have sustained complete remissions with combination chemotherapy regimens or aggressive consolidation with marrow or stem cell support.[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.)

References:

  1. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. Last accessed February 21, 2008.
  2. Armitage JO: Treatment of non-Hodgkin's lymphoma. N Engl J Med 328 (14): 1023-30, 1993.
  3. Cabanillas F, Velasquez WS, Hagemeister FB, et al.: Clinical, biologic, and histologic features of late relapses in diffuse large cell lymphoma. Blood 79 (4): 1024-8, 1992.
  4. Bastion Y, Sebban C, Berger F, et al.: Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol 15 (4): 1587-94, 1997.
  5. Yuen AR, Kamel OW, Halpern J, et al.: Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 13 (7): 1726-33, 1995.

Cellular Classification of Adult Non-Hodgkin Lymphoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

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.

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.[9,10,11]

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.[9,10,11]

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.
    1. B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma.
    2. B-cell prolymphocytic leukemia.
    3. Lymphoplasmacytic lymphoma/immunocytoma.
    4. Mantle cell lymphoma.
    5. Follicular lymphoma.
    6. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type.
    7. Nodal marginal zone B-cell lymphoma (± monocytoid B-cells).
    8. Splenic marginal zone lymphoma (± villous lymphocytes).
    9. Hairy cell leukemia.
    10. Plasmacytoma/plasma cell myeloma.
    11. Diffuse large B-cell lymphoma.
    12. Burkitt lymphoma.

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.
    1. T-cell chronic lymphocytic leukemia/prolymphocytic leukemia.
    2. T-cell granular lymphocytic leukemia.
    3. Mycosis fungoides/Sézary syndrome.
    4. Peripheral T-cell lymphoma, not otherwise characterized.
    5. Hepatosplenic gamma/delta T-cell lymphoma.
    6. Subcutaneous panniculitis-like T-cell lymphoma.
    7. Angioimmunoblastic T-cell lymphoma.
    8. Extranodal T-/NK-cell lymphoma, nasal type.
    9. Enteropathy-type intestinal T-cell lymphoma.
    10. Adult T-cell lymphoma/leukemia (human T-lymphotrophic virus [HTLV] 1+).
    11. Anaplastic large cell lymphoma, primary systemic type.
    12. Anaplastic large cell lymphoma, primary cutaneous type.
    13. Aggressive NK-cell leukemia.

Hodgkin lymphoma

  1. Nodular lymphocyte–predominant Hodgkin lymphoma.
  2. Classical Hodgkin lymphoma.
    1. Nodular sclerosis Hodgkin lymphoma.
    2. Lymphocyte-rich classical Hodgkin lymphoma.
    3. Mixed-cellularity Hodgkin lymphoma.
    4. Lymphocyte-depleted 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
  • Multiple Myeloma and Other Plasma Cell Neoplasms Treatment
  • Mycosis Fungoides/Sézary Syndrome Treatment
  • Primary Central Nervous System 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 Multiple Myeloma and Other Plasma Cell Neoplasms Treatment for more information.)
    1. Bone.
    2. Extramedullary.
      1. Monoclonal gammopathy of undetermined significance.
      2. Plasmacytoma.
      3. Multiple myeloma.
      4. Amyloidosis.
  2. Hodgkin lymphoma. (Refer to the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.)
    1. Nodular sclerosis Hodgkin lymphoma.
    2. Lymphocyte-rich classical Hodgkin lymphoma.
    3. Mixed-cellularity Hodgkin lymphoma.
    4. Lymphocyte-depleted Hodgkin lymphoma.
  3. Indolent lymphoma/leukemia.
    1. Follicular lymphoma (follicular small-cleaved cell [grade 1], follicular mixed small-cleaved, and large cell [grade 2], and diffuse small-cleaved cell).
    2. Chronic lymphocytic leukemia/small lymphocytic lymphoma. (Refer to the PDQ summary on Chronic Lymphocytic Leukemia Treatment for more information.)
    3. Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia).
    4. Extranodal marginal zone B-cell lymphoma (MALT lymphoma).
    5. Nodal marginal zone B-cell lymphoma (monocytoid B-cell lymphoma).
    6. Splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes).
    7. Hairy cell leukemia. (Refer to the PDQ summary on Hairy Cell Leukemia Treatment for more information.)
    8. Mycosis fungoides/Sézary syndrome. (Refer to the PDQ summary on Mycosis Fungoides/Sézary Syndrome Treatment for more information.)
    9. T-cell granular lymphocytic leukemia. (Refer to the PDQ summary on Chronic Lymphocytic Leukemia Treatment for more information.)
    10. Primary cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis (CD30+).
    11. Nodular lymphocyte–predominant Hodgkin lymphoma. (Refer to the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.)
  4. Aggressive lymphoma/leukemia.
    1. Diffuse large cell lymphoma (includes diffuse mixed-cell, diffuse large cell, immunoblastic, and T-cell rich large B-cell lymphoma).

      Distinguish:

      1. Mediastinal large B-cell lymphoma.
      2. Follicular large cell lymphoma (grade 3).
      3. Anaplastic large cell lymphoma (CD30+).
      4. Extranodal NK-/T-cell lymphoma, nasal type/aggressive NK-cell leukemia/blastic NK-cell lymphoma.
      5. Lymphomatoid granulomatosis (angiocentric pulmonary B-cell lymphoma).
      6. Angioimmunoblastic T-cell lymphoma.
      7. Peripheral T-cell lymphoma, unspecified.
        1. Subcutaneous panniculitis-like T-cell lymphoma.
        2. Hepatosplenic T-cell lymphoma.
      8. Enteropathy-type T-cell lymphoma.
      9. Intravascular large B-cell lymphoma.
    2. Burkitt lymphoma/Burkitt cell leukemia/Burkitt-like lymphoma.
    3. Precursor B-cell or T-cell lymphoblastic lymphoma/leukemia. (Refer the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)
    4. Primary central nervous system (CNS) lymphoma. (Refer to the PDQ summary on Primary Central Nervous System Lymphoma Treatment for more information.)
    5. Adult T-cell leukemia/lymphoma (HTLV 1+).
    6. Mantle cell lymphoma.
    7. Polymorphic posttransplantation lymphoproliferative disorder (PTLD).
    8. AIDS-related lymphoma. (Refer to the PDQ summary on AIDS-Related Lymphoma Treatment for more information.)
    9. True histiocytic lymphoma.
    10. Primary effusion lymphoma.
    11. B-cell or T-cell prolymphocytic leukemia. (Refer to the PDQ summary on Chronic Lymphocytic Leukemia Treatment for more information.)

Indolent NHL

FOLLICULAR LYMPHOMA

Follicular lymphoma comprises 20% of all non-Hodgkin lymphomas and as many as 70% of the indolent lymphomas reported in American and European clinical trials.[7,8,11] 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.[12]

Despite the advanced stage, the median survival ranges from 8 to 15 years, leading to the designation of being indolent.[13,14,15] Patients with advanced-stage follicular lymphoma are not cured with current therapeutic options.[16] The rate of relapse is fairly consistent over time, even in patients who have achieved complete responses to treatment.[17] Watchful waiting, i.e., the deferring of treatment until the patient becomes symptomatic, is an option for patients with advanced-stage follicular lymphoma.[18] An international index for follicular lymphoma (i.e., the Follicular Lymphoma International Prognostic Index [FLIPI])[19,20,21] identified five significant risk factors prognostic of overall survival (OS):

  1. Age (=60 years vs. >60 years).
  2. Serum lactate dehydrogenase (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 0 to 1 risk factors have an 85% 10-year survival rate, while three or more risk factors confer a 40% 10-year survival rate.[19] 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] These infiltrating nonmalignant cells may be valuable therapeutic targets.[23]

Follicular small-cleaved cell lymphoma and follicular mixed small-cleaved and large cell lymphoma do not have reproducibly different disease-free survival or OS.[10] Therapeutic options include watchful waiting; rituximab, an anti-CD20 monoclonal antibody, alone or with purine nucleoside analogs; oral alkylating agents; and combination chemotherapy.[24] Radiolabeled monoclonal antibodies, vaccines, and autologous or allogeneic bone marrow or peripheral stem cell transplantation are also under clinical evaluation.[24] 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.

LYMPHOPLASMACYTIC LYMPHOMA (WALDENSTRöM MACROGLOBULINEMIA)

Lymphoplasmacytic lymphoma is usually associated with a monoclonal serum paraprotein of immunoglobulin M (IgM) type (Waldenström macroglobulinemia).[25,26,27] Most patients have bone marrow, lymph node, and splenic involvement, and some patients may develop hyperviscosity syndrome. Other lymphomas may also be associated with serum paraproteins.

The management of lymphoplasmacytic lymphoma is similar to that of other low-grade lymphomas, especially diffuse small lymphocytic lymphoma/chronic lymphocytic leukemia.[26,27,28,29,30] 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 CNS 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; chlorambucil, with or without prednisone, is the mainstay. 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.[18] First-line regimens include rituximab, the nucleoside analogs, and alkylating agents, either as single agents or as part of combination chemotherapy.[31] 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.[31,32,33][Level of evidence: 3iiiDiv] The nucleoside analogues 2-chlorodeoxyadenosine and fludarabine have shown similar response rates for previously untreated patients with lymphoplasmacytic lymphoma.[34,35,36][Level of evidence: 3iiiDiv] Single-agent alkylators and combination chemotherapy also show similar response rates.[37][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.[27,31]

Interferon-alpha also shows activity in this disease, in contrast to poor responses in patients with multiple myeloma.[38] Myeloablative therapy with autologous hematopoietic stem cell support is under clinical evaluation.[39,40] Candidates for this approach should avoid long-term use of alkylating agents or purine nucleoside analogs, which can deplete hematopoietic stem cells.[31] After relapse from alkylating-agent therapy, 92 patients with lymphoplasmacytic lymphoma were randomized to fludarabine versus 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.[41][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.[42][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 MALT lymphomas.[4,43,44,45,46,47,48,49,50,51]

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 many cases of localized gastric involvement.[50,52,53,54,55,56] 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.[57] 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.[58,59] Stable asymptomatic patients with persistently positive biopsies have been successfully followed on a watchful waiting approach until disease progression.[55,56] Patients who progress are treated with radiation therapy,[60,61,62] rituximab,[63] surgery (total gastrectomy or partial gastrectomy plus radiation therapy),[64] chemotherapy,[48] or combined modality therapy.[65] The use of endoscopic ultrasonography may help clinicians to follow responses in these patients.[66]

Localized involvement of other sites can be treated with radiation or surgery.[61,62,67] 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.[68] Many of these recurrences involve different MALT sites than the original location. When disseminated to lymph nodes, bone marrow, or blood, this entity behaves like other low-grade lymphomas.[49,69] Extragastric MALT lymphoma does not respond to antibiotic treatment.[70] For patients with ocular adnexal MALT, antibiotic therapy using doxycycline targeting Chlamydia psittaci resulted in durable remissions for several patients in a small anecdotal series.[71][Level of evidence: 3iiiDiv] Large B-cell lymphomas of MALT sites are classified and treated as diffuse large cell lymphomas.[72] Three small case series (two retrospective and one prospective) report 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 months).[73,74,75]

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.[42][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.[76] Campylobacter jejuni has been identified as one of the bacterial species associated with IPSID, and antibiotic therapy may result in remission of the disease.[77]

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.[78,79,80] This type of lymphoma is otherwise known as splenic lymphoma with villous lymphocytes. Splenectomy may result in prolonged remission.[51,81] 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.[82] Splenic marginal zone lymphoma responds less well to chemotherapy, which would ordinarily be effective for chronic lymphocytic leukemia.[79,80,82] 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.[42,83,84][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.[85,86] 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.[85,86]

(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 non-Hodgkin lymphomas 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). The vast majority of patients with localized disease are curable with combined modality therapy or combination chemotherapy alone.[87] For patients with advanced-stage disease, 50% of presenting patients are cured with doxorubicin-based combination chemotherapy and rituximab.[88,89,90]

An International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS:[91]

  1. Age (=60 years of age vs. >60 years of age).
  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, CNS, liver, lung, and spleen. Age-adjusted and stage-adjusted modifications of this IPI are used for younger patients with localized disease.[92] Patients at high risk of relapse may be considered for clinical trials.[93] 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.[94,95,96,97]

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.[98] CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, others do not.[99] 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.[