Adult Non-Hodgkin Lymphoma Treatment - National Cancer Institute

Table of Contents

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 ¹.

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 ² 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 ³, written in less technical language, and in Spanish ⁴.

General Information About Adult Non-Hodgkin Lymphoma

Related Summaries

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

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 ⁵ for more information.)

References

American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. ⁸ Last accessed October 1, 2008.
Armitage JO: Treatment of non-Hodgkin's lymphoma. N Engl J Med 328 (14): 1023-30, 1993. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]

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 ² 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

Enlarge ⁹

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.[5-8] 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.[9-11]

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.[9-11]

Updated REAL/WHO Classification

B-cell neoplasms

Precursor B-cell neoplasm: precursor B-acute lymphoblastic leukemia/lymphoblastic lymphoma (LBL).
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

Precursor T-cell neoplasm: precursor T-acute lymphoblastic leukemia/LBL.
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

Nodular lymphocyte–predominant Hodgkin lymphoma.
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:

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

Plasma cell disorders. (Refer to the PDQ summary on Multiple Myeloma and Other Plasma Cell Neoplasms Treatment ¹⁴ for more information.)
1. Bone.
2. Extramedullary.
  1. Monoclonal gammopathy of undetermined significance.
  2. Plasmacytoma.
  3. Multiple myeloma.
  4. Amyloidosis.
Hodgkin lymphoma. (Refer to the PDQ summary on Adult Hodgkin Lymphoma Treatment ¹¹ for more information.)
1. Nodular sclerosis Hodgkin lymphoma.
2. Lymphocyte-rich classical Hodgkin lymphoma.
3. Mixed-cellularity Hodgkin lymphoma.
4. Lymphocyte-depleted Hodgkin lymphoma.
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 ¹² 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 ¹³ for more information.)
8. Mycosis fungoides/Sézary syndrome. (Refer to the PDQ summary on Mycosis Fungoides/Sézary Syndrome Treatment ¹⁵ for more information.)
9. T-cell granular lymphocytic leukemia. (Refer to the PDQ summary on Chronic Lymphocytic Leukemia Treatment ¹² 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 ¹¹ for more information.)
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 ¹⁰ for more information.)
4. Primary central nervous system (CNS) lymphoma. (Refer to the PDQ summary on Primary Central Nervous System Lymphoma Treatment ⁶ 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 ⁵ 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 ¹² 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.[13-15] 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])[19-21] identified five significant risk factors prognostic of overall survival (OS):

Age (≤60 years vs. >60 years).
Serum lactate dehydrogenase (normal vs. elevated).
Stage (stage I or stage II vs. stage III or stage IV).
Hemoglobin level (≥120 g/L vs. <120 g/L).
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.

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.[25] 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.[26] In this series, high-risk factors for subsequent histologic transformation were advanced stage, high-risk Follicular Lymphoma International Prognostic Index (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.[27] Histologic conversions should be treated with the regimens described in the Aggressive, Recurrent Adult Non-Hodgkin's Lymphoma ¹⁶ section of this summary. The durability of the second remission may be short, and clinical trials should be considered.[27-29]

Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia)

Lymphoplasmacytic lymphoma is usually associated with a monoclonal serum paraprotein of immunoglobulin M (IgM) type (Waldenström macroglobulinemia).[30-32] 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.[31-35] 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.[36,37] 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.[36,38,39][Level of evidence: 3iiiDiv] The nucleoside analogues 2-chlorodeoxyadenosine and fludarabine have shown similar response rates for previously untreated patients with lymphoplasmacytic lymphoma.[40-42][Level of evidence: 3iiiDiv] Single-agent alkylators and combination chemotherapy also show similar response rates.[43][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.[31,32,36]

Interferon-alpha also shows activity in this disease, in contrast to poor responses in patients with multiple myeloma.[44] Myeloablative therapy with autologous hematopoietic stem cell support is under clinical evaluation.[45,46] Candidates for this approach should avoid long-term use of alkylating agents or purine nucleoside analogs, which can deplete hematopoietic stem cells.[36] 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.[47][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.[48][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.[4,49-57]

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.[56,58-62] 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.[63] 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.[64-66] Stable asymptomatic patients with persistently positive biopsies have been successfully followed on a watchful waiting approach until disease progression.[61,62] Patients who progress are treated with radiation therapy,[67-70] rituximab,[71] surgery (total gastrectomy or partial gastrectomy plus radiation therapy),[72] chemotherapy,[54] or combined modality therapy.[73] The use of endoscopic ultrasonography may help clinicians to follow responses in these patients.[74] 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 months).[75-77]

Localized involvement of other sites can be treated with radiation or surgery.[68-70,78] 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.[79] 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.[55,80] 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.[81][Level of evidence: 3iiiDiv] Large B-cell lymphomas of MALT sites are classified and treated as diffuse large cell lymphomas.[82]

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.[48][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.[83] Campylobacter jejuni has been identified as one of the bacterial species associated with IPSID, and antibiotic therapy may result in remission of the disease.[84]

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.[85-87] This type of lymphoma is otherwise known as splenic lymphoma with villous lymphocytes. Splenectomy may result in prolonged remission.[57,88] 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.[89] Splenic marginal zone lymphoma responds less well to chemotherapy, which would ordinarily be effective for chronic lymphocytic leukemia.[86,87,89] 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.[48,90,91][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.[92,93] 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.[92,93]

(Refer to the PDQ summaries on Chronic Lymphocytic Leukemia Treatment ¹²; Mycosis Fungoides/Sézary Syndrome Treatment ¹⁵; Hairy Cell Leukemia Treatment ¹³; and Adult Hodgkin Lymphoma Treatment ¹¹ 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). (Refer to the PDQ summary on Fever, Sweats, and Hot Flashes ¹⁷and for more information on weight loss, refer to the Nutrition in Cancer Care ¹⁸ summary.) The vast majority of patients with localized disease are curable with combined modality therapy or combination chemotherapy alone.[94] For patients with advanced-stage disease, 50% of presenting patients are cured with doxorubicin-based combination chemotherapy and rituximab.[95-97]

An International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS:[98]

Age (≤60 years of age vs. >60 years of age).
Serum lactate dehydrogenase (LDH) (normal vs. elevated).
Performance status (0 or 1 vs. 2–4).
Stage (stage I or stage II vs. stage III or stage IV).
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.[99] Patients at high risk of relapse may be considered for clinical trials.[100] 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.[101-104]

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.[105] CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, others do not.[106] 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.[107][Level of evidence: 3iiiDiii] 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.[108-110] 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.[111]

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.[112-118] 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 prognoses (progression-free survival is less than 20%) whether the effusion is cytologically positive or negative. (For information on superior vena cava syndrome and pleural effusion, refer to the Cardiopulmonary Syndromes ¹⁹ summary.) High-dose chemotherapy with hematopoietic stem cell rescue has been applied to these poor prognosis patients. Evidence for this approach is anecdotal.[118]

Follicular large cell lymphoma

The natural history of follicular large cell lymphoma remains controversial.[119] 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).[120] Other investigators report a plateau in freedom-from-progression at levels expected for an aggressive lymphoma (40% at 10 years).[121,122] 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.[123] 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.[124][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.[125] 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.[126] Patients with these types of lymphomas are generally treated the same as patients with diffuse large cell lymphomas and have as good a prognosis as comparably staged patients, as evidenced in the NHL-BFM-90 ²⁰ trial. Anaplastic large cell lymphoma in children is usually characterized by systemic and cutaneous disease and has high response rates and good OS with doxorubicin-based combination chemotherapy.[127]

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.[128-133] 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.[134] 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. In addition to doxorubicin-based combination chemotherapy, the increased risk of CNS involvement and of local recurrence has led to recommendations for radiation therapy locally, often prior to the start of chemotherapy, and for intrathecal prophylaxis and/or prophylactic cranial radiation therapy.[129,133,135-138] The highly aggressive course, with poor response and short survival with standard therapies, especially for patients with advanced stage disease, has led some investigators to recommend bone marrow or peripheral stem cell transplantation consolidation.[130-132] NK-/T-cell lymphoma that presents only in the skin has a more favorable prognosis, especially in patients with coexpression of CD30 with CD56.[139]

Lymphomatoid granulomatosis

Lymphomatoid granulomatosis is an EBV-positive large B-cell lymphoma with a predominant T-cell background.[140,141] 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.[142-144] Patients present with profound lymphadenopathy, fever, night sweats, weight loss, skin rash, a positive Coomb test, and polyclonal hypergammaglobulinemia.[134] (For information on night sweats, weight loss, and skin rash, refer to the PDQ summaries on Fever, Sweats, and Hot Flashes ¹⁷, Nutrition in Cancer Care ¹⁸, and Pruritus ²¹, respectively.) Opportunistic infections are frequent because of an underlying immune deficiency. Doxorubicin-based combination chemotherapy is recommended as it is for other aggressive lymphomas.[142] Myeloablative chemotherapy and radiation therapy with autologous peripheral stem cell support has been described in anecdotal reports.[145] Occasional spontaneous remissions and protracted responses to steroids only have been reported. B-cell EBV genomes are detected in most affected patients.[146]

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.[147] Peripheral T-cell lymphoma encompasses a group of heterogeneous nodal T-cell lymphomas that will require future delineation.[134] 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.[148-150] Therapy involves doxorubicin-based combination chemotherapy, which is also used for B-cell diffuse large cell lymphoma. 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.[150] High-dose chemotherapy with hematopoietic stem cell support has been applied to patients with advanced-stage peripheral T-cell lymphoma. Evidence for this approach is anecdotal.[145,151] Anecdotal responses have also been seen with alemtuzumab, an anti-CD52 monoclonal antibody, or denileukin difitox, a toxin-antibody ligand, after relapse from previous chemotherapy.[152,153] 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.[154-158] Another variant, subcutaneous panniculitis-like T-cell lymphoma, is localized to subcutaneous tissue associated with hemophagocytic syndrome.[159-162] 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.[163-165] 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.

Enteropathy-type intestinal T-cell lymphoma

Enteropathy-type intestinal T-cell lymphoma involves the small bowel of patients with gluten-sensitive enteropathy (celiac sprue).[134,166,167] 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.[167,168] 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 ²² summary and the Nutrition in Cancer Care ¹⁸ 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.[167] 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.[169,170] 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 non-Hodgkin lymphoma.[171] These types of aggressive extranodal B-cell lymphomas are characterized by translocation and deregulation of the C-myc gene on chromosome 8.[172] A subgroup of patients with dual translocation of C-myc and bcl-2 appear to have an extremely poor outcome despite aggressive therapy (5-month OS).[173][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.[10,174,175] 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 lactate dehydrogenase 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).[176-178] Aggressive combination chemotherapy, which is patterned after that used in childhood Burkitt lymphoma, has been described in CALGB-9251 ²³, for example, and has been very successful for adult patients with more than 60% of advanced-stage patients free of disease at 5 years.[179-184] Adverse prognostic factors include bulky abdominal disease and high serum LDH. In some institutions, treatment includes the use of consolidative bone marrow transplantation (BMT).[185,186] 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.[187] (Refer to the PDQ summaries on Primary Central Nervous System Lymphoma Treatment ⁶ and AIDS-Related Lymphoma Treatment ⁵ 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.[188] 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.[189-191] 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 ¹⁰ for more information.)

Adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma is caused by infection with the retrovirus human T-cell lymphotropic virus type I and is frequently associated with lymphadenopathy, hypercalcemia, circulating leukemic cells, bone and skin involvement, hepatosplenomegaly, a rapidly progressive course, and poor response to chemotherapy.[192,193] (Refer to the PDQ summary on Hypercalcemia ²⁴ for more information.) Using combination chemotherapy, only 10% to 20% of patients survived even 3 years in a trial of 118 patients.[194] The combination of zidovudine and interferon-alpha has activity against adult T-cell leukemia/lymphoma, even for patients who failed previous cytotoxic therapy. Durable remissions are seen in 66% of presenting patients with this combination, but long-term disease-free survival rates are not yet available.[195-197]

Mantle cell lymphoma

Mantle cell lymphoma is found in lymph nodes, the spleen, bone marrow, blood, and sometimes the gastrointestinal system (lymphomatous polyposis).[4,198,199] 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.[200] 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.[201] 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.[202] 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.[49,203] A high cell proliferation rate (increased Ki-67, mitotic index, beta-2-microglobulin) may be associated with a poorer prognosis.[200,204] It is unclear which chemotherapeutic approach offers the best long-term survival in this clinicopathologic entity; refractoriness to chemotherapy is a usual feature.[202,205-210] Many investigators are exploring high-dose therapy with stem cell/marrow support or the use of interferon or anti-CD20 antibodies after CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy.[207-209,211-218] Thus far, randomized trials have not shown OS benefits from these newer approaches.[218] 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.[219-221][Level of evidence: 3iiiDiv]

Polymorphic posttransplantation lymphoproliferative disorder (PTLD)

Patients who undergo transplantation of the heart, lung, liver, kidney, or pancreas usually require life-long immunosuppression. This may result in PTLD in 1% to 3% of recipients, which appears as an aggressive lymphoma.[222] Pathologists can distinguish a polyclonal B-cell hyperplasia from a monoclonal B-cell lymphoma; both are almost always associated with EBV.[223] Poor performance status, grafted organ involvement, high IPI, elevated LDH, and multiple sites of disease are poor prognostic factors for PTLD.[224,225] In some cases, withdrawal of immunosuppression results in eradication of the lymphoma.[226] 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.[227] Sometimes, a combination of acyclovir and interferon-alpha has been used.[222,228] If these measures fail, doxorubicin-based combination chemotherapy is recommended, though most patients can avoid cytotoxic therapy.[229] 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.[223] Multifocal, rapidly progressive disease occurs late after transplantation (>1 year) and is usually phenotypically monoclonal and associated with EBV.[230] These patients may have durable remissions using standard chemotherapy regimens for aggressive lymphoma.[230-232] Instances of EBV-negative PTLD occur late (median, 5 years posttransplant) and have particularly poor prognoses.[233] 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).[234] An anti-interleukin-6 monoclonal antibody is also under clinical evaluation.[235]

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.[236,237] Care must be taken with immunophenotypic tests to exclude anaplastic large cell lymphoma 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.[238] 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

Zeppa P, Marino G, Troncone G, et al.: Fine-needle cytology and flow cytometry immunophenotyping and subclassification of non-Hodgkin lymphoma: a critical review of 307 cases with technical suggestions. Cancer 102 (1): 55-65, 2004. [PUBMED Abstract]
Young NA, Al-Saleem T: Diagnosis of lymphoma by fine-needle aspiration cytology using the revised European-American classification of lymphoid neoplasms. Cancer 87 (6): 325-45, 1999. [PUBMED Abstract]
National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer 49 (10): 2112-35, 1982. [PUBMED Abstract]
Pugh WC: Is the working formulation adequate for the classification of the low grade lymphomas? Leuk Lymphoma 10(Suppl): 1-8, 1993.
Harris NL, Jaffe ES, Stein H, et al.: A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84 (5): 1361-92, 1994. [PUBMED Abstract]
Pittaluga S, Bijnens L, Teodorovic I, et al.: Clinical analysis of 670 cases in two trials of the European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group subtyped according to the Revised European-American Classification of Lymphoid Neoplasms: a comparison with the Working Formulation. Blood 87 (10): 4358-67, 1996. [PUBMED Abstract]
Armitage JO, Weisenburger DD: New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 16 (8): 2780-95, 1998. [PUBMED Abstract]
A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 89 (11): 3909-18, 1997. [PUBMED Abstract]
Pileri SA, Milani M, Fraternali-Orcioni G, et al.: From the R.E.A.L. Classification to the upcoming WHO scheme: a step toward universal categorization of lymphoma entities? Ann Oncol 9 (6): 607-12, 1998. [PUBMED Abstract]
Harris NL, Jaffe ES, Armitage JO, et al.: Lymphoma classification: from R.E.A.L. to W.H.O. and beyond. Cancer: Principles and Practice of Oncology Updates 13(3): 1-14, 1999.
Society for Hematopathology Program.: Society for Hematopathology Program. Am J Surg Pathol 21(1): 114-121, 1997.
López-Guillermo A, Cabanillas F, McDonnell TI, et al.: Correlation of bcl-2 rearrangement with clinical characteristics and outcome in indolent follicular lymphoma. Blood 93 (9): 3081-7, 1999. [PUBMED Abstract]
Peterson BA, Petroni GR, Frizzera G, et al.: Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B. J Clin Oncol 21 (1): 5-15, 2003. [PUBMED Abstract]
Swenson WT, Wooldridge JE, Lynch CF, et al.: Improved survival of follicular lymphoma patients in the United States. J Clin Oncol 23 (22): 5019-26, 2005. [PUBMED Abstract]
Liu Q, Fayad L, Cabanillas F, et al.: Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol 24 (10): 1582-9, 2006. [PUBMED Abstract]
Hiddemann W, Buske C, Dreyling M, et al.: Treatment strategies in follicular lymphomas: current status and future perspectives. J Clin Oncol 23 (26): 6394-9, 2005. [PUBMED Abstract]
Fisher RI, LeBlanc M, Press OW, et al.: New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol 23 (33): 8447-52, 2005. [PUBMED Abstract]
Ardeshna KM, Smith P, Norton A, et al.: Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet 362 (9383): 516-22, 2003. [PUBMED Abstract]
Solal-Céligny P, Roy P, Colombat P, et al.: Follicular lymphoma international prognostic index. Blood 104 (5): 1258-65, 2004. [PUBMED Abstract]
Perea G, Altés A, Montoto S, et al.: Prognostic indexes in follicular lymphoma: a comparison of different prognostic systems. Ann Oncol 16 (9): 1508-13, 2005. [PUBMED Abstract]
Buske C, Hoster E, Dreyling M, et al.: The Follicular Lymphoma International Prognostic Index (FLIPI) separates high-risk from intermediate- or low-risk patients with advanced-stage follicular lymphoma treated front-line with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with respect to treatment outcome. Blood 108 (5): 1504-8, 2006. [PUBMED Abstract]
Dave SS, Wright G, Tan B, et al.: Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351 (21): 2159-69, 2004. [PUBMED Abstract]
Küppers R: Prognosis in follicular lymphoma--it's in the microenvironment. N Engl J Med 351 (21): 2152-3, 2004. [PUBMED Abstract]
Peterson BA: Current treatment of follicular low-grade lymphomas. Semin Oncol 26 (5 Suppl 14): 2-11, 1999. [PUBMED Abstract]
Tsimberidou AM, O'Brien S, Khouri I, et al.: Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol 24 (15): 2343-51, 2006. [PUBMED Abstract]
Montoto S, Davies AJ, Matthews J, et al.: Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 25 (17): 2426-33, 2007. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
Williams CD, Harrison CN, Lister TA, et al.: High-dose therapy and autologous stem-cell support for chemosensitive transformed low-grade follicular non-Hodgkin's lymphoma: a case-matched study from the European Bone Marrow Transplant Registry. J Clin Oncol 19 (3): 727-35, 2001. [PUBMED Abstract]
Facon T, Brouillard M, Duhamel A, et al.: Prognostic factors in Waldenström's macroglobulinemia: a report of 167 cases. J Clin Oncol 11 (8): 1553-8, 1993. [PUBMED Abstract]
Vijay A, Gertz MA: Waldenström macroglobulinemia. Blood 109 (12): 5096-103, 2007. [PUBMED Abstract]
Dimopoulos MA, Kyle RA, Anagnostopoulos A, et al.: Diagnosis and management of Waldenstrom's macroglobulinemia. J Clin Oncol 23 (7): 1564-77, 2005. [PUBMED Abstract]
Leblond V, Ben-Othman T, Deconinck E, et al.: Activity of fludarabine in previously treated Waldenström's macroglobulinemia: a report of 71 cases. Groupe Coopératif Macroglobulinémie. J Clin Oncol 16 (6): 2060-4, 1998. [PUBMED Abstract]
Foran JM, Rohatiner AZ, Coiffier B, et al.: Multicenter phase II study of fludarabine phosphate for patients with newly diagnosed lymphoplasmacytoid lymphoma, Waldenström's macroglobulinemia, and mantle-cell lymphoma. J Clin Oncol 17 (2): 546-53, 1999. [PUBMED Abstract]
Baldini L, Goldaniga M, Guffanti A, et al.: Immunoglobulin M monoclonal gammopathies of undetermined significance and indolent Waldenstrom's macroglobulinemia recognize the same determinants of evolution into symptomatic lymphoid disorders: proposal for a common prognostic scoring system. J Clin Oncol 23 (21): 4662-8, 2005. [PUBMED Abstract]
Gertz MA, Anagnostopoulos A, Anderson K, et al.: Treatment recommendations in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol 30 (2): 121-6, 2003. [PUBMED Abstract]
Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, et al.: Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol 25 (22): 3344-9, 2007. [PUBMED Abstract]
Dimopoulos MA, Zervas C, Zomas A, et al.: Treatment of Waldenström's macroglobulinemia with rituximab. J Clin Oncol 20 (9): 2327-33, 2002. [PUBMED Abstract]
Treon SP, Branagan AR, Hunter Z, et al.: Paradoxical increases in serum IgM and viscosity levels following rituximab in Waldenstrom's macroglobulinemia. Ann Oncol 15 (10): 1481-3, 2004. [PUBMED Abstract]
Dimopoulos MA, Kantarjian H, Weber D, et al.: Primary therapy of Waldenström's macroglobulinemia with 2-chlorodeoxyadenosine. J Clin Oncol 12 (12): 2694-8, 1994. [PUBMED Abstract]
Dimopoulos MA, Alexanian R: Waldenstrom's macroglobulinemia. Blood 83 (6): 1452-9, 1994. [PUBMED Abstract]
Hellmann A, Lewandowski K, Zaucha JM, et al.: Effect of a 2-hour infusion of 2-chlorodeoxyadenosine in the treatment of refractory or previously untreated Waldenström's macroglobulinemia. Eur J Haematol 63 (1): 35-41, 1999. [PUBMED Abstract]
García-Sanz R, Montoto S, Torrequebrada A, et al.: Waldenström macroglobulinaemia: presenting features and outcome in a series with 217 cases. Br J Haematol 115 (3): 575-82, 2001. [PUBMED Abstract]
Rotoli B, De Renzo A, Frigeri F, et al.: A phase II trial on alpha-interferon (alpha IFN) effect in patients with monoclonal IgM gammopathy. Leuk Lymphoma 13 (5-6): 463-9, 1994. [PUBMED Abstract]
Dreger P, Glass B, Kuse R, et al.: Myeloablative radiochemotherapy followed by reinfusion of purged autologous stem cells for Waldenström's macroglobulinaemia. Br J Haematol 106 (1): 115-8, 1999. [PUBMED Abstract]
Desikan R, Dhodapkar M, Siegel D, et al.: High-dose therapy with autologous haemopoietic stem cell support for Waldenström's macroglobulinaemia. Br J Haematol 105 (4): 993-6, 1999. [PUBMED Abstract]
Leblond V, Lévy V, Maloisel F, et al.: Multicenter, randomized comparative trial of fludarabine and the combination of cyclophosphamide-doxorubicin-prednisone in 92 patients with Waldenström macroglobulinemia in first relapse or with primary refractory disease. Blood 98 (9): 2640-4, 2001. [PUBMED Abstract]
Vallisa D, Bernuzzi P, Arcaini L, et al.: Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-grade, B-cell, non-Hodgkin's lymphoma: a multicenter Italian experience. J Clin Oncol 23 (3): 468-73, 2005. [PUBMED Abstract]
Fisher RI, Dahlberg S, Nathwani BN, et al.: A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study. Blood 85 (4): 1075-82, 1995. [PUBMED Abstract]
Isaacson PG: Lymphomas of mucosa-associated lymphoid tissue (MALT). Histopathology 16: 617-619, 1990.
Nizze H, Cogliatti SB, von Schilling C, et al.: Monocytoid B-cell lymphoma: morphological variants and relationship to low-grade B-cell lymphoma of the mucosa-associated lymphoid tissue. Histopathology 18 (5): 403-14, 1991. [PUBMED Abstract]
Pimpinelli N, Santucci M, Mori M, et al.: Primary cutaneous B-cell lymphoma: a clinically homogeneous entity? J Am Acad Dermatol 37 (6): 1012-6, 1997. [PUBMED Abstract]
Li G, Hansmann ML, Zwingers T, et al.: Primary lymphomas of the lung: morphological, immunohistochemical and clinical features. Histopathology 16 (6): 519-31, 1990. [PUBMED Abstract]
Zinzani PL, Magagnoli M, Galieni P, et al.: Nongastrointestinal low-grade mucosa-associated lymphoid tissue lymphoma: analysis of 75 patients. J Clin Oncol 17 (4): 1254, 1999. [PUBMED Abstract]
Nathwani BN, Drachenberg MR, Hernandez AM, et al.: Nodal monocytoid B-cell lymphoma (nodal marginal-zone B-cell lymphoma). Semin Hematol 36 (2): 128-38, 1999. [PUBMED Abstract]
Isaacson PG: Mucosa-associated lymphoid tissue lymphoma. Semin Hematol 36 (2): 139-47, 1999. [PUBMED Abstract]
Bertoni F, Zucca E: State-of-the-art therapeutics: marginal-zone lymphoma. J Clin Oncol 23 (26): 6415-20, 2005. [PUBMED Abstract]
Wotherspoon AC, Doglioni C, Diss TC, et al.: Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 342 (8871): 575-7, 1993. [PUBMED Abstract]
Neubauer A, Thiede C, Morgner A, et al.: Cure of Helicobacter pylori infection and duration of remission of low-grade gastric mucosa-associated lymphoid tissue lymphoma. J Natl Cancer Inst 89 (18): 1350-5, 1997. [PUBMED Abstract]
Roggero E, Zucca E, Pinotti G, et al.: Eradication of Helicobacter pylori infection in primary low-grade gastric lymphoma of mucosa-associated lymphoid tissue. Ann Intern Med 122 (10): 767-9, 1995. [PUBMED Abstract]
Zucca E, Roggero E, Pileri S: B-cell lymphoma of MALT type: a review with special emphasis on diagnostic and management problems of low-grade gastric tumours. Br J Haematol 100 (1): 3-14, 1998. [PUBMED Abstract]
Steinbach G, Ford R, Glober G, et al.: Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue. An uncontrolled trial. Ann Intern Med 131 (2): 88-95, 1999. [PUBMED Abstract]
Wündisch T, Thiede C, Morgner A, et al.: Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication. J Clin Oncol 23 (31): 8018-24, 2005. [PUBMED Abstract]
Ye H, Liu H, Raderer M, et al.: High incidence of t(11;18)(q21;q21) in Helicobacter pylori-negative gastric MALT lymphoma. Blood 101 (7): 2547-50, 2003. [PUBMED Abstract]
Lévy M, Copie-Bergman C, Gameiro C, et al.: Prognostic value of translocation t(11;18) in tumoral response of low-grade gastric lymphoma of mucosa-associated lymphoid tissue type to oral chemotherapy. J Clin Oncol 23 (22): 5061-6, 2005. [PUBMED Abstract]
Nakamura S, Ye H, Bacon CM, et al.: Clinical impact of genetic aberrations in gastric MALT lymphoma: a comprehensive analysis using interphase fluorescence in situ hybridisation. Gut 56 (10): 1358-63, 2007. [PUBMED Abstract]
Schechter NR, Yahalom J: Low-grade MALT lymphoma of the stomach: a review of treatment options. Int J Radiat Oncol Biol Phys 46 (5): 1093-103, 2000. [PUBMED Abstract]
Tsang RW, Gospodarowicz MK, Pintilie M, et al.: Stage I and II MALT lymphoma: results of treatment with radiotherapy. Int J Radiat Oncol Biol Phys 50 (5): 1258-64, 2001. [PUBMED Abstract]
Tsang RW, Gospodarowicz MK, Pintilie M, et al.: Localized mucosa-associated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical outcome. J Clin Oncol 21 (22): 4157-64, 2003. [PUBMED Abstract]
Tsai HK, Li S, Ng AK, et al.: Role of radiation therapy in the treatment of stage I/II mucosa-associated lymphoid tissue lymphoma. Ann Oncol 18 (4): 672-8, 2007. [PUBMED Abstract]
Martinelli G, Laszlo D, Ferreri AJ, et al.: Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol 23 (9): 1979-83, 2005. [PUBMED Abstract]
Cogliatti SB, Schmid U, Schumacher U, et al.: Primary B-cell gastric lymphoma: a clinicopathological study of 145 patients. Gastroenterology 101 (5): 1159-70, 1991. [PUBMED Abstract]
Thieblemont C, Bastion Y, Berger F, et al.: Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: analysis of 108 patients. J Clin Oncol 15 (4): 1624-30, 1997. [PUBMED Abstract]
Pavlick AC, Gerdes H, Portlock CS: Endoscopic ultrasound in the evaluation of gastric small lymphocytic mucosa-associated lymphoid tumors. J Clin Oncol 15 (5): 1761-6, 1997. [PUBMED Abstract]
Morgner A, Miehlke S, Fischbach W, et al.: Complete remission of primary high-grade B-cell gastric lymphoma after cure of Helicobacter pylori infection. J Clin Oncol 19 (7): 2041-8, 2001. [PUBMED Abstract]
Chen LT, Lin JT, Shyu RY, et al.: Prospective study of Helicobacter pylori eradication therapy in stage I(E) high-grade mucosa-associated lymphoid tissue lymphoma of the stomach. J Clin Oncol 19 (22): 4245-51, 2001. [PUBMED Abstract]
Chen LT, Lin JT, Tai JJ, et al.: Long-term results of anti-Helicobacter pylori therapy in early-stage gastric high-grade transformed MALT lymphoma. J Natl Cancer Inst 97 (18): 1345-53, 2005. [PUBMED Abstract]
Uno T, Isobe K, Shikama N, et al.: Radiotherapy for extranodal, marginal zone, B-cell lymphoma of mucosa-associated lymphoid tissue originating in the ocular adnexa: a multiinstitutional, retrospective review of 50 patients. Cancer 98 (4): 865-71, 2003. [PUBMED Abstract]
Raderer M, Streubel B, Woehrer S, et al.: High relapse rate in patients with MALT lymphoma warrants lifelong follow-up. Clin Cancer Res 11 (9): 3349-52, 2005. [PUBMED Abstract]
Raderer M, Wöhrer S, Streubel B, et al.: Assessment of disease dissemination in gastric compared with extragastric mucosa-associated lymphoid tissue lymphoma using extensive staging: a single-center experience. J Clin Oncol 24 (19): 3136-41, 2006. [PUBMED Abstract]
Ferreri AJ, Ponzoni M, Guidoboni M, et al.: Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multicenter prospective trial. J Natl Cancer Inst 98 (19): 1375-82, 2006. [PUBMED Abstract]
Kuo SH, Chen LT, Yeh KH, et al.: Nuclear expression of BCL10 or nuclear factor kappa B predicts Helicobacter pylori-independent status of early-stage, high-grade gastric mucosa-associated lymphoid tissue lymphomas. J Clin Oncol 22 (17): 3491-7, 2004. [PUBMED Abstract]
Isaacson PG: Gastrointestinal lymphoma. Hum Pathol 25 (10): 1020-9, 1994. [PUBMED Abstract]
Lecuit M, Abachin E, Martin A, et al.: Immunoproliferative small intestinal disease associated with Campylobacter jejuni. N Engl J Med 350 (3): 239-48, 2004. [PUBMED Abstract]
Franco V, Florena AM, Iannitto E: Splenic marginal zone lymphoma. Blood 101 (7): 2464-72, 2003. [PUBMED Abstract]
Iannitto E, Ambrosetti A, Ammatuna E, et al.: Splenic marginal zone lymphoma with or without villous lymphocytes. Hematologic findings and outcomes in a series of 57 patients. Cancer 101 (9): 2050-7, 2004. [PUBMED Abstract]
Arcaini L, Paulli M, Boveri E, et al.: Splenic and nodal marginal zone lymphomas are indolent disorders at high hepatitis C virus seroprevalence with distinct presenting features but similar morphologic and phenotypic profiles. Cancer 100 (1): 107-15, 2004. [PUBMED Abstract]
Parry-Jones N, Matutes E, Gruszka-Westwood AM, et al.: Prognostic features of splenic lymphoma with villous lymphocytes: a report on 129 patients. Br J Haematol 120 (5): 759-64, 2003. [PUBMED Abstract]
Arcaini L, Lazzarino M, Colombo N, et al.: Splenic marginal zone lymphoma: a prognostic model for clinical use. Blood 107 (12): 4643-9, 2006. [PUBMED Abstract]
Hermine O, Lefrère F, Bronowicki JP, et al.: Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 347 (2): 89-94, 2002. [PUBMED Abstract]
Kelaidi C, Rollot F, Park S, et al.: Response to antiviral treatment in hepatitis C virus-associated marginal zone lymphomas. Leukemia 18 (10): 1711-6, 2004. [PUBMED Abstract]
de Bruin PC, Beljaards RC, van Heerde P, et al.: Differences in clinical behaviour and immunophenotype between primary cutaneous and primary nodal anaplastic large cell lymphoma of T-cell or null cell phenotype. Histopathology 23 (2): 127-35, 1993. [PUBMED Abstract]
Willemze R, Beljaards RC: Spectrum of primary cutaneous CD30 (Ki-1)-positive lymphoproliferative disorders. A proposal for classification and guidelines for management and treatment. J Am Acad Dermatol 28 (6): 973-80, 1993. [PUBMED Abstract]
Miller TP, Dahlberg S, Cassady JR, et al.: Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med 339 (1): 21-6, 1998. [PUBMED Abstract]
Coiffier B, Lepage E, Briere J, et al.: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346 (4): 235-42, 2002. [PUBMED Abstract]
Coiffier B: State-of-the-art therapeutics: diffuse large B-cell lymphoma. J Clin Oncol 23 (26): 6387-93, 2005. [PUBMED Abstract]
Habermann TM, Weller EA, Morrison VA, et al.: Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 24 (19): 3121-7, 2006. [PUBMED Abstract]
A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329 (14): 987-94, 1993. [PUBMED Abstract]
Møller MB, Christensen BE, Pedersen NT: Prognosis of localized diffuse large B-cell lymphoma in younger patients. Cancer 98 (3): 516-21, 2003. [PUBMED Abstract]
Canellos GP: CHOP may have been part of the beginning but certainly not the end: issues in risk-related therapy of large-cell lymphoma. J Clin Oncol 15 (5): 1713-6, 1997. [PUBMED Abstract]
Lossos IS, Czerwinski DK, Alizadeh AA, et al.: Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 350 (18): 1828-37, 2004. [PUBMED Abstract]
Rosenwald A, Wright G, Chan WC, et al.: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346 (25): 1937-47, 2002. [PUBMED Abstract]
Abramson JS, Shipp MA: Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach. Blood 106 (4): 1164-74, 2005. [PUBMED Abstract]
de Jong D, Rosenwald A, Chhanabhai M, et al.: Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications--a study from the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol 25 (7): 805-12, 2007. [PUBMED Abstract]
Glantz MJ, Cole BF, Recht L, et al.: High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol 16 (4): 1561-7, 1998. [PUBMED Abstract]
Fisher RI, Gaynor ER, Dahlberg S, et al.: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 328 (14): 1002-6, 1993. [PUBMED Abstract]
van Besien K, Ha CS, Murphy S, et al.: Risk factors, treatment, and outcome of central nervous system recurrence in adults with intermediate-grade and immunoblastic lymphoma. Blood 91 (4): 1178-84, 1998. [PUBMED Abstract]
Delabie J, Vandenberghe E, Kennes C, et al.: Histiocyte-rich B-cell lymphoma. A distinct clinicopathologic entity possibly related to lymphocyte predominant Hodgkin's disease, paragranuloma subtype. Am J Surg Pathol 16 (1): 37-48, 1992. [PUBMED Abstract]
Achten R, Verhoef G, Vanuytsel L, et al.: T-cell/histiocyte-rich large B-cell lymphoma: a distinct clinicopathologic entity. J Clin Oncol 20 (5): 1269-77, 2002. [PUBMED Abstract]
Bouabdallah R, Mounier N, Guettier C, et al.: T-cell/histiocyte-rich large B-cell lymphomas and classical diffuse large B-cell lymphomas have similar outcome after chemotherapy: a matched-control analysis. J Clin Oncol 21 (7): 1271-7, 2003. [PUBMED Abstract]
Ghesquières H, Berger F, Felman P, et al.: Clinicopathologic characteristics and outcome of diffuse large B-cell lymphomas presenting with an associated low-grade component at diagnosis. J Clin Oncol 24 (33): 5234-41, 2006. [PUBMED Abstract]
Lazzarino M, Orlandi E, Paulli M, et al.: Primary mediastinal B-cell lymphoma with sclerosis: an aggressive tumor with distinctive clinical and pathologic features. J Clin Oncol 11 (12): 2306-13, 1993. [PUBMED Abstract]
Kirn D, Mauch P, Shaffer K, et al.: Large-cell and immunoblastic lymphoma of the mediastinum: prognostic features and treatment outcome in 57 patients. J Clin Oncol 11 (7): 1336-43, 1993. [PUBMED Abstract]
Aisenberg AC: Primary large-cell lymphoma of the mediastinum. J Clin Oncol 11 (12): 2291-4, 1993. [PUBMED Abstract]
Abou-Elella AA, Weisenburger DD, Vose JM, et al.: Primary mediastinal large B-cell lymphoma: a clinicopathologic study of 43 patients from the Nebraska Lymphoma Study Group. J Clin Oncol 17 (3): 784-90, 1999. [PUBMED Abstract]
Cazals-Hatem D, Lepage E, Brice P, et al.: Primary mediastinal large B-cell lymphoma. A clinicopathologic study of 141 cases compared with 916 nonmediastinal large B-cell lymphomas, a GELA ("Groupe d'Etude des Lymphomes de l'Adulte") study. Am J Surg Pathol 20 (7): 877-88, 1996. [PUBMED Abstract]
Popat U, Przepiork D, Champlin R, et al.: High-dose chemotherapy for relapsed and refractory diffuse large B-cell lymphoma: mediastinal localization predicts for a favorable outcome. J Clin Oncol 16 (1): 63-9, 1998. [PUBMED Abstract]
van Besien K, Kelta M, Bahaguna P: Primary mediastinal B-cell lymphoma: a review of pathology and management. J Clin Oncol 19 (6): 1855-64, 2001. [PUBMED Abstract]
Longo DL: What's the deal with follicular lymphomas? J Clin Oncol 11 (2): 202-8, 1993. [PUBMED Abstract]
Anderson JR, Vose JM, Bierman PJ, et al.: Clinical features and prognosis of follicular large-cell lymphoma: a report from the Nebraska Lymphoma Study Group. J Clin Oncol 11 (2): 218-24, 1993. [PUBMED Abstract]
Bartlett NL, Rizeq M, Dorfman RF, et al.: Follicular large-cell lymphoma: intermediate or low grade? J Clin Oncol 12 (7): 1349-57, 1994. [PUBMED Abstract]
Wendum D, Sebban C, Gaulard P, et al.: Follicular large-cell lymphoma treated with intensive chemotherapy: an analysis of 89 cases included in the LNH87 trial and comparison with the outcome of diffuse large B-cell lymphoma. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 15 (4): 1654-63, 1997. [PUBMED Abstract]
Hans CP, Weisenburger DD, Vose JM, et al.: A significant diffuse component predicts for inferior survival in grade 3 follicular lymphoma, but cytologic subtypes do not predict survival. Blood 101 (6): 2363-7, 2003. [PUBMED Abstract]
Vose JM, Bierman PJ, Lynch JC, et al.: Effect of follicularity on autologous transplantation for large-cell non-Hodgkin's lymphoma. J Clin Oncol 16 (3): 844-9, 1998. [PUBMED Abstract]
Bai RY, Ouyang T, Miething C, et al.: Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. Blood 96 (13): 4319-27, 2000. [PUBMED Abstract]
Gascoyne RD, Aoun P, Wu D, et al.: Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. Blood 93 (11): 3913-21, 1999. [PUBMED Abstract]
Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001. [PUBMED Abstract]
Lipford EH Jr, Margolick JB, Longo DL, et al.: Angiocentric immunoproliferative lesions: a clinicopathologic spectrum of post-thymic T-cell proliferations. Blood 72 (5): 1674-81, 1988. [PUBMED Abstract]
Logsdon MD, Ha CS, Kavadi VS, et al.: Lymphoma of the nasal cavity and paranasal sinuses: improved outcome and altered prognostic factors with combined modality therapy. Cancer 80 (3): 477-88, 1997. [PUBMED Abstract]
Liang R, Todd D, Chan TK, et al.: Treatment outcome and prognostic factors for primary nasal lymphoma. J Clin Oncol 13 (3): 666-70, 1995. [PUBMED Abstract]
Cheung MM, Chan JK, Lau WH, et al.: Primary non-Hodgkin's lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients. J Clin Oncol 16 (1): 70-7, 1998. [PUBMED Abstract]
Hausdorff J, Davis E, Long G, et al.: Non-Hodgkin's lymphoma of the paranasal sinuses: clinical and pathological features, and response to combined-modality therapy. Cancer J Sci Am 3 (5): 303-11, 1997 Sep-Oct. [PUBMED Abstract]
Liang R: Diagnosis and management of primary nasal lymphoma of T-cell or NK-cell origin. Clin Lymphoma 1 (1): 33-7; discussion 38, 2000. [PUBMED Abstract]
Rizvi MA, Evens AM, Tallman MS, et al.: T-cell non-Hodgkin lymphoma. Blood 107 (4): 1255-64, 2006. [PUBMED Abstract]
Kim GE, Cho JH, Yang WI, et al.: Angiocentric lymphoma of the head and neck: patterns of systemic failure after radiation treatment. J Clin Oncol 18 (1): 54-63, 2000. [PUBMED Abstract]
Li YX, Yao B, Jin J, et al.: Radiotherapy as primary treatment for stage IE and IIE nasal natural killer/T-cell lymphoma. J Clin Oncol 24 (1): 181-9, 2006. [PUBMED Abstract]
Lee J, Suh C, Park YH, et al.: Extranodal natural killer T-cell lymphoma, nasal-type: a prognostic model from a retrospective multicenter study. J Clin Oncol 24 (4): 612-8, 2006. [PUBMED Abstract]
Li CC, Tien HF, Tang JL, et al.: Treatment outcome and pattern of failure in 77 patients with sinonasal natural killer/T-cell or T-cell lymphoma. Cancer 100 (2): 366-75, 2004. [PUBMED Abstract]
Mraz-Gernhard S, Natkunam Y, Hoppe RT, et al.: Natural killer/natural killer-like T-cell lymphoma, CD56+, presenting in the skin: an increasingly recognized entity with an aggressive course. J Clin Oncol 19 (8): 2179-88, 2001. [PUBMED Abstract]
Guinee D Jr, Jaffe E, Kingma D, et al.: Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol 18 (8): 753-64, 1994. [PUBMED Abstract]
Myers JL, Kurtin PJ, Katzenstein AL, et al.: Lymphomatoid granulomatosis. Evidence of immunophenotypic diversity and relationship to Epstein-Barr virus infection. Am J Surg Pathol 19 (11): 1300-12, 1995. [PUBMED Abstract]
Siegert W, Agthe A, Griesser H, et al.: Treatment of angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma using prednisone with or without the COPBLAM/IMVP-16 regimen. A multicenter study. Kiel Lymphoma Study Group. Ann Intern Med 117 (5): 364-70, 1992. [PUBMED Abstract]
Jaffe ES: Angioimmunoblastic T-cell lymphoma: new insights, but the clinical challenge remains. Ann Oncol 6 (7): 631-2, 1995. [PUBMED Abstract]
Siegert W, Nerl C, Agthe A, et al.: Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma: prognostic impact of clinical observations and laboratory findings at presentation. The Kiel Lymphoma Study Group. Ann Oncol 6 (7): 659-64, 1995. [PUBMED Abstract]
Reimer P, Schertlin T, Rüdiger T, et al.: Myeloablative radiochemotherapy followed by autologous peripheral blood stem cell transplantation as first-line therapy in peripheral T-cell lymphomas: first results of a prospective multicenter study. Hematol J 5 (4): 304-11, 2004. [PUBMED Abstract]
Bräuninger A, Spieker T, Willenbrock K, et al.: Survival and clonal expansion of mutating "forbidden" (immunoglobulin receptor-deficient) epstein-barr virus-infected b cells in angioimmunoblastic t cell lymphoma. J Exp Med 194 (7): 927-40, 2001. [PUBMED Abstract]
Rüdiger T, Weisenburger DD, Anderson JR, et al.: Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin's Lymphoma Classification Project. Ann Oncol 13 (1): 140-9, 2002. [PUBMED Abstract]
López-Guillermo A, Cid J, Salar A, et al.: Peripheral T-cell lymphomas: initial features, natural history, and prognostic factors in a series of 174 patients diagnosed according to the R.E.A.L. Classification. Ann Oncol 9 (8): 849-55, 1998. [PUBMED Abstract]
Gisselbrecht C, Gaulard P, Lepage E, et al.: Prognostic significance of T-cell phenotype in aggressive non-Hodgkin's lymphomas. Groupe d'Etudes des Lymphomes de l'Adulte (GELA). Blood 92 (1): 76-82, 1998. [PUBMED Abstract]
Sonnen R, Schmidt WP, Müller-Hermelink HK, et al.: The International Prognostic Index determines the outcome of patients with nodal mature T-cell lymphomas. Br J Haematol 129 (3): 366-72, 2005. [PUBMED Abstract]
Rodriguez J, Munsell M, Yazji S, et al.: Impact of high-dose chemotherapy on peripheral T-cell lymphomas. J Clin Oncol 19 (17): 3766-70, 2001. [PUBMED Abstract]
Enblad G, Hagberg H, Erlanson M, et al.: A pilot study of alemtuzumab (anti-CD52 monoclonal antibody) therapy for patients with relapsed or chemotherapy-refractory peripheral T-cell lymphomas. Blood 103 (8): 2920-4, 2004. [PUBMED Abstract]
Talpur R, Apisarnthanarax N, Ward S, et al.: Treatment of refractory peripheral T-cell lymphoma with denileukin diftitox (ONTAK). Leuk Lymphoma 43 (1): 121-6, 2002. [PUBMED Abstract]
Farcet JP, Gaulard P, Marolleau JP, et al.: Hepatosplenic T-cell lymphoma: sinusal/sinusoidal localization of malignant cells expressing the T-cell receptor gamma delta. Blood 75 (11): 2213-9, 1990. [PUBMED Abstract]
Wong KF, Chan JK, Matutes E, et al.: Hepatosplenic gamma delta T-cell lymphoma. A distinctive aggressive lymphoma type. Am J Surg Pathol 19 (6): 718-26, 1995. [PUBMED Abstract]
François A, Lesesve JF, Stamatoullas A, et al.: Hepatosplenic gamma/delta T-cell lymphoma: a report of two cases in immunocompromised patients, associated with isochromosome 7q. Am J Surg Pathol 21 (7): 781-90, 1997. [PUBMED Abstract]
Belhadj K, Reyes F, Farcet JP, et al.: Hepatosplenic gammadelta T-cell lymphoma is a rare clinicopathologic entity with poor outcome: report on a series of 21 patients. Blood 102 (13): 4261-9, 2003. [PUBMED Abstract]
Chanan-Khan A, Islam T, Alam A, et al.: Long-term survival with allogeneic stem cell transplant and donor lymphocyte infusion following salvage therapy with anti-CD52 monoclonal antibody (Campath) in a patient with alpha/beta hepatosplenic T-cell non-Hodgkin's lymphoma. Leuk Lymphoma 45 (8): 1673-5, 2004. [PUBMED Abstract]
Go RS, Wester SM: Immunophenotypic and molecular features, clinical outcomes, treatments, and prognostic factors associated with subcutaneous panniculitis-like T-cell lymphoma: a systematic analysis of 156 patients reported in the literature. Cancer 101 (6): 1404-13, 2004. [PUBMED Abstract]
Marzano AV, Berti E, Paulli M, et al.: Cytophagic histiocytic panniculitis and subcutaneous panniculitis-like T-cell lymphoma: report of 7 cases. Arch Dermatol 136 (7): 889-96, 2000. [PUBMED Abstract]
Hoque SR, Child FJ, Whittaker SJ, et al.: Subcutaneous panniculitis-like T-cell lymphoma: a clinicopathological, immunophenotypic and molecular analysis of six patients. Br J Dermatol 148 (3): 516-25, 2003. [PUBMED Abstract]
Salhany KE, Macon WR, Choi JK, et al.: Subcutaneous panniculitis-like T-cell lymphoma: clinicopathologic, immunophenotypic, and genotypic analysis of alpha/beta and gamma/delta subtypes. Am J Surg Pathol 22 (7): 881-93, 1998. [PUBMED Abstract]
Massone C, Chott A, Metze D, et al.: Subcutaneous, blastic natural killer (NK), NK/T-cell, and other cytotoxic lymphomas of the skin: a morphologic, immunophenotypic, and molecular study of 50 patients. Am J Surg Pathol 28 (6): 719-35, 2004. [PUBMED Abstract]
Arnulf B, Copie-Bergman C, Delfau-Larue MH, et al.: Nonhepatosplenic gammadelta T-cell lymphoma: a subset of cytotoxic lymphomas with mucosal or skin localization. Blood 91 (5): 1723-31, 1998. [PUBMED Abstract]
Toro JR, Liewehr DJ, Pabby N, et al.: Gamma-delta T-cell phenotype is associated with significantly decreased survival in cutaneous T-cell lymphoma. Blood 101 (9): 3407-12, 2003. [PUBMED Abstract]
Egan LJ, Walsh SV, Stevens FM, et al.: Celiac-associated lymphoma. A single institution experience of 30 cases in the combination chemotherapy era. J Clin Gastroenterol 21 (2): 123-9, 1995. [PUBMED Abstract]
Gale J, Simmonds PD, Mead GM, et al.: Enteropathy-type intestinal T-cell lymphoma: clinical features and treatment of 31 patients in a single center. J Clin Oncol 18 (4): 795-803, 2000. [PUBMED Abstract]
Daum S, Ullrich R, Heise W, et al.: Intestinal non-Hodgkin's lymphoma: a multicenter prospective clinical study from the German Study Group on Intestinal non-Hodgkin's Lymphoma. J Clin Oncol 21 (14): 2740-6, 2003. [PUBMED Abstract]
Murase T, Yamaguchi M, Suzuki R, et al.: Intravascular large B-cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5. Blood 109 (2): 478-85, 2007. [PUBMED Abstract]
Ponzoni M, Ferreri AJ, Campo E, et al.: Definition, diagnosis, and management of intravascular large B-cell lymphoma: proposals and perspectives from an international consensus meeting. J Clin Oncol 25 (21): 3168-73, 2007. [PUBMED Abstract]
Blum KA, Lozanski G, Byrd JC: Adult Burkitt leukemia and lymphoma. Blood 104 (10): 3009-20, 2004. [PUBMED Abstract]
Onciu M, Schlette E, Zhou Y, et al.: Secondary chromosomal abnormalities predict outcome in pediatric and adult high-stage Burkitt lymphoma. Cancer 107 (5): 1084-92, 2006. [PUBMED Abstract]
Macpherson N, Lesack D, Klasa R, et al.: Small noncleaved, non-Burkitt's (Burkit-Like) lymphoma: cytogenetics predict outcome and reflect clinical presentation. J Clin Oncol 17 (5): 1558-67, 1999. [PUBMED Abstract]
Dave SS, Fu K, Wright GW, et al.: Molecular diagnosis of Burkitt's lymphoma. N Engl J Med 354 (23): 2431-42, 2006. [PUBMED Abstract]
Hummel M, Bentink S, Berger H, et al.: A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling. N Engl J Med 354 (23): 2419-30, 2006. [PUBMED Abstract]
Longo DL, Duffey PL, Jaffe ES, et al.: Diffuse small noncleaved-cell, non-Burkitt's lymphoma in adults: a high-grade lymphoma responsive to ProMACE-based combination chemotherapy. J Clin Oncol 12 (10): 2153-9, 1994. [PUBMED Abstract]
McMaster ML, Greer JP, Greco FA, et al.: Effective treatment of small-noncleaved-cell lymphoma with high-intensity, brief-duration chemotherapy. J Clin Oncol 9 (6): 941-6, 1991. [PUBMED Abstract]
Thomas DA, Faderl S, O'Brien S, et al.: Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 106 (7): 1569-80, 2006. [PUBMED Abstract]
Soussain C, Patte C, Ostronoff M, et al.: Small noncleaved cell lymphoma and leukemia in adults. A retrospective study of 65 adults treated with the LMB pediatric protocols. Blood 85 (3): 664-74, 1995. [PUBMED Abstract]
Magrath I, Adde M, Shad A, et al.: Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 14 (3): 925-34, 1996. [PUBMED Abstract]
Adde M, Shad A, Venzon D, et al.: Additional chemotherapy agents improve treatment outcome for children and adults with advanced B-cell lymphomas. Semin Oncol 25 (2 Suppl 4): 33-9; discussion 45-8, 1998. [PUBMED Abstract]
Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996. [PUBMED Abstract]
Lee EJ, Petroni GR, Schiffer CA, et al.: Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251. J Clin Oncol 19 (20): 4014-22, 2001. [PUBMED Abstract]
Mead GM, Sydes MR, Walewski J, et al.: An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol 13 (8): 1264-74, 2002. [PUBMED Abstract]
Freedman AS, Takvorian T, Anderson KC, et al.: Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: very low treatment-related mortality in 100 patients in sensitive relapse. J Clin Oncol 8 (5): 784-91, 1990. [PUBMED Abstract]
Sweetenham JW, Pearce R, Philip T, et al.: High-dose therapy and autologous bone marrow transplantation for intermediate and high grade non-Hodgkin's lymphoma in patients aged 55 years and over: results from the European Group for Bone Marrow Transplantation. The EBMT Lymphoma Working Party. Bone Marrow Transplant 14 (6): 981-7, 1994. [PUBMED Abstract]
Rizzieri DA, Johnson JL, Niedzwiecki D, et al.: Intensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: final results of Cancer and Leukemia Group B Study 9251. Cancer 100 (7): 1438-48, 2004. [PUBMED Abstract]
Morel P, Lepage E, Brice P, et al.: Prognosis and treatment of lymphoblastic lymphoma in adults: a report on 80 patients. J Clin Oncol 10 (7): 1078-85, 1992. [PUBMED Abstract]
Verdonck LF, Dekker AW, de Gast GC, et al.: Autologous bone marrow transplantation for adult poor-risk lymphoblastic lymphoma in first remission. J Clin Oncol 10 (4): 644-6, 1992. [PUBMED Abstract]
Thomas DA, O'Brien S, Cortes J, et al.: Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood 104 (6): 1624-30, 2004. [PUBMED Abstract]
Sweetenham JW, Santini G, Qian W, et al.: High-dose therapy and autologous stem-cell transplantation versus conventional-dose consolidation/maintenance therapy as postremission therapy for adult patients with lymphoblastic lymphoma: results of a randomized trial of the European Group for Blood and Marrow Transplantation and the United Kingdom Lymphoma Group. J Clin Oncol 19 (11): 2927-36, 2001. [PUBMED Abstract]
Höllsberg P, Hafler DA: Seminars in medicine of the Beth Israel Hospital, Boston. Pathogenesis of diseases induced by human lymphotropic virus type I infection. N Engl J Med 328 (16): 1173-82, 1993. [PUBMED Abstract]
Foss FM, Aquino SL, Ferry JA: Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 10-2003. A 72-year-old man with rapidly progressive leukemia, rash, and multiorgan failure. N Engl J Med 348 (13): 1267-75, 2003. [PUBMED Abstract]
Tsukasaki K, Utsunomiya A, Fukuda H, et al.: VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol 25 (34): 5458-64, 2007. [PUBMED Abstract]
Gill PS, Harrington W Jr, Kaplan MH, et al.: Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine. N Engl J Med 332 (26): 1744-8, 1995. [PUBMED Abstract]
Matutes E, Taylor GP, Cavenagh J, et al.: Interferon alpha and zidovudine therapy in adult T-cell leukaemia lymphoma: response and outcome in 15 patients. Br J Haematol 113 (3): 779-84, 2001. [PUBMED Abstract]
Hermine O, Allard I, Lévy V, et al.: A prospective phase II clinical trial with the use of zidovudine and interferon-alpha in the acute and lymphoma forms of adult T-cell leukemia/lymphoma. Hematol J 3 (6): 276-82, 2002. [PUBMED Abstract]
Norton AJ, Matthews J, Pappa V, et al.: Mantle cell lymphoma: natural history defined in a serially biopsied population over a 20-year period. Ann Oncol 6 (3): 249-56, 1995. [PUBMED Abstract]
Zucca E, Roggero E, Pinotti G, et al.: Patterns of survival in mantle cell lymphoma. Ann Oncol 6 (3): 257-62, 1995. [PUBMED Abstract]
Campo E, Raffeld M, Jaffe ES: Mantle-cell lymphoma. Semin Hematol 36 (2): 115-27, 1999. [PUBMED Abstract]
Weisenburger DD, Armitage JO: Mantle cell lymphoma-- an entity comes of age. Blood 87 (11): 4483-94, 1996. [PUBMED Abstract]
Hiddemann W, Unterhalt M, Herrmann R, et al.: Mantle-cell lymphomas have more widespread disease and a slower response to chemotherapy compared with follicle-center lymphomas: results of a prospective comparative analysis of the German Low-Grade Lymphoma Study Group. J Clin Oncol 16 (5): 1922-30, 1998. [PUBMED Abstract]
Majlis A, Pugh WC, Rodriguez MA, et al.: Mantle cell lymphoma: correlation of clinical outcome and biologic features with three histologic variants. J Clin Oncol 15 (4): 1664-71, 1997. [PUBMED Abstract]
Tiemann M, Schrader C, Klapper W, et al.: Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): a clinicopathological study from the European MCL Network. Br J Haematol 131 (1): 29-38, 2005. [PUBMED Abstract]
Velders GA, Kluin-Nelemans JC, De Boer CJ, et al.: Mantle-cell lymphoma: a population-based clinical study. J Clin Oncol 14 (4): 1269-74, 1996. [PUBMED Abstract]
Teodorovic I, Pittaluga S, Kluin-Nelemans JC, et al.: Efficacy of four different regimens in 64 mantle-cell lymphoma cases: clinicopathologic comparison with 498 other non-Hodgkin's lymphoma subtypes. European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 13 (11): 2819-26, 1995. [PUBMED Abstract]
Vandenberghe E, Ruiz de Elvira C, Loberiza FR, et al.: Outcome of autologous transplantation for mantle cell lymphoma: a study by the European Blood and Bone Marrow Transplant and Autologous Blood and Marrow Transplant Registries. Br J Haematol 120 (5): 793-800, 2003. [PUBMED Abstract]
Lenz G, Dreyling M, Hoster E, et al.: Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 23 (9): 1984-92, 2005. [PUBMED Abstract]
Romaguera JE, Fayad L, Rodriguez MA, et al.: High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol 23 (28): 7013-23, 2005. [PUBMED Abstract]
Witzig TE: Current treatment approaches for mantle-cell lymphoma. J Clin Oncol 23 (26): 6409-14, 2005. [PUBMED Abstract]
Khouri IF, Lee MS, Saliba RM, et al.: Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma. J Clin Oncol 21 (23): 4407-12, 2003. [PUBMED Abstract]
Khouri IF, Romaguera J, Kantarjian H, et al.: Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma. J Clin Oncol 16 (12): 3803-9, 1998. [PUBMED Abstract]
Howard OM, Gribben JG, Neuberg DS, et al.: Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival. J Clin Oncol 20 (5): 1288-94, 2002. [PUBMED Abstract]
Lefrère F, Delmer A, Suzan F, et al.: Sequential chemotherapy by CHOP and DHAP regimens followed by high-dose therapy with stem cell transplantation induces a high rate of complete response and improves event-free survival in mantle cell lymphoma: a prospective study. Leukemia 16 (4): 587-93, 2002. [PUBMED Abstract]
Gopal AK, Rajendran JG, Petersdorf SH, et al.: High-dose chemo-radioimmunotherapy with autologous stem cell support for relapsed mantle cell lymphoma. Blood 99 (9): 3158-62, 2002. [PUBMED Abstract]
Gianni AM, Magni M, Martelli M, et al.: Long-term remission in mantle cell lymphoma following high-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting (R-HDS regimen). Blood 102 (2): 749-55, 2003. [PUBMED Abstract]
Forstpointner R, Dreyling M, Repp R, et al.: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104 (10): 3064-71, 2004. [PUBMED Abstract]
Dreyling M, Lenz G, Hoster E, et al.: Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood 105 (7): 2677-84, 2005. [PUBMED Abstract]
Goy A, Younes A, McLaughlin P, et al.: Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol 23 (4): 667-75, 2005. [PUBMED Abstract]
O'Connor OA, Wright J, Moskowitz C, et al.: Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol 23 (4): 676-84, 2005. [PUBMED Abstract]
Fisher RI, Bernstein SH, Kahl BS, et al.: Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 24 (30): 4867-74, 2006. [PUBMED Abstract]
Morrison VA, Dunn DL, Manivel JC, et al.: Clinical characteristics of post-transplant lymphoproliferative disorders. Am J Med 97 (1): 14-24, 1994. [PUBMED Abstract]
Knowles DM, Cesarman E, Chadburn A, et al.: Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. Blood 85 (2): 552-65, 1995. [PUBMED Abstract]
Leblond V, Dhedin N, Mamzer Bruneel MF, et al.: Identification of prognostic factors in 61 patients with posttransplantation lymphoproliferative disorders. J Clin Oncol 19 (3): 772-8, 2001. [PUBMED Abstract]
Ghobrial IM, Habermann TM, Maurer MJ, et al.: Prognostic analysis for survival in adult solid organ transplant recipients with post-transplantation lymphoproliferative disorders. J Clin Oncol 23 (30): 7574-82, 2005. [PUBMED Abstract]
Armitage JM, Kormos RL, Stuart RS, et al.: Posttransplant lymphoproliferative disease in thoracic organ transplant patients: ten years of cyclosporine-based immunosuppression. J Heart Lung Transplant 10 (6): 877-86; discussion 886-7, 1991 Nov-Dec. [PUBMED Abstract]
Kuehnle I, Huls MH, Liu Z, et al.: CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation. Blood 95 (4): 1502-5, 2000. [PUBMED Abstract]
Shapiro RS, Chauvenet A, McGuire W, et al.: Treatment of B-cell lymphoproliferative disorders with interferon alfa and intravenous gamma globulin. N Engl J Med 318 (20): 1334, 1988. [PUBMED Abstract]
Leblond V, Sutton L, Dorent R, et al.: Lymphoproliferative disorders after organ transplantation: a report of 24 cases observed in a single center. J Clin Oncol 13 (4): 961-8, 1995. [PUBMED Abstract]
Mamzer-Bruneel MF, Lomé C, Morelon E, et al.: Durable remission after aggressive chemotherapy for very late post-kidney transplant lymphoproliferation: A report of 16 cases observed in a single center. J Clin Oncol 18 (21): 3622-32, 2000. [PUBMED Abstract]
Swinnen LJ: Durable remission after aggressive chemotherapy for post-cardiac transplant lymphoproliferation. Leuk Lymphoma 28 (1-2): 89-101, 1997. [PUBMED Abstract]
McCarthy M, Ramage J, McNair A, et al.: The clinical diversity and role of chemotherapy in lymphoproliferative disorder in liver transplant recipients. J Hepatol 27 (6): 1015-21, 1997. [PUBMED Abstract]
Leblond V, Davi F, Charlotte F, et al.: Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity? J Clin Oncol 16 (6): 2052-9, 1998. [PUBMED Abstract]
Senderowicz AM, Vitetta E, Headlee D, et al.: Complete sustained response of a refractory, post-transplantation, large B-cell lymphoma to an anti-CD22 immunotoxin. Ann Intern Med 126 (11): 882-5, 1997. [PUBMED Abstract]
Haddad E, Paczesny S, Leblond V, et al.: Treatment of B-lymphoproliferative disorder with a monoclonal anti-interleukin-6 antibody in 12 patients: a multicenter phase 1-2 clinical trial. Blood 97 (6): 1590-7, 2001. [PUBMED Abstract]
Soslow RA, Davis RE, Warnke RA, et al.: True histiocytic lymphoma following therapy for lymphoblastic neoplasms. Blood 87 (12): 5207-12, 1996. [PUBMED Abstract]
Kamel OW, Gocke CD, Kell DL, et al.: True histiocytic lymphoma: a study of 12 cases based on current definition. Leuk Lymphoma 18 (1-2): 81-6, 1995. [PUBMED Abstract]
Nador RG, Cesarman E, Chadburn A, et al.: Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood 88 (2): 645-56, 1996. [PUBMED Abstract]

Stage Information for Adult Non-Hodgkin Lymphoma

Stage is important in selecting a treatment for patients with non-Hodgkin lymphoma (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 with fluorine-18-fluorodeoxyglucose can be used for initial staging and for follow-up after therapy as a supplement to CT scanning.[2-5]

Staging Subclassification System

The Ann Arbor staging system is commonly used for patients with NHL.[6,7] 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.

Stage I

Stage I NHL means involvement of a single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE).

Stage II

Stage II NHL means involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ or site and its regional lymph nodes with or without other lymph node regions on the same side of the diaphragm (IIE). [Note: The number of lymph node regions involved may be indicated by a subscript (e.g., II₃).]

Stage III

Stage III NHL means involvement of lymph node regions on both sides of the diaphragm (III) that may also be accompanied by localized involvement of an extralymphatic organ or site (IIIE), by involvement of the spleen (IIIS), or both (IIIS+E).

Stage IV

Stage IV NHL means disseminated (multifocal) involvement of one or more extralymphatic sites with or without associated lymph node involvement or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement.

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.

Sites are identified by the following notation:

Enlarge ²⁵

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 age, performance status, tumor size, lactate dehydrogenase (LDH) values, and 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.[8] After validation by several cancer centers, 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 years vs. >60 years), 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.[8] 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.[9,10]

References

Mann GB, Conlon KC, LaQuaglia M, et al.: Emerging role of laparoscopy in the diagnosis of lymphoma. J Clin Oncol 16 (5): 1909-15, 1998. [PUBMED Abstract]
Zijlstra JM, Hoekstra OS, Raijmakers PG, et al.: 18FDG positron emission tomography versus 67Ga scintigraphy as prognostic test during chemotherapy for non-Hodgkin's lymphoma. Br J Haematol 123 (3): 454-62, 2003. [PUBMED Abstract]
Juweid ME, Cheson BD: Role of positron emission tomography in lymphoma. J Clin Oncol 23 (21): 4577-80, 2005. [PUBMED Abstract]
Juweid ME, Stroobants S, Hoekstra OS, et al.: Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 25 (5): 571-8, 2007. [PUBMED Abstract]
Cheson BD, Pfistner B, Juweid ME, et al.: Revised response criteria for malignant lymphoma. J Clin Oncol 25 (5): 579-86, 2007. [PUBMED Abstract]
Lymphoid neoplasms. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 393-406.
National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer 49 (10): 2112-35, 1982. [PUBMED Abstract]
A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329 (14): 987-94, 1993. [PUBMED Abstract]
Rosenwald A, Wright G, Chan WC, et al.: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346 (25): 1937-47, 2002. [PUBMED Abstract]
Abramson JS, Shipp MA: Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach. Blood 106 (4): 1164-74, 2005. [PUBMED Abstract]

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 2 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.[3-5] 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.[4,8-14] Most of these patients show clonal hematopoiesis even before the transplantation, suggesting that the hematologic injury usually occurs during induction or reinduction chemotherapy.[11,15,16] 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.[17] Successful pregnancies with children born free of congenital abnormalities have been reported in young women after autologous BMT.[18]

Aggressive lymphomas are increasingly seen in HIV-positive patients whose treatment requires special consideration. (Refer to the PDQ summary on AIDS-Related Lymphoma Treatment ⁵ for more information.)

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,[19-27] thyroid,[28,29] spleen,[30] testis,[31] paranasal sinuses,[32-36] bone,[37,38] orbit,[39-41] and skin.[42-50]

(Refer to the PDQ summary on Primary Central Nervous System Lymphoma Treatment ⁶ for more information.)

References

Cheson BD, Horning SJ, Coiffier B, et al.: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17 (4): 1244, 1999. [PUBMED Abstract]
Pryzant RM, Meistrich ML, Wilson G, et al.: Long-term reduction in sperm count after chemotherapy with and without radiation therapy for non-Hodgkin's lymphomas. J Clin Oncol 11 (2): 239-47, 1993. [PUBMED Abstract]
Travis LB, Curtis RE, Glimelius B, et al.: Second cancers among long-term survivors of non-Hodgkin's lymphoma. J Natl Cancer Inst 85 (23): 1932-7, 1993. [PUBMED Abstract]
Mudie NY, Swerdlow AJ, Higgins CD, et al.: Risk of second malignancy after non-Hodgkin's lymphoma: a British Cohort Study. J Clin Oncol 24 (10): 1568-74, 2006. [PUBMED Abstract]
Tward JD, Wendland MM, Shrieve DC, et al.: The risk of secondary malignancies over 30 years after the treatment of non-Hodgkin lymphoma. Cancer 107 (1): 108-15, 2006. [PUBMED Abstract]
Haddy TB, Adde MA, McCalla J, et al.: Late effects in long-term survivors of high-grade non-Hodgkin's lymphomas. J Clin Oncol 16 (6): 2070-9, 1998. [PUBMED Abstract]
Moser EC, Noordijk EM, van Leeuwen FE, et al.: Long-term risk of cardiovascular disease after treatment for aggressive non-Hodgkin lymphoma. Blood 107 (7): 2912-9, 2006. [PUBMED Abstract]
Darrington DL, Vose JM, Anderson JR, et al.: Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 12 (12): 2527-34, 1994. [PUBMED Abstract]
Stone RM, Neuberg D, Soiffer R, et al.: Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 12 (12): 2535-42, 1994. [PUBMED Abstract]
Oddou S, Vey N, Viens P, et al.: Second neoplasms following high-dose chemotherapy and autologous stem cell transplantation for malignant lymphomas: a report of six cases in a cohort of 171 patients from a single institution. Leuk Lymphoma 31 (1-2): 187-94, 1998. [PUBMED Abstract]
Armitage JO, Carbone PP, Connors JM, et al.: Treatment-related myelodysplasia and acute leukemia in non-Hodgkin's lymphoma patients. J Clin Oncol 21 (5): 897-906, 2003. [PUBMED Abstract]
André M, Mounier N, Leleu X, et al.: Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients. Blood 103 (4): 1222-8, 2004. [PUBMED Abstract]
Lenz G, Dreyling M, Schiegnitz E, et al.: Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 22 (24): 4926-33, 2004. [PUBMED Abstract]
McLaughlin P, Estey E, Glassman A, et al.: Myelodysplasia and acute myeloid leukemia following therapy for indolent lymphoma with fludarabine, mitoxantrone, and dexamethasone (FND) plus rituximab and interferon alpha. Blood 105 (12): 4573-5, 2005. [PUBMED Abstract]
Mach-Pascual S, Legare RD, Lu D, et al.: Predictive value of clonality assays in patients with non-Hodgkin's lymphoma undergoing autologous bone marrow transplant: a single institution study. Blood 91 (12): 4496-503, 1998. [PUBMED Abstract]
Lillington DM, Micallef IN, Carpenter E, et al.: Detection of chromosome abnormalities pre-high-dose treatment in patients developing therapy-related myelodysplasia and secondary acute myelogenous leukemia after treatment for non-Hodgkin's lymphoma. J Clin Oncol 19 (9): 2472-81, 2001. [PUBMED Abstract]
Brown JR, Yeckes H, Friedberg JW, et al.: Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total-body irradiation and autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 23 (10): 2208-14, 2005. [PUBMED Abstract]
Jackson GH, Wood A, Taylor PR, et al.: Early high dose chemotherapy intensification with autologous bone marrow transplantation in lymphoma associated with retention of fertility and normal pregnancies in females. Scotland and Newcastle Lymphoma Group, UK. Leuk Lymphoma 28 (1-2): 127-32, 1997. [PUBMED Abstract]
Maor MH, Velasquez WS, Fuller LM, et al.: Stomach conservation in stages IE and IIE gastric non-Hodgkin's lymphoma. J Clin Oncol 8 (2): 266-71, 1990. [PUBMED Abstract]
Salles G, Herbrecht R, Tilly H, et al.: Aggressive primary gastrointestinal lymphomas: review of 91 patients treated with the LNH-84 regimen. A study of the Groupe d'Etude des Lymphomes Agressifs. Am J Med 90 (1): 77-84, 1991. [PUBMED Abstract]
Taal BG, Burgers JM, van Heerde P, et al.: The clinical spectrum and treatment of primary non-Hodgkin's lymphoma of the stomach. Ann Oncol 4 (10): 839-46, 1993. [PUBMED Abstract]
Tondini C, Giardini R, Bozzetti F, et al.: Combined modality treatment for primary gastrointestinal non-Hodgkin's lymphoma: the Milan Cancer Institute experience. Ann Oncol 4 (10): 831-7, 1993. [PUBMED Abstract]
d'Amore F, Brincker H, Grønbaek K, et al.: Non-Hodgkin's lymphoma of the gastrointestinal tract: a population-based analysis of incidence, geographic distribution, clinicopathologic presentation features, and prognosis. Danish Lymphoma Study Group. J Clin Oncol 12 (8): 1673-84, 1994. [PUBMED Abstract]
Haim N, Leviov M, Ben-Arieh Y, et al.: Intermediate and high-grade gastric non-Hodgkin's lymphoma: a prospective study of non-surgical treatment with primary chemotherapy, with or without radiotherapy. Leuk Lymphoma 17 (3-4): 321-6, 1995. [PUBMED Abstract]
Koch P, del Valle F, Berdel WE, et al.: Primary gastrointestinal non-Hodgkin's lymphoma: I. Anatomic and histologic distribution, clinical features, and survival data of 371 patients registered in the German Multicenter Study GIT NHL 01/92. J Clin Oncol 19 (18): 3861-73, 2001. [PUBMED Abstract]
Koch P, del Valle F, Berdel WE, et al.: Primary gastrointestinal non-Hodgkin's lymphoma: II. Combined surgical and conservative or conservative management only in localized gastric lymphoma--results of the prospective German Multicenter Study GIT NHL 01/92. J Clin Oncol 19 (18): 3874-83, 2001. [PUBMED Abstract]
Koch P, Probst A, Berdel WE, et al.: Treatment results in localized primary gastric lymphoma: data of patients registered within the German multicenter study (GIT NHL 02/96). J Clin Oncol 23 (28): 7050-9, 2005. [PUBMED Abstract]
Blair TJ, Evans RG, Buskirk SJ, et al.: Radiotherapeutic management of primary thyroid lymphoma. Int J Radiat Oncol Biol Phys 11 (2): 365-70, 1985. [PUBMED Abstract]
Junor EJ, Paul J, Reed NS: Primary non-Hodgkin's lymphoma of the thyroid. Eur J Surg Oncol 18 (4): 313-21, 1992. [PUBMED Abstract]
Morel P, Dupriez B, Gosselin B, et al.: Role of early splenectomy in malignant lymphomas with prominent splenic involvement (primary lymphomas of the spleen). A study of 59 cases. Cancer 71 (1): 207-15, 1993. [PUBMED Abstract]
Zucca E, Conconi A, Mughal TI, et al.: Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the International Extranodal Lymphoma Study Group. J Clin Oncol 21 (1): 20-7, 2003. [PUBMED Abstract]
Liang R, Todd D, Chan TK, et al.: Treatment outcome and prognostic factors for primary nasal lymphoma. J Clin Oncol 13 (3): 666-70, 1995. [PUBMED Abstract]
Cheung MM, Chan JK, Lau WH, et al.: Primary non-Hodgkin's lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients. J Clin Oncol 16 (1): 70-7, 1998. [PUBMED Abstract]
Logsdon MD, Ha CS, Kavadi VS, et al.: Lymphoma of the nasal cavity and paranasal sinuses: improved outcome and altered prognostic factors with combined modality therapy. Cancer 80 (3): 477-88, 1997. [PUBMED Abstract]
Hausdorff J, Davis E, Long G, et al.: Non-Hodgkin's lymphoma of the paranasal sinuses: clinical and pathological features, and response to combined-modality therapy. Cancer J Sci Am 3 (5): 303-11, 1997 Sep-Oct. [PUBMED Abstract]
Sasai K, Yamabe H, Kokubo M, et al.: Head-and-neck stages I and II extranodal non-Hodgkin's lymphomas: real classification and selection for treatment modality. Int J Radiat Oncol Biol Phys 48 (1): 153-60, 2000. [PUBMED Abstract]
Ferreri AJ, Reni M, Ceresoli GL, et al.: Therapeutic management with adriamycin-containing chemotherapy and radiotherapy of monostotic and polyostotic primary non-Hodgkin's lymphoma of bone in adults. Cancer Invest 16 (8): 554-61, 1998. [PUBMED Abstract]
Dubey P, Ha CS, Besa PC, et al.: Localized primary malignant lymphoma of bone. Int J Radiat Oncol Biol Phys 37 (5): 1087-93, 1997. [PUBMED Abstract]
Martinet S, Ozsahin M, Belkacémi Y, et al.: Outcome and prognostic factors in orbital lymphoma: a Rare Cancer Network study on 90 consecutive patients treated with radiotherapy. Int J Radiat Oncol Biol Phys 55 (4): 892-8, 2003. [PUBMED Abstract]
Uno T, Isobe K, Shikama N, et al.: Radiotherapy for extranodal, marginal zone, B-cell lymphoma of mucosa-associated lymphoid tissue originating in the ocular adnexa: a multiinstitutional, retrospective review of 50 patients. Cancer 98 (4): 865-71, 2003. [PUBMED Abstract]
Sjö LD, Ralfkiaer E, Juhl BR, et al.: Primary lymphoma of the lacrimal sac: an EORTC ophthalmic oncology task force study. Br J Ophthalmol 90 (8): 1004-9, 2006. [PUBMED Abstract]
Geelen FA, Vermeer MH, Meijer CJ, et al.: bcl-2 protein expression in primary cutaneous large B-cell lymphoma is site-related. J Clin Oncol 16 (6): 2080-5, 1998. [PUBMED Abstract]
Pandolfino TL, Siegel RS, Kuzel TM, et al.: Primary cutaneous B-cell lymphoma: review and current concepts. J Clin Oncol 18 (10): 2152-68, 2000. [PUBMED Abstract]
Sarris AH, Braunschweig I, Medeiros LJ, et al.: Primary cutaneous non-Hodgkin's lymphoma of Ann Arbor stage I: preferential cutaneous relapses but high cure rate with doxorubicin-based therapy. J Clin Oncol 19 (2): 398-405, 2001. [PUBMED Abstract]
Grange F, Bekkenk MW, Wechsler J, et al.: Prognostic factors in primary cutaneous large B-cell lymphomas: a European multicenter study. J Clin Oncol 19 (16): 3602-10, 2001. [PUBMED Abstract]
Mirza I, Macpherson N, Paproski S, et al.: Primary cutaneous follicular lymphoma: an assessment of clinical, histopathologic, immunophenotypic, and molecular features. J Clin Oncol 20 (3): 647-55, 2002. [PUBMED Abstract]
Smith BD, Glusac EJ, McNiff JM, et al.: Primary cutaneous B-cell lymphoma treated with radiotherapy: a comparison of the European Organization for Research and Treatment of Cancer and the WHO classification systems. J Clin Oncol 22 (4): 634-9, 2004. [PUBMED Abstract]
Willemze R, Jaffe ES, Burg G, et al.: WHO-EORTC classification for cutaneous lymphomas. Blood 105 (10): 3768-85, 2005. [PUBMED Abstract]
El-Helw L, Goodwin S, Slater D, et al.: Primary B-cell lymphoma of the skin: the Sheffield Lymphoma Group Experience (1984-2003). Int J Oncol 25 (5): 1453-8, 2004. [PUBMED Abstract]
Zinzani PL, Quaglino P, Pimpinelli N, et al.: Prognostic factors in primary cutaneous B-cell lymphoma: the Italian Study Group for Cutaneous Lymphomas. J Clin Oncol 24 (9): 1376-82, 2006. [PUBMED Abstract]

Indolent, Stage I and Contiguous Stage II Adult Non-Hodgkin Lymphoma

Although localized presentations are uncommon in non-Hodgkin lymphoma (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.[1-4] The value of adjuvant chemotherapy (single-agent chlorambucil or doxorubicin-based combination chemotherapy), in addition to radiation to decrease relapse, has not been proven conclusively.[5,6]

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.[7]

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:

Involved-field radiation therapy.[1-4]
Watchful waiting.[7]
Chemotherapy with radiation therapy.[6]
Extended (regional) radiation therapy to cover adjacent prophylactic nodes.[1-4,8]
Rituximab, an anti-CD20 monoclonal antibody, either alone or in combination with chemotherapy and extrapolated from trials of patients with advanced-stage disease.
Other therapies as designated for patients with advanced-stage disease.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with indolent, stage I adult non-Hodgkin lymphoma ²⁶ and indolent, contiguous stage II adult non-Hodgkin lymphoma ²⁷. 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 ²⁸.

References

Mac Manus MP, Hoppe RT: Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol 14 (4): 1282-90, 1996. [PUBMED Abstract]
Vaughan Hudson B, Vaughan Hudson G, MacLennan KA, et al.: Clinical stage 1 non-Hodgkin's lymphoma: long-term follow-up of patients treated by the British National Lymphoma Investigation with radiotherapy alone as initial therapy. Br J Cancer 69 (6): 1088-93, 1994. [PUBMED Abstract]
Denham JW, Denham E, Dear KB, et al.: The follicular non-Hodgkin's lymphomas--I. The possibility of cure. Eur J Cancer 32A (3): 470-9, 1996. [PUBMED Abstract]
Haas RL, Poortmans P, de Jong D, et al.: High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas. J Clin Oncol 21 (13): 2474-80, 2003. [PUBMED Abstract]
Kelsey SM, Newland AC, Hudson GV, et al.: A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade, localised non-Hodgkins lymphoma. Med Oncol 11 (1): 19-25, 1994. [PUBMED Abstract]
Seymour JF, Pro B, Fuller LM, et al.: Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent non-Hodgkin's lymphoma. J Clin Oncol 21 (11): 2115-22, 2003. [PUBMED Abstract]
Advani R, Rosenberg SA, Horning SJ: Stage I and II follicular non-Hodgkin's lymphoma: long-term follow-up of no initial therapy. J Clin Oncol 22 (8): 1454-9, 2004. [PUBMED Abstract]
Ha CS, Kong JS, Tucker SL, et al.: Central lymphatic irradiation for stage I-III follicular lymphoma: report from a single-institutional prospective study. Int J Radiat Oncol Biol Phys 57 (2): 316-20, 2003. [PUBMED Abstract]

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).[1-5]

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 (ECOG-1484 ²⁹) 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-0014 ³⁰, for example, has suggested the use of R-CHOP (rituximab + CHOP) with or without radiation therapy but only on the basis of historical comparison to prior studies.[6]

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 PDQ Cancer Clinical Trials Registry that are now accepting patients with aggressive, stage I adult non-Hodgkin lymphoma ³¹ and aggressive, contiguous stage II adult non-Hodgkin lymphoma ³². 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 ²⁸.

References

Bonnet C, Fillet G, Mounier N, et al.: CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 25 (7): 787-92, 2007. [PUBMED Abstract]
Miller TP, Dahlberg S, Cassady JR, et al.: Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med 339 (1): 21-6, 1998. [PUBMED Abstract]
Miller TP, Leblanc M, Spier C, et al.: CHOP alone compared to CHOP plus radiotherapy for early stage aggressive non-Hodgkin's lymphomas: update of the Southwest Oncology Group (SWOG) randomized trial. [Abstract] Blood 98 (11): A-3024, 2001.
Horning SJ, Weller E, Kim K, et al.: Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin's lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol 22 (15): 3032-8, 2004. [PUBMED Abstract]
Reyes F, Lepage E, Ganem G, et al.: ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 352 (12): 1197-205, 2005. [PUBMED Abstract]
Miller TP, Unger JM, Spier C, et al.: Effect of adding rituximab to three cycles of CHOP plus involved-field radiotherapy for limited-stage aggressive diffuse B-cell lymphoma (SWOG-0014). [Abstract] Blood 104 (11): A-158, 2004.

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.[1-3] Three randomized trials compared watchful waiting to immediate chemotherapy. All three trials showed no difference in cause-specific or overall survival. For patients randomized 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 years).[2,4,5][Level of evidence: 1iiA] An ongoing international study, known as the PRIMA ³³ trial, is comparing watchful waiting to immediate rituximab, the anti-CD20 monoclonal antibody, with or without maintenance doses. Numerous prospective clinical trials, including SWOG-8809 ³⁴, of interferon-alpha have shown no consistent benefit; the role of interferon in patients with indolent lymphoma remains controversial.[6-17]

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. Since none of these therapies are curative for advanced-stage disease, innovative approaches are under clinical evaluation. The approaches include intensive therapy with chemotherapy and total-body irradiation (TBI) followed by autologous or allogeneic bone marrow transplantation (BMT) or peripheral stem cell transplantation, 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.[3,18] [Level of evidence: 1iiDiii]

However, 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 to 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 = 0.63 [0.51–0.79] for the meta-analysis).[19-23][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. In a prospective randomized trial of 465 patients with relapsed follicular lymphoma, responders to R-CHOP or CHOP were further randomly assigned to rituximab maintenance (one dose every 3 months for 2 years) or no maintenance. With 39 months' median follow-up, rituximab maintenance was better by median progression-free survival (52 months vs. 15 months, P < .0001) and by 3-year OS (85% vs. 77%, P = .011).[24] This benefit for maintenance was evident even for patients who received rituximab during induction therapy.

For patients with indolent, noncontiguous stage II and stage III lymphoma, central lymphatic radiation therapy has been proposed but is not usually recommended as a form of treatment.[25,26]

Standard treatment options:

For asymptomatic patients, deferred therapy with careful observation.[2,27]

Rituximab may be considered as first-line therapy.
- Rituximab alone.[28-32]
- R-F: rituximab plus fludarabine.[33]
- R-CVP: rituximab plus cyclophosphamide plus vincristine plus prednisone.[21,34]
- R-CHOP: rituximab plus cyclophosphamide plus doxorubicin plus vincristine plus prednisone.[20,35,36]
- R-FM: rituximab plus fludarabine plus mitoxantrone.[37]
- R-FCM: rituximab plus fludarabine plus cyclophosphamide plus mitoxantrone.[38]

Purine nucleoside analog:
- Fludarabine.[18,39,40]
- 2-chlorodeoxyadenosine.[41,42]

Oral alkylating agents (with or without steroids):
- Cyclophosphamide.[43]
- Chlorambucil.

Combination chemotherapy alone:
- CVP: cyclophosphamide plus vincristine plus prednisone.[18,44]
- C-MOPP: cyclophosphamide plus vincristine plus procarbazine plus prednisone.[45,46]
- CHOP: cyclophosphamide plus doxorubicin plus vincristine plus prednisone.[43,47]
- FND: fludarabine plus mitoxantrone plus or minus dexamethasone, as evidenced in the SWOG-9501 ³⁵ trial, for example.[48,49]

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 evidenced in the SWOG S-9911 ³⁶ trial, for example.[50,51] Randomized prospective studies are required to determine the optimal utilization of this modality.

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.[52-61]

Phase III trials comparing chemotherapy alone versus chemotherapy followed by anti-idiotype vaccine.[62-64]

Extended-field radiation therapy (stage III patients only).[65]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with indolent, noncontiguous stage II adult non-Hodgkin lymphoma ³⁷, indolent, stage III adult non-Hodgkin lymphoma ³⁸ and indolent, stage IV adult non-Hodgkin lymphoma ³⁹. 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 ²⁸.

References

Eek R, Falkson G: The low-grade lymphoproliferative disorders. Oncology 54 (6): 441-58, 1997 Nov-Dec. [PUBMED Abstract]
Ardeshna KM, Smith P, Norton A, et al.: Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet 362 (9383): 516-22, 2003. [PUBMED Abstract]
Gribben JG: How I treat indolent lymphoma. Blood 109 (11): 4617-26, 2007. [PUBMED Abstract]
Brice P, Bastion Y, Lepage E, et al.: Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 15 (3): 1110-7, 1997. [PUBMED Abstract]
Longo DL: Idiotype vaccination in follicular lymphoma: knocking on the doorway to cure. J Natl Cancer Inst 98 (18): 1263-5, 2006. [PUBMED Abstract]
Smalley RV, Andersen JW, Hawkins MJ, et al.: Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin's lymphoma. N Engl J Med 327 (19): 1336-41, 1992. [PUBMED Abstract]
Solal-Céligny P, Lepage E, Brousse N, et al.: Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: final analysis of survival and toxicity in the Groupe d'Etude des Lymphomes Folliculaires 86 Trial. J Clin Oncol 16 (7): 2332-8, 1998. [PUBMED Abstract]
Andersen JW, Smalley RV: Interferon alfa plus chemotherapy for non-Hodgkin's lymphoma: five-year follow-up. N Engl J Med 329 (24): 1821-2, 1993. [PUBMED Abstract]
Hagenbeek A, Carde P, Meerwaldt JH, et al.: Maintenance of remission with human recombinant interferon alfa-2a in patients with stages III and IV low-grade malignant non-Hodgkin's lymphoma. European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 16 (1): 41-7, 1998. [PUBMED Abstract]
Aviles A, Duque G, Talavera A, et al.: Interferon alpha 2b as maintenance therapy in low grade malignant lymphoma improves duration of remission and survival. Leuk Lymphoma 20 (5-6): 495-9, 1996. [PUBMED Abstract]
Arranz R, García-Alfonso P, Sobrino P, et al.: Role of interferon alfa-2b in the induction and maintenance treatment of low-grade non-Hodgkin's lymphoma: results from a prospective, multicenter trial with double randomization. J Clin Oncol 16 (4): 1538-46, 1998. [PUBMED Abstract]
Fisher RI, Dana BW, LeBlanc M, et al.: Interferon alpha consolidation after intensive chemotherapy does not prolong the progression-free survival of patients with low-grade non-Hodgkin's lymphoma: results of the Southwest Oncology Group randomized phase III study 8809. J Clin Oncol 18 (10): 2010-6, 2000. [PUBMED Abstract]
Cole BF, Solal-Céligny P, Gelber RD, et al.: Quality-of-life-adjusted survival analysis of interferon alfa-2b treatment for advanced follicular lymphoma: an aid to clinical decision making. J Clin Oncol 16 (7): 2339-44, 1998. [PUBMED Abstract]
Ozer H, Wiernik PH, Giles F, et al.: Recombinant interferon-alpha therapy in patients with follicular lymphoma. Cancer 82 (10): 1821-30, 1998. [PUBMED Abstract]
Allen IE, Ross SD, Borden SP, et al.: Meta-analysis to assess the efficacy of interferon-alpha in patients with follicular non-Hodgkin's lymphoma. J Immunother 24 (1): 58-65, 2001 Jan-Feb. [PUBMED Abstract]
Cheson BD: The curious case of the baffling biological. J Clin Oncol 18 (10): 2007-9, 2000. [PUBMED Abstract]
Rohatiner AZ, Gregory WM, Peterson B, et al.: Meta-analysis to evaluate the role of interferon in follicular lymphoma. J Clin Oncol 23 (10): 2215-23, 2005. [PUBMED Abstract]
Hagenbeek A, Eghbali H, Monfardini S, et al.: Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage III and IV low-grade malignant Non-Hodgkin's lymphoma. J Clin Oncol 24 (10): 1590-6, 2006. [PUBMED Abstract]
Herold M, Haas A, Srock S, et al.: Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol 25 (15): 1986-92, 2007. [PUBMED Abstract]
Hiddemann W, Kneba M, Dreyling M, et al.: Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106 (12): 3725-32, 2005. [PUBMED Abstract]
Marcus RE, Solal-Celigny P, Imrie K, et al.: MabThera (rituximab) plus cyclophosphamide, vincristine and prednisone (CVP) chemotherapy improves survival in previously untreated patients with advanced follicular non-Hodgkin’s lymphoma (NHL). [Abstract] Blood 108 (11): A-481, 2006.
Salles GA, Mounier N, de Guibert S, et al.: Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: final analysis of the GELA-GOELAMS FL2000 study with a 5-year follow-up. [Abstract] Blood 110 (11): A-792, 2007.
Schulz H, Bohlius J, Skoetz N, et al.: Combined immunochemotherapy with rituximab improves overall survival in patients with follicular and mantle cell lymphoma: updated meta-analysis results. [Abstract] Blood 108 (11): A-2760, 2006.
van Oers MH, Klasa R, Marcus RE, et al.: Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 108 (10): 3295-301, 2006. [PUBMED Abstract]
Jacobs JP, Murray KJ, Schultz CJ, et al.: Central lymphatic irradiation for stage III nodular malignant lymphoma: long-term results. J Clin Oncol 11 (2): 233-8, 1993. [PUBMED Abstract]
Mendenhall NP, Million RR: Comprehensive lymphatic irradiation for stage II-III non-Hodgkin's lymphoma. Am J Clin Oncol 12 (3): 190-4, 1989. [PUBMED Abstract]
Portlock CS, Rosenberg SA: No initial therapy for stage III and IV non-Hodgkin's lymphomas of favorable histologic types. Ann Intern Med 90(1): 10-13, 1979.
Ghielmini M, Schmitz SF, Cogliatti SB, et al.: Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 103 (12): 4416-23, 2004. [PUBMED Abstract]
Witzig TE, Vukov AM, Habermann TM, et al.: Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin's lymphoma: a phase II trial in the North Central Cancer Treatment Group. J Clin Oncol 23 (6): 1103-8, 2005. [PUBMED Abstract]
Hainsworth JD, Litchy S, Shaffer DW, et al.: Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma--a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23 (6): 1088-95, 2005. [PUBMED Abstract]
Williams ME: ECOG 4402: randomized phase III-trial comparing two different rituximab dosing regimens for patients with low tumor burden indolent non-Hodgkin's lymphoma. Curr Hematol Rep 3 (6): 395-6, 2004. [PUBMED Abstract]
Buske C, Hiddemann W: Rituximab maintenance therapy in indolent NHL: a clinical review. Leuk Res 30 (Suppl 1): S11-5, 2006. [PUBMED Abstract]
Czuczman MS, Koryzna A, Mohr A, et al.: Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma. J Clin Oncol 23 (4): 694-704, 2005. [PUBMED Abstract]
Marcus R, Imrie K, Belch A, et al.: CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105 (4): 1417-23, 2005. [PUBMED Abstract]
Czuczman MS, Weaver R, Alkuzweny B, et al.: Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol 22 (23): 4711-6, 2004. [PUBMED Abstract]
Hainsworth JD, Litchy S, Morrissey LH, et al.: Rituximab plus short-duration chemotherapy as first-line treatment for follicular non-Hodgkin's lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23 (7): 1500-6, 2005. [PUBMED Abstract]
Zinzani PL, Pulsoni A, Perrotti A, et al.: Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol 22 (13): 2654-61, 2004. [PUBMED Abstract]
Forstpointner R, Dreyling M, Repp R, et al.: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104 (10): 3064-71, 2004. [PUBMED Abstract]
Whelan JS, Davis CL, Rule S, et al.: Fludarabine phosphate for the treatment of low grade lymphoid malignancy. Br J Cancer 64 (1): 120-3, 1991. [PUBMED Abstract]
Solal-Céligny P, Brice P, Brousse N, et al.: Phase II trial of fludarabine monophosphate as first-line treatment in patients with advanced follicular lymphoma: a multicenter study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 14 (2): 514-9, 1996. [PUBMED Abstract]
Saven A, Emanuele S, Kosty M, et al.: 2-Chlorodeoxyadenosine activity in patients with untreated, indolent non-Hodgkin's lymphoma. Blood 86 (5): 1710-6, 1995. [PUBMED Abstract]
Fridrik MA, Jäger G, Kienzer HR, et al.: Efficacy and toxicity of 2-Chlorodeoxyadenosine (Cladribine)--2 h infusion for 5 days--as first-line treatment for advanced low grade non-Hodgkin's lymphoma. Eur J Cancer 34 (10): 1560-4, 1998. [PUBMED Abstract]
Peterson BA, Petroni GR, Frizzera G, et al.: Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B. J Clin Oncol 21 (1): 5-15, 2003. [PUBMED Abstract]
Hoppe RT, Kushlan P, Kaplan HS, et al.: The treatment of advanced stage favorable histology non-Hodgkin's lymphoma: a preliminary report of a randomized trial comparing single agent chemotherapy, combination chemotherapy, and whole body irradiation. Blood 58 (3): 592-8, 1981. [PUBMED Abstract]
Anderson T, DeVita VT Jr, Simon RM, et al.: Malignant lymphoma. II Prognostic factors and response to treatment of 473 patients at the National Cancer Institute. Cancer 50 (12): 2708-21, 1982. [PUBMED Abstract]
Longo DL, Young RC, Hubbard SM, et al.: Prolonged initial remission in patients with nodular mixed lymphoma. Ann Intern Med 100 (5): 651-6, 1984. [PUBMED Abstract]
Dana BW, Dahlberg S, Nathwani BN, et al.: Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy. J Clin Oncol 11 (4): 644-51, 1993. [PUBMED Abstract]
Tsimberidou AM, McLaughlin P, Younes A, et al.: Fludarabine, mitoxantrone, dexamethasone (FND) compared with an alternating triple therapy (ATT) regimen in patients with stage IV indolent lymphoma. Blood 100 (13): 4351-7, 2002. [PUBMED Abstract]
Velasquez WS, Lew D, Grogan TM, et al.: Combination of fludarabine and mitoxantrone in untreated stages III and IV low-grade lymphoma: S9501. J Clin Oncol 21 (10): 1996-2003, 2003. [PUBMED Abstract]
Kaminski MS, Tuck M, Estes J, et al.: 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 352 (5): 441-9, 2005. [PUBMED Abstract]
Press OW, Unger JM, Braziel RM, et al.: Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin's lymphoma: five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol 24 (25): 4143-9, 2006. [PUBMED Abstract]
Apostolidis J, Gupta RK, Grenzelias D, et al.: High-dose therapy with autologous bone marrow support as consolidation of remission in follicular lymphoma: long-term clinical and molecular follow-up. J Clin Oncol 18 (3): 527-36, 2000. [PUBMED Abstract]
van Besien K, Sobocinski KA, Rowlings PA, et al.: Allogeneic bone marrow transplantation for low-grade lymphoma. Blood 92 (5): 1832-6, 1998. [PUBMED Abstract]
Gopal AK, Gooley TA, Maloney DG, et al.: High-dose radioimmunotherapy versus conventional high-dose therapy and autologous hematopoietic stem cell transplantation for relapsed follicular non-Hodgkin lymphoma: a multivariable cohort analysis. Blood 102 (7): 2351-7, 2003. [PUBMED Abstract]
van Besien K, Loberiza FR Jr, Bajorunaite R, et al.: Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 102 (10): 3521-9, 2003. [PUBMED Abstract]
Schouten HC, Qian W, Kvaloy S, et al.: High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial. J Clin Oncol 21 (21): 3918-27, 2003. [PUBMED Abstract]
Deconinck E, Foussard C, Milpied N, et al.: High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS. Blood 105 (10): 3817-23, 2005. [PUBMED Abstract]
Sebban C, Mounier N, Brousse N, et al.: Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 108 (8): 2540-4, 2006. [PUBMED Abstract]
Lenz G, Dreyling M, Schiegnitz E, et al.: Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 104 (9): 2667-74, 2004. [PUBMED Abstract]
Rohatiner AZ, Nadler L, Davies AJ, et al.: Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: long-term follow-up. J Clin Oncol 25 (18): 2554-9, 2007. [PUBMED Abstract]
Gopal AK, Rajendran JG, Gooley TA, et al.: High-dose [131I]tositumomab (anti-CD20) radioimmunotherapy and autologous hematopoietic stem-cell transplantation for adults > or = 60 years old with relapsed or refractory B-cell lymphoma. J Clin Oncol 25 (11): 1396-402, 2007. [PUBMED Abstract]
Bendandi M, Gocke CD, Kobrin CB, et al.: Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma. Nat Med 5 (10): 1171-7, 1999. [PUBMED Abstract]
Neelapu SS, Gause BL, Nikcevich DA, et al.: Phase III randomized trial of patient-specific vaccination for previously untreated patients with follicular lymphoma in first complete remission: protocol summary and interim report. Clin Lymphoma 6 (1): 61-4, 2005. [PUBMED Abstract]
Inogès S, Rodrìguez-Calvillo M, Zabalegui N, et al.: Clinical benefit associated with idiotypic vaccination in patients with follicular lymphoma. J Natl Cancer Inst 98 (18): 1292-301, 2006. [PUBMED Abstract]
Ha CS, Kong JS, Tucker SL, et al.: Central lymphatic irradiation for stage I-III follicular lymphoma: report from a single-institutional prospective study. Int J Radiat Oncol Biol Phys 57 (2): 316-20, 2003. [PUBMED Abstract]

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.[2-4] 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 (TTF) 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 years).[8][Level of evidence: 1iiA] At 5-years' median follow-up, the OS of patients who received R-CHOP compared with patients who received CHOP was 58% vs. 45%, P < .007.[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 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, randomized 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).[12][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.[13,14][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.[15,16][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.[17][Level of evidence: 1iiA] Clinical trials such as SWOG-9349 ⁴⁰, for example, 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.[12,18-20]

An International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS:[21]

Age (≤60 years vs. >60 years).
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).
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.[22] 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.[23,24]

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.[25-33][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 patients (more than three risk factors) as defined by IPI suggest improved survival with BMT in two of the trials.[26,32] 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.[34] 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 ⁴¹, for example, employing 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.[35] CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, and others do not.[4] 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.[36][Level of evidence: 3iiiDiii] 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.

Standard treatment options:

CHOP plus rituximab.[8]
Combination chemotherapy alone:
- CHOP.[4-6]
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 PDQ Cancer Clinical Trials Registry that are now accepting patients with aggressive, noncontiguous stage II adult non-Hodgkin lymphoma ⁴², aggressive, stage III adult non-Hodgkin lymphoma ⁴³ and aggressive, stage IV adult non-Hodgkin lymphoma ⁴⁴. 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 ²⁸.

References

Armitage JO: Treatment of non-Hodgkin's lymphoma. N Engl J Med 328 (14): 1023-30, 1993. [PUBMED Abstract]
Longo DL, DeVita VT Jr, Duffey PL, et al.: Superiority of ProMACE-CytaBOM over ProMACE-MOPP in the treatment of advanced diffuse aggressive lymphoma: results of a prospective randomized trial. J Clin Oncol 9 (1): 25-38, 1991. [PUBMED Abstract]
Shipp MA, Yeap BY, Harrington DP, et al.: The m-BACOD combination chemotherapy regimen in large-cell lymphoma: analysis of the completed trial and comparison with the M-BACOD regimen. J Clin Oncol 8 (1): 84-93, 1990. [PUBMED Abstract]
Fisher RI, Gaynor ER, Dahlberg S, et al.: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 328 (14): 1002-6, 1993. [PUBMED Abstract]
Gordon LI, Harrington D, Andersen J, et al.: Comparison of a second-generation combination chemotherapeutic regimen (m-BACOD) with a standard regimen (CHOP) for advanced diffuse non-Hodgkin's lymphoma. N Engl J Med 327 (19): 1342-9, 1992. [PUBMED Abstract]
Cooper IA, Wolf MM, Robertson TI, et al.: Randomized comparison of MACOP-B with CHOP in patients with intermediate-grade non-Hodgkin's lymphoma. The Australian and New Zealand Lymphoma Group. J Clin Oncol 12 (4): 769-78, 1994. [PUBMED Abstract]
O'Connell MJ, Harrington DP, Earle JD, et al.: Prospectively randomized clinical trial of three intensive chemotherapy regimens for the treatment of advanced unfavorable histology non-Hodgkin's lymphoma. J Clin Oncol 5 (9): 1329-39, 1987. [PUBMED Abstract]
Coiffier B, Lepage E, Briere J, et al.: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346 (4): 235-42, 2002. [PUBMED Abstract]
Feugier P, Van Hoof A, Sebban C, et al.: Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 23 (18): 4117-26, 2005. [PUBMED Abstract]
Pfreundschuh M, Trümper L, Osterborg A, et al.: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7 (5): 379-91, 2006. [PUBMED Abstract]
Coiffier B: State-of-the-art therapeutics: diffuse large B-cell lymphoma. J Clin Oncol 23 (26): 6387-93, 2005. [PUBMED Abstract]
Tilly H, Lepage E, Coiffier B, et al.: Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood 102 (13): 4284-9, 2003. [PUBMED Abstract]
Sonneveld P, de Ridder M, van der Lelie H, et al.: Comparison of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse non-Hodgkin's lymphoma using CHOP versus CNOP chemotherapy. J Clin Oncol 13 (10): 2530-9, 1995. [PUBMED Abstract]
Osby E, Hagberg H, Kvaløy S, et al.: CHOP is superior to CNOP in elderly patients with aggressive lymphoma while outcome is unaffected by filgrastim treatment: results of a Nordic Lymphoma Group randomized trial. Blood 101 (10): 3840-8, 2003. [PUBMED Abstract]
Bastion Y, Blay JY, Divine M, et al.: Elderly patients with aggressive non-Hodgkin's lymphoma: disease presentation, response to treatment, and survival--a Groupe d'Etude des Lymphomes de l'Adulte study on 453 patients older than 69 years. J Clin Oncol 15 (8): 2945-53, 1997. [PUBMED Abstract]
Tirelli U, Errante D, Van Glabbeke M, et al.: CHOP is the standard regimen in patients > or = 70 years of age with intermediate-grade and high-grade non-Hodgkin's lymphoma: results of a randomized study of the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Study Group. J Clin Oncol 16 (1): 27-34, 1998. [PUBMED Abstract]
Gaynor ER, Unger JM, Miller TP, et al.: Infusional CHOP chemotherapy (CVAD) with or without chemosensitizers offers no advantage over standard CHOP therapy in the treatment of lymphoma: a Southwest Oncology Group Study. J Clin Oncol 19 (3): 750-5, 2001. [PUBMED Abstract]
Blayney DW, LeBlanc ML, Grogan T, et al.: Dose-intense chemotherapy every 2 weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and prednisone may improve survival in intermediate- and high-grade lymphoma: a phase II study of the Southwest Oncology Group (SWOG 9349). J Clin Oncol 21 (13): 2466-73, 2003. [PUBMED Abstract]
Coiffier B: Increasing chemotherapy intensity in aggressive lymphomas: a renewal? J Clin Oncol 21 (13): 2457-9, 2003. [PUBMED Abstract]
Pfreundschuh M, Trümper L, Kloess M, et al.: Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood 104 (3): 626-33, 2004. [PUBMED Abstract]
A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329 (14): 987-94, 1993. [PUBMED Abstract]
Canellos GP: CHOP may have been part of the beginning but certainly not the end: issues in risk-related therapy of large-cell lymphoma. J Clin Oncol 15 (5): 1713-6, 1997. [PUBMED Abstract]
Rosenwald A, Wright G, Chan WC, et al.: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346 (25): 1937-47, 2002. [PUBMED Abstract]
Lossos IS, Czerwinski DK, Alizadeh AA, et al.: Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 350 (18): 1828-37, 2004. [PUBMED Abstract]
Haioun C, Lepage E, Gisselbrecht C, et al.: Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol--a groupe d'Etude des lymphomes de l'Adulte study. J Clin Oncol 18 (16): 3025-30, 2000. [PUBMED Abstract]
Haioun C, Lepage E, Gisselbrecht C, et al.: Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87-2. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 15 (3): 1131-7, 1997. [PUBMED Abstract]
Santini G, Salvagno L, Leoni P, et al.: VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 16 (8): 2796-802, 1998. [PUBMED Abstract]
Gianni AM, Bregni M, Siena S, et al.: High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 336 (18): 1290-7, 1997. [PUBMED Abstract]
Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al.: Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study. J Natl Cancer Inst 93 (1): 22-30, 2001. [PUBMED Abstract]
Gisselbrecht C, Lepage E, Molina T, et al.: Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 20 (10): 2472-9, 2002. [PUBMED Abstract]
Martelli M, Gherlinzoni F, De Renzo A, et al.: Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin's lymphoma: an Italian multicenter randomized trial. J Clin Oncol 21 (7): 1255-62, 2003. [PUBMED Abstract]
Milpied N, Deconinck E, Gaillard F, et al.: Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 350 (13): 1287-95, 2004. [PUBMED Abstract]
Betticher DC, Martinelli G, Radford JA, et al.: Sequential high dose chemotherapy as initial treatment for aggressive sub-types of non-Hodgkin lymphoma: results of the international randomized phase III trial (MISTRAL). Ann Oncol 17 (10): 1546-52, 2006. [PUBMED Abstract]
Shipp MA, Abeloff MD, Antman KH, et al.: International Consensus Conference on high-dose therapy with hematopoietic stem-cell transplantation in aggressive non-Hodgkin's lymphomas: report of the jury. Ann Oncol 10 (1): 13-9, 1999. [PUBMED Abstract]
Glantz MJ, Cole BF, Recht L, et al.: High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol 16 (4): 1561-7, 1998. [PUBMED Abstract]
van Besien K, Ha CS, Murphy S, et al.: Risk factors, treatment, and outcome of central nervous system recurrence in adults with intermediate-grade and immunoblastic lymphoma. Blood 91 (4): 1178-84, 1998. [PUBMED Abstract]

Adult Lymphoblastic Lymphoma

Lymphoblastic lymphoma is a very aggressive form of non-Hodgkin lymphoma (NHL), which often occurs in young patients, but not exclusively. Lymphoblastic lymphoma is commonly associated with large mediastinal masses and has a high predilection for disseminating to bone marrow and the central nervous system (CNS), 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 ¹⁰ for more information.)

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with adult lymphoblastic lymphoma ⁴⁵. 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 ²⁸.

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).[1-3] An intensive clinical trial, namely CALGB-9251 ²³, using aggressive combination chemotherapy patterned after that used in childhood Burkitt lymphoma has been described and has been very successful for adult patients.[4-8] 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 central nervous system (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 PDQ Cancer Clinical Trials Registry that are now accepting patients with adult Burkitt lymphoma ⁴⁶. 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 ²⁸.

References

Longo DL, Duffey PL, Jaffe ES, et al.: Diffuse small noncleaved-cell, non-Burkitt's lymphoma in adults: a high-grade lymphoma responsive to ProMACE-based combination chemotherapy. J Clin Oncol 12 (10): 2153-9, 1994. [PUBMED Abstract]
McMaster ML, Greer JP, Greco FA, et al.: Effective treatment of small-noncleaved-cell lymphoma with high-intensity, brief-duration chemotherapy. J Clin Oncol 9 (6): 941-6, 1991. [PUBMED Abstract]
Thomas DA, Faderl S, O'Brien S, et al.: Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 106 (7): 1569-80, 2006. [PUBMED Abstract]
Soussain C, Patte C, Ostronoff M, et al.: Small noncleaved cell lymphoma and leukemia in adults. A retrospective study of 65 adults treated with the LMB pediatric protocols. Blood 85 (3): 664-74, 1995. [PUBMED Abstract]
Magrath I, Adde M, Shad A, et al.: Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 14 (3): 925-34, 1996. [PUBMED Abstract]
Adde M, Shad A, Venzon D, et al.: Additional chemotherapy agents improve treatment outcome for children and adults with advanced B-cell lymphomas. Semin Oncol 25 (2 Suppl 4): 33-9; discussion 45-8, 1998. [PUBMED Abstract]
Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996. [PUBMED Abstract]
Lee EJ, Petroni GR, Schiffer CA, et al.: Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251. J Clin Oncol 19 (20): 4014-22, 2001. [PUBMED Abstract]
Freedman AS, Takvorian T, Anderson KC, et al.: Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: very low treatment-related mortality in 100 patients in sensitive relapse. J Clin Oncol 8 (5): 784-91, 1990. [PUBMED Abstract]
Sweetenham JW, Pearce R, Philip T, et al.: High-dose therapy and autologous bone marrow transplantation for intermediate and high grade non-Hodgkin's lymphoma in patients aged 55 years and over: results from the European Group for Bone Marrow Transplantation. The EBMT Lymphoma Working Party. Bone Marrow Transplant 14 (6): 981-7, 1994. [PUBMED Abstract]
Rizzieri DA, Johnson JL, Niedzwiecki D, et al.: Intensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: final results of Cancer and Leukemia Group B Study 9251. Cancer 100 (7): 1438-48, 2004. [PUBMED Abstract]
Magrath IT, Haddy TB, Adde MA: Treatment of patients with high grade non-Hodgkin's lymphomas and central nervous system involvement: is radiation an essential component of therapy? Leuk Lymphoma 21 (1-2): 99-105, 1996. [PUBMED Abstract]

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 10-fold 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.[4-9] Rituximab results in a 40% to 50% response rate in patients who relapse with indolent B-cell lymphomas.[10-13] Rituximab can also be combined with combination chemotherapy.[14] Durable responses to radiolabeled monoclonal antibodies, such as yttrium-90 ibritumomab (commercially available) and iodine-131 tositumomab, have also been reported; subsequent chemotherapy regimens can be delivered at the time of relapse following radioimmunotherapy.[15-20] In two 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); both trials showed prolongation of response duration,[21,22] and one trial demonstrated improvement in median progression-free survival (52 vs. 15 months, P < .001) and overall survival (OS) (85% vs. 77%, P = .01) at 3 years with a median folllow-up of 39 months favoring maintenance rituximab.[22][Level of evidence: 1iiA]

In many institutions, bone marrow transplantation (BMT) is 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.[23-28] The German Low-Grade Lymphoma Study Group treated 307 patients with follicular lymphoma with two cycles of CHOP-like induction chemotherapy and then randomized to autologous stem cell transplantation versus interferon maintenance.[29] 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.[29][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.[30] 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.[31] In this series, high risk factors for subsequent histologic transformation were advanced stage, high-risk Follicular Lymphoma International Prognostic Index (FLIPI), and expectant management. The median survival after transformation was one to two years, with 25% of patients alive at 5 years and with approximately 10% to 20% of patients alive 10 years after retreatment.[32] Histologic conversions should be treated with the regimens described in the Aggressive, Recurrent Adult Non-Hodgkin's Lymphoma ¹⁶ section of this summary. The durability of the second remission may be short, and clinical trials, should be considered.[32-34]

Palliation may be achieved with very low-dose (4 Gy) involved-field radiation therapy for patients with indolent and aggressive relapsed disease.[35]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with indolent, recurrent adult non-Hodgkin lymphoma ⁴⁷. 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 ²⁸.

References

Weisdorf DJ, Andersen JW, Glick JH, et al.: Survival after relapse of low-grade non-Hodgkin's lymphoma: implications for marrow transplantation. J Clin Oncol 10 (6): 942-7, 1992. [PUBMED Abstract]
Peterson BA: Current treatment of follicular low-grade lymphomas. Semin Oncol 26 (5 Suppl 14): 2-11, 1999. [PUBMED Abstract]
Haas RL, Poortmans P, de Jong D, et al.: High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas. J Clin Oncol 21 (13): 2474-80, 2003. [PUBMED Abstract]
Hochster HS, Kim KM, Green MD, et al.: Activity of fludarabine in previously treated non-Hodgkin's low-grade lymphoma: results of an Eastern Cooperative Oncology Group study. J Clin Oncol 10 (1): 28-32, 1992. [PUBMED Abstract]
Kay AC, Saven A, Carrera CJ, et al.: 2-Chlorodeoxyadenosine treatment of low-grade lymphomas. J Clin Oncol 10 (3): 371-7, 1992. [PUBMED Abstract]
Redman JR, Cabanillas F, Velasquez WS, et al.: Phase II trial of fludarabine phosphate in lymphoma: an effective new agent in low-grade lymphoma. J Clin Oncol 10 (5): 790-4, 1992. [PUBMED Abstract]
Tsimberidou AM, McLaughlin P, Younes A, et al.: Fludarabine, mitoxantrone, dexamethasone (FND) compared with an alternating triple therapy (ATT) regimen in patients with stage IV indolent lymphoma. Blood 100 (13): 4351-7, 2002. [PUBMED Abstract]
Tulpule A, Schiller G, Harvey-Buchanan LA, et al.: Cladribine in the treatment of advanced relapsed or refractory low and intermediate grade non-Hodgkin's lymphoma. Cancer 83 (11): 2370-6, 1998. [PUBMED Abstract]
Klasa RJ, Meyer RM, Shustik C, et al.: Randomized phase III study of fludarabine phosphate versus cyclophosphamide, vincristine, and prednisone in patients with recurrent low-grade non-Hodgkin's lymphoma previously treated with an alkylating agent or alkylator-containing regimen. J Clin Oncol 20 (24): 4649-54, 2002. [PUBMED Abstract]
Davis TA, White CA, Grillo-López AJ, et al.: Single-agent monoclonal antibody efficacy in bulky non-Hodgkin's lymphoma: results of a phase II trial of rituximab. J Clin Oncol 17 (6): 1851-7, 1999. [PUBMED Abstract]
Piro LD, White CA, Grillo-López AJ, et al.: Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol 10 (6): 655-61, 1999. [PUBMED Abstract]
Davis TA, Grillo-López AJ, White CA, et al.: Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment. J Clin Oncol 18 (17): 3135-43, 2000. [PUBMED Abstract]
Hainsworth JD, Litchy S, Shaffer DW, et al.: Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma--a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23 (6): 1088-95, 2005. [PUBMED Abstract]
Forstpointner R, Dreyling M, Repp R, et al.: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104 (10): 3064-71, 2004. [PUBMED Abstract]
Witzig TE, Gordon LI, Cabanillas F, et al.: Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 20 (10): 2453-63, 2002. [PUBMED Abstract]
Witzig TE, Flinn IW, Gordon LI, et al.: Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. J Clin Oncol 20 (15): 3262-9, 2002. [PUBMED Abstract]
Ansell SM, Ristow KM, Habermann TM, et al.: Subsequent chemotherapy regimens are well tolerated after radioimmunotherapy with yttrium-90 ibritumomab tiuxetan for non-Hodgkin's lymphoma. J Clin Oncol 20 (18): 3885-90, 2002. [PUBMED Abstract]
Davies AJ, Rohatiner AZ, Howell S, et al.: Tositumomab and iodine I 131 tositumomab for recurrent indolent and transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 22 (8): 1469-79, 2004. [PUBMED Abstract]
Fisher RI, Kaminski MS, Wahl RL, et al.: Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas. J Clin Oncol 23 (30): 7565-73, 2005. [PUBMED Abstract]
Leahy MF, Seymour JF, Hicks RJ, et al.: Multicenter phase II clinical study of iodine-131-rituximab radioimmunotherapy in relapsed or refractory indolent non-Hodgkin's lymphoma. J Clin Oncol 24 (27): 4418-25, 2006. [PUBMED Abstract]
Forstpointner R, Unterhalt M, Dreyling M, et al.: Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 108 (13): 4003-8, 2006. [PUBMED Abstract]
van Oers MH, Klasa R, Marcus RE, et al.: Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 108 (10): 3295-301, 2006. [PUBMED Abstract]
Freedman A, Friedberg JW, Gribben J: High-dose therapy for follicular lymphoma. Oncology (Huntingt) 14 (3): 321-6, 329; discussion 330-2, 338, 2000. [PUBMED Abstract]
van Besien KW, Khouri IF, Giralt SA, et al.: Allogeneic bone marrow transplantation for refractory and recurrent low-grade lymphoma: the case for aggressive management. J Clin Oncol 13 (5): 1096-102, 1995. [PUBMED Abstract]
Bierman PJ, Vose JM, Anderson JR, et al.: High-dose therapy with autologous hematopoietic rescue for follicular low-grade non-Hodgkin's lymphoma. J Clin Oncol 15 (2): 445-50, 1997. [PUBMED Abstract]
Apostolidis J, Foran JM, Johnson PW, et al.: Patterns of outcome following recurrence after myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma. J Clin Oncol 17 (1): 216-21, 1999. [PUBMED Abstract]
Boussiotis VA, Freedman AS, Nadler LM: Bone marrow transplantation for low-grade lymphoma and chronic lymphocytic leukemia. Semin Hematol 36 (2): 209-16, 1999. [PUBMED Abstract]
Brice P, Simon D, Bouabdallah R, et al.: High-dose therapy with autologous stem-cell transplantation (ASCT) after first progression prolonged survival of follicular lymphoma patients included in the prospective GELF 86 protocol. Ann Oncol 11 (12): 1585-90, 2000. [PUBMED Abstract]
Lenz G, Dreyling M, Schiegnitz E, et al.: Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 104 (9): 2667-74, 2004. [PUBMED Abstract]
Tsimberidou AM, O'Brien S, Khouri I, et al.: Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol 24 (15): 2343-51, 2006. [PUBMED Abstract]
Montoto S, Davies AJ, Matthews J, et al.: Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 25 (17): 2426-33, 2007. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
Williams CD, Harrison CN, Lister TA, et al.: High-dose therapy and autologous stem-cell support for chemosensitive transformed low-grade follicular non-Hodgkin's lymphoma: a case-matched study from the European Bone Marrow Transplant Registry. J Clin Oncol 19 (3): 727-35, 2001. [PUBMED Abstract]
Haas RL, Poortmans P, de Jong D, et al.: Effective palliation by low dose local radiotherapy for recurrent and/or chemotherapy refractory non-follicular lymphoma patients. Eur J Cancer 41 (12): 1724-30, 2005. [PUBMED Abstract]

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.[2-6]

In a prospective randomized study known as the 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 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. In a prospective trial, patients who relapsed late (more than 12 months after diagnosis) had better OS than patients who relapsed earlier (8-year survival was 29% vs. 13%, P = .001).[8][Level of evidence: 3iiiA] Peripheral stem cell transplantation has yielded results equivalent to standard autologous transplantation.[9,10] 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.[11][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.[12,13][Level of evidence: 3iiiDiv] Since toxic effects can be severe, and patients require specialized team management, BMT should be done at institutions that have the appropriate expertise and resources available.

In general, retreatment with standard agents rarely produces a cure in patients whose lymphomas relapse. Patients who relapse with aggressive lymphoma after 3 years in remission have similar prognoses to de novo lymphoma using curative therapy.[14] Several salvage chemotherapy regimens are available.[15-17] Rituximab, an anti-CD20 monoclonal antibody, can induce responses in 33% of patients with relapsing aggressive lymphoma of appropriate phenotype (CD20-positive).[18,19][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.[20-22][Level of evidence: 3iiiDiv] Denileukin difitox, a fusion protein combining diptheria toxin and interleukin-2, resulted in a 25% objective response rate in 45 heavily pretreated patients as evidenced in E-1497 ⁴⁸, for example, with aggressive B-cell non-Hodgkin lymphoma (CD25, i.e., interleukin-2 receptor, expression was not correlated with response).[23][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.[24-27] Durable responses to radiolabeled monoclonal antibodies have been reported for transformed low-grade B-cell lymphoma.[20,21] 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.[14]

Palliation may be achieved with very low-dose (4 Gy) IF-XRT for patients with indolent and aggressive relapsed disease.[28]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with aggressive, recurrent adult non-Hodgkin lymphoma ⁴⁹. 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 ²⁸.

References

Shipp MA, Abeloff MD, Antman KH, et al.: International Consensus Conference on high-dose therapy with hematopoietic stem-cell transplantation in aggressive non-Hodgkin's lymphomas: report of the jury. Ann Oncol 10 (1): 13-9, 1999. [PUBMED Abstract]
Freedman AS, Takvorian T, Anderson KC, et al.: Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: very low treatment-related mortality in 100 patients in sensitive relapse. J Clin Oncol 8 (5): 784-91, 1990. [PUBMED Abstract]
Phillips GL, Fay JW, Herzig RH, et al.: The treatment of progressive non-Hodgkin's lymphoma with intensive chemoradiotherapy and autologous marrow transplantation. Blood 75 (4): 831-8, 1990. [PUBMED Abstract]
Chopra R, Goldstone AH, Pearce R, et al.: Autologous versus allogeneic bone marrow transplantation for non-Hodgkin's lymphoma: a case-controlled analysis of the European Bone Marrow Transplant Group Registry data. J Clin Oncol 10 (11): 1690-5, 1992. [PUBMED Abstract]
Ratanatharathorn V, Uberti J, Karanes C, et al.: Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma. Blood 84 (4): 1050-5, 1994. [PUBMED Abstract]
Mills W, Chopra R, McMillan A, et al.: BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma. J Clin Oncol 13 (3): 588-95, 1995. [PUBMED Abstract]
Philip T, Guglielmi C, Hagenbeek A, et al.: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 333 (23): 1540-5, 1995. [PUBMED Abstract]
Guglielmi C, Gomez F, Philip T, et al.: Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial. J Clin Oncol 16 (10): 3264-9, 1998. [PUBMED Abstract]
Vose JM, Anderson JR, Kessinger A, et al.: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma. J Clin Oncol 11 (10): 1846-51, 1993. [PUBMED Abstract]
Liberti G, Pearce R, Taghipour G, et al.: Comparison of peripheral blood stem-cell and autologous bone marrow transplantation for lymphoma patients: a case-controlled analysis of the EBMT Registry data. Lymphoma Working Party of the EBMT. Ann Oncol 5 (Suppl 2): 151-3, 1994. [PUBMED Abstract]
Vose JM, Zhang MJ, Rowlings PA, et al.: Autologous transplantation for diffuse aggressive non-Hodgkin's lymphoma in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 19 (2): 406-13, 2001. [PUBMED Abstract]
Escalón MP, Champlin RE, Saliba RM, et al.: Nonmyeloablative allogeneic hematopoietic transplantation: a promising salvage therapy for patients with non-Hodgkin's lymphoma whose disease has failed a prior autologous transplantation. J Clin Oncol 22 (12): 2419-23, 2004. [PUBMED Abstract]
Freytes CO, Loberiza FR, Rizzo JD, et al.: Myeloablative allogeneic hematopoietic stem cell transplantation in patients who experience relapse after autologous stem cell transplantation for lymphoma: a report of the International Bone Marrow Transplant Registry. Blood 104 (12): 3797-803, 2004. [PUBMED Abstract]
Lee AY, Connors JM, Klimo P, et al.: Late relapse in patients with diffuse large-cell lymphoma treated with MACOP-B. J Clin Oncol 15 (5): 1745-53, 1997. [PUBMED Abstract]
Rodriguez MA, Cabanillas FC, Velasquez W, et al.: Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP. J Clin Oncol 13 (7): 1734-41, 1995. [PUBMED Abstract]
Rizzieri DA, Sand GJ, McGaughey D, et al.: Low-dose weekly paclitaxel for recurrent or refractory aggressive non-Hodgkin lymphoma. Cancer 100 (11): 2408-14, 2004. [PUBMED Abstract]
Kewalramani T, Zelenetz AD, Nimer SD, et al.: Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood 103 (10): 3684-8, 2004. [PUBMED Abstract]
Coiffier B, Haioun C, Ketterer N, et al.: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 92 (6): 1927-32, 1998. [PUBMED Abstract]
Tobinai K, Igarashi T, Itoh K, et al.: Japanese multicenter phase II and pharmacokinetic study of rituximab in relapsed or refractory patients with aggressive B-cell lymphoma. Ann Oncol 15 (5): 821-30, 2004. [PUBMED Abstract]
Fisher RI, Kaminski MS, Wahl RL, et al.: Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas. J Clin Oncol 23 (30): 7565-73, 2005. [PUBMED Abstract]
Witzig TE, Gordon LI, Cabanillas F, et al.: Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 20 (10): 2453-63, 2002. [PUBMED Abstract]
Wiseman GA, Gordon LI, Multani PS, et al.: Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: a phase II multicenter trial. Blood 99 (12): 4336-42, 2002. [PUBMED Abstract]
Dang NH, Hagemeister FB, Pro B, et al.: Phase II study of denileukin diftitox for relapsed/refractory B-Cell non-Hodgkin's lymphoma. J Clin Oncol 22 (20): 4095-102, 2004. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
Williams CD, Harrison CN, Lister TA, et al.: High-dose therapy and autologous stem-cell support for chemosensitive transformed low-grade follicular non-Hodgkin's lymphoma: a case-matched study from the European Bone Marrow Transplant Registry. J Clin Oncol 19 (3): 727-35, 2001. [PUBMED Abstract]
Tsimberidou AM, O'Brien S, Khouri I, et al.: Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol 24 (15): 2343-51, 2006. [PUBMED Abstract]
Haas RL, Poortmans P, de Jong D, et al.: Effective palliation by low dose local radiotherapy for recurrent and/or chemotherapy refractory non-follicular lymphoma patients. Eur J Cancer 41 (12): 1724-30, 2005. [PUBMED Abstract]

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

To avoid exposure to ionizing radiation, magnetic resonance imaging is the preferred tool for staging evaluation.[2] (Refer to the Stage Information section for more information.)

Treatment Option Overview

According to anecdotal case series, most NHL are aggressive, and delay of therapy until after delivery appears to have poor outcomes.[1,3-5] 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.[5-8] 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

Ward FT, Weiss RB: Lymphoma and pregnancy. Semin Oncol 16 (5): 397-409, 1989. [PUBMED Abstract]
Nicklas AH, Baker ME: Imaging strategies in the pregnant cancer patient. Semin Oncol 27 (6): 623-32, 2000. [PUBMED Abstract]
Steiner-Salz D, Yahalom J, Samuelov A, et al.: Non-Hodgkin's lymphoma associated with pregnancy. A report of six cases, with a review of the literature. Cancer 56 (8): 2087-91, 1985. [PUBMED Abstract]
Spitzer M, Citron M, Ilardi CF, et al.: Non-Hodgkin's lymphoma during pregnancy. Gynecol Oncol 43 (3): 309-12, 1991. [PUBMED Abstract]
Gelb AB, van de Rijn M, Warnke RA, et al.: Pregnancy-associated lymphomas. A clinicopathologic study. Cancer 78 (2): 304-10, 1996. [PUBMED Abstract]
Avilés A, Díaz-Maqueo JC, Torras V, et al.: Non-Hodgkin's lymphomas and pregnancy: presentation of 16 cases. Gynecol Oncol 37 (3): 335-7, 1990. [PUBMED Abstract]
Moore DT, Taslimi MM: Multi-agent chemotherapy in a case of non-Hodgkin's lymphoma in second trimester of pregnancy. J Tenn Med Assoc 84 (9): 435-6, 1991. [PUBMED Abstract]
Nantel S, Parboosingh J, Poon MC: Treatment of an aggressive non-Hodgkin's lymphoma during pregnancy with MACOP-B chemotherapy. Med Pediatr Oncol 18 (2): 143-5, 1990. [PUBMED Abstract]

Get More Information From NCI

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Changes to This Summary (01/09/2009)

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.

Editorial changes were made to this summary.

More Information

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PDQ® - NCI's Comprehensive Cancer Database ⁵³.
Full description of the NCI PDQ database.

Additional PDQ Summaries

PDQ® Cancer Information Summaries: Adult Treatment ⁵⁴

Treatment options for adult cancers.
PDQ® Cancer Information Summaries: Pediatric Treatment ⁵⁵

Treatment options for childhood cancers.
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Glossary Terms

Level of evidence 1iiA

Randomized, controlled, nonblinded clinical trial with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Level of evidence 1iiDii

Randomized, controlled, nonblinded clinical trial with disease-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Level of evidence 1iiDiii

Randomized, controlled, nonblinded clinical trial with progression-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Level of evidence 3iiiA

Nonconsecutive case series with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Level of evidence 3iiiDiii

Nonconsecutive case series with progression-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Level of evidence 3iiiDiv

Nonconsecutive case series with tumor response rate as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Table of Links

¹ http://www.cancer.gov/cancerinfo/pdq/adult-treatment-board

² http://www.cancer.gov/cancertopics/pdq/levels-evidence-adult-treatment/HealthPr
ofessional

³ http://www.cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/Patient

⁴ http://www.cancer.gov/espanol/pdq/tratamiento/no-hodgkin-adultos/HealthProfessi
onal

⁵ http://www.cancer.gov/cancertopics/pdq/treatment/AIDS-related-lymphoma/HealthPr
ofessional

⁶ http://www.cancer.gov/cancertopics/pdq/treatment/primary-CNS-lymphoma/HealthPro
fessional

⁷ http://www.cancer.gov/cancertopics/pdq/treatment/child-non-hodgkins/HealthProfe
ssional

⁸ http://www.cancer.org/downloads/STT/2008CAFFfinalsecured.pdf

⁹ http://www.cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/HealthProfe
ssional/Table1

¹⁰ http://www.cancer.gov/cancertopics/pdq/treatment/adultALL/HealthProfessional

¹¹ http://www.cancer.gov/cancertopics/pdq/treatment/adulthodgkins/HealthProfession
al

¹² http://www.cancer.gov/cancertopics/pdq/treatment/CLL/healthprofessional

¹³ http://www.cancer.gov/cancertopics/pdq/treatment/hairy-cell-leukemia/HealthProf
essional

¹⁴ http://www.cancer.gov/cancertopics/pdq/treatment/myeloma/HealthProfessional

¹⁵ http://www.cancer.gov/cancertopics/pdq/treatment/mycosisfungoides/HealthProfess
ional

¹⁶ http://www.cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/HealthProfe
ssional/174.cdr#Section_174

¹⁷ http://www.cancer.gov/cancertopics/pdq/supportivecare/fever/healthprofessional/
allpages

¹⁸ http://www.cancer.gov/cancertopics/pdq/supportivecare/nutrition/healthprofessio
nal/allpages

¹⁹ http://www.cancer.gov/cancertopics/pdq/supportivecare/cardiopulmonary/HealthPro
fessional

²⁰ http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=77645

²¹ http://www.cancer.gov/cancertopics/pdq/supportivecare/pruritus/healthprofession
al/allpages

²² http://www.cancer.gov/cancertopics/pdq/supportivecare/gastrointestinalcomplicat
ions/HealthProfessional/183.cdr#Section_183

²³ http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=77643

²⁴ http://www.cancer.gov/cancertopics/pdq/supportivecare/hypercalcemia/healthprofe
ssional/allpages

²⁵ http://www.cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/HealthProfe
ssional/Table2

²⁶ http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=42712&tt=1&a
mp;format=2&cn=1

²⁷ http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=42716&tt=1&a
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²⁸ http://www.cancer.gov/clinicaltrials

²⁹ http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=71510

³⁰ http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
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³¹ http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=42714&tt=1&a
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³² http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=42721&tt=1&a
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³³ http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=446847

³⁴ http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=75288

³⁵ http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=64195

³⁶ http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=66917

³⁷ http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=42730&tt=1&a
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³⁸ http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=42742&tt=1&a
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³⁹ http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=42749&tt=1&a
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⁴⁰ http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
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⁴¹ http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=68321

⁴² http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=42736&tt=1&a
mp;format=2&cn=1

⁴³ http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=42748&tt=1&a
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⁴⁴ http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=42752&tt=1&a
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⁴⁵ http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=37769&tt=1&a
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⁴⁶ http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=38422&tt=1&a
mp;format=2&cn=1

⁴⁷ http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=42753&tt=1&a
mp;format=2&cn=1

⁴⁸ http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=66692

⁴⁹ http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=42756&tt=1&a
mp;format=2&cn=1

⁵⁰ https://cissecure.nci.nih.gov/livehelp/welcome.asp

⁵¹ http://cancer.gov

⁵² https://cissecure.nci.nih.gov/ncipubs

⁵³ http://cancer.gov/cancerinfo/pdq/cancerdatabase

⁵⁴ http://cancer.gov/cancerinfo/pdq/adulttreatment

⁵⁵ http://cancer.gov/cancerinfo/pdq/pediatrictreatment

⁵⁶ http://cancer.gov/cancerinfo/pdq/supportivecare

⁵⁷ http://cancer.gov/cancerinfo/pdq/screening

⁵⁸ http://cancer.gov/cancerinfo/pdq/prevention

⁵⁹ http://cancer.gov/cancerinfo/pdq/genetics

⁶⁰ http://cancer.gov/cancerinfo/pdq/cam