Adult Non-Hodgkin Lymphoma Treatment (PDQ®)

General Information About Adult Non-Hodgkin Lymphoma (NHL)
The NHLs are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment.
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.
Incidence and Mortality
Estimated new cases and deaths from NHL in the United States in 2015:
  • New cases: 71,850.
  • Deaths: 19,790.

Anatomy
NHL usually originates in lymphoid tissues.
The aggressive type of NHL has a shorter natural history, but a significant number of these patients can be cured with intensive combination chemotherapy regimens.
In general, with modern treatment of patients with NHL, overall survival at 5 years is over 60%. Of patients with aggressive NHL, more than 50% can be cured. The vast majority of relapses occur in the first 2 years after therapy. The risk of late relapse is higher in patients who manifest both indolent and aggressive histologies.
While indolent NHL is responsive to immunotherapy, radiation therapy, and chemotherapy, a continuous rate of relapse is usually seen in advanced stages. Patients, however, can often be re-treated with considerable success as long as the disease histology remains low grade. Patients who present with or convert to aggressive forms of NHL may have sustained complete remissions with combination chemotherapy regimens or aggressive consolidation with marrow or stem cell support.

Late Effects of Treatment for Adult NHL
Late effects of treatment for non-Hodgkin lymphoma (NHL) have been observed. Pelvic radiation therapy and large cumulative doses of cyclophosphamide have been associated with a high risk of permanent sterility. For as many as three decades after diagnosis, patients are at a significantly elevated risk for second primary cancers, especially the following:
  • Lung cancer.
  • Brain cancer.
  • Kidney cancer.
  • Bladder cancer.
  • Melanoma.
  • Hodgkin lymphoma.
  • Acute nonlymphocytic leukemia.
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.
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. Most of these patients show clonal hematopoiesis even before the transplantation, suggesting that the hematologic injury usually occurs during induction or reinduction chemotherapy. 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.
Successful pregnancies with children born free of congenital abnormalities have been reported in young women after autologous BMT.
Some patients have osteopenia or osteoporosis at the start of therapy; bone density may worsen after therapy for lymphoma.
Mudie NY, Swerdlow AJ, Higgins CD, et al.: Risk of second malignancy after non-Hodgkin's lymphoma: a British Cohort Study. J Clin Oncol 24 (10): 1568-74, 2006.Travis LB, Curtis RE, Glimelius B, et al.: Second cancers among long-term survivors of non-Hodgkin's lymphoma. J Natl Cancer Inst 85 (23): 1932-7, 1993.Hemminki K, Lenner P, Sundquist J, et al.: Risk of subsequent solid tumors after non-Hodgkin's lymphoma: effect of diagnostic age and time since diagnosis. J Clin Oncol 26 (11): 1850-7, 2008.Haddy TB, Adde MA, McCalla J, et al.: Late effects in long-term survivors of high-grade non-Hodgkin's lymphomas. J Clin Oncol 16 (6): 2070-9, 1998.Moser EC, Noordijk EM, van Leeuwen FE, et al.: Long-term risk of cardiovascular disease after treatment for aggressive non-Hodgkin lymphoma. Blood 107 (7): 2912-9, 2006.Darrington DL, Vose JM, Anderson JR, et al.: Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 12 (12): 2527-34, 1994.Stone RM, Neuberg D, Soiffer R, et al.: Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 12 (12): 2535-42, 1994.Armitage JO, Carbone PP, Connors JM, et al.: Treatment-related myelodysplasia and acute leukemia in non-Hodgkin's lymphoma patients. J Clin Oncol 21 (5): 897-906, 2003.André M, Mounier N, Leleu X, et al.: Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients. Blood 103 (4): 1222-8, 2004.Oddou S, Vey N, Viens P, et al.: Second neoplasms following high-dose chemotherapy and autologous stem cell transplantation for malignant lymphomas: a report of six cases in a cohort of 171 patients from a single institution. Leuk Lymphoma 31 (1-2): 187-94, 1998.Lenz G, Dreyling M, Schiegnitz E, et al.: Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 22 (24): 4926-33, 2004.McLaughlin P, Estey E, Glassman A, et al.: Myelodysplasia and acute myeloid leukemia following therapy for indolent lymphoma with fludarabine, mitoxantrone, and dexamethasone (FND) plus rituximab and interferon alpha. Blood 105 (12): 4573-5, 2005.Morton LM, Curtis RE, Linet MS, et al.: Second malignancy risks after non-Hodgkin's lymphoma and chronic lymphocytic leukemia: differences by lymphoma subtype. J Clin Oncol 28 (33): 4935-44, 2010.Mach-Pascual S, Legare RD, Lu D, et al.: Predictive value of clonality assays in patients with non-Hodgkin's lymphoma undergoing autologous bone marrow transplant: a single institution study. Blood 91 (12): 4496-503, 1998.Lillington DM, Micallef IN, Carpenter E, et al.: Detection of chromosome abnormalities pre-high-dose treatment in patients developing therapy-related myelodysplasia and secondary acute myelogenous leukemia after treatment for non-Hodgkin's lymphoma. J Clin Oncol 19 (9): 2472-81, 2001.Brown JR, Yeckes H, Friedberg JW, et al.: Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total-body irradiation and autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 23 (10): 2208-14, 2005.Jackson GH, Wood A, Taylor PR, et al.: Early high dose chemotherapy intensification with autologous bone marrow transplantation in lymphoma associated with retention of fertility and normal pregnancies in females. Scotland and Newcastle Lymphoma Group, UK. Leuk Lymphoma 28 (1-2): 127-32, 1997.Westin JR, Thompson MA, Cataldo VD, et al.: Zoledronic acid for prevention of bone loss in patients receiving primary therapy for lymphomas: a prospective, randomized controlled phase III trial. Clin Lymphoma Myeloma Leuk 13 (2): 99-105, 2013.

Cellular Classification of Adult NHL
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.
Historical Classification Systems
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. The Working Formulation combined results from six major classification systems into one classification. This allowed comparison of studies from different institutions and countries. The Rappaport classification, which also follows, is no longer in common use.
Table 1. Historical Classification Systems for NHL
Working Formulation Rappaport Classification Low gradeA. Small lymphocytic, consistent with chronic lymphocytic leukemiaDiffuse lymphocytic, well-differentiatedB. Follicular, predominantly small-cleaved cellNodular lymphocytic, poorly differentiatedC. Follicular, mixed small-cleaved, and large cellNodular mixed, lymphocytic, and histiocyticIntermediate gradeD. Follicular, predominantly large cellNodular histiocyticE. Diffuse, small-cleaved cellDiffuse lymphocytic, poorly differentiatedF. Diffuse mixed, small and large cellDiffuse mixed, lymphocytic, and histiocyticG. Diffuse, large cell, cleaved, or noncleaved cellDiffuse histiocyticHigh gradeH. Immunoblastic, large cellDiffuse histiocyticI. Lymphoblastic, convoluted, or nonconvoluted cellDiffuse lymphoblasticJ. Small noncleaved-cell, Burkitt, or non-BurkittDiffuse undifferentiated Burkitt or non-Burkitt

Current Classification Systems
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. 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. 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.
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 (HL). 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 (CLL) 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.
Updated REAL/WHO classification
B-cell neoplasms
  • Precursor B-cell neoplasm: precursor B-acute lymphoblastic leukemia/lymphoblastic lymphoma (LBL).
  • Peripheral B-cell neoplasms. B-cell CLL/small lymphocytic lymphoma.
  • B-cell prolymphocytic leukemia.
  • Lymphoplasmacytic lymphoma/immunocytoma.
  • Mantle cell lymphoma.
  • Follicular lymphoma.
  • Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type.
  • Nodal marginal zone B-cell lymphoma (± monocytoid B-cells).
  • Splenic marginal zone lymphoma (± villous lymphocytes).
  • Hairy cell leukemia.
  • Plasmacytoma/plasma cell myeloma.
  • Diffuse large B-cell lymphoma.
  • 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. T-cell CLL/prolymphocytic leukemia.
  • T-cell granular lymphocytic leukemia.
  • Mycosis fungoides/Sézary syndrome.
  • Peripheral T-cell lymphoma, not otherwise characterized.
  • Hepatosplenic gamma/delta T-cell lymphoma.
  • Subcutaneous panniculitis-like T-cell lymphoma.
  • Angioimmunoblastic T-cell lymphoma.
  • Extranodal T-/NK-cell lymphoma, nasal type.
  • Enteropathy-type intestinal T-cell lymphoma.
  • Adult T-cell lymphoma/leukemia (human T-lymphotrophic virus [HTLV] 1+).
  • Anaplastic large cell lymphoma, primary systemic type.
  • Anaplastic large cell lymphoma, primary cutaneous type.
  • Aggressive NK-cell leukemia.
  • HL
  • Nodular lymphocyte-predominant HL.
  • Classical HL. Nodular sclerosis HL.
  • Lymphocyte-rich classical HL.
  • Mixed-cellularity HL.
  • Lymphocyte-depleted HL.
  • The REAL classification encompasses all the lymphoproliferative neoplasms. Refer to the following PDQ summaries for more information:
    • Adult Acute Lymphoblastic Leukemia Treatment
    • Adult Hodgkin Lymphoma Treatment
    • AIDS-Related Lymphoma Treatment
    • Chronic Lymphocytic Leukemia Treatment
    • Hairy Cell Leukemia Treatment
    • Mycosis Fungoides and the Sézary Syndrome Treatment
    • Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment
    • Primary CNS Lymphoma Treatment

    PDQ modification of REAL classification of lymphoproliferative diseases
  • Plasma cell disorders. (Refer to the PDQ summary on Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment for more information.) Bone.
  • Extramedullary. Monoclonal gammopathy of undetermined significance.
  • Plasmacytoma.
  • Multiple myeloma.
  • Amyloidosis.
  • HL. (Refer to the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.) Nodular sclerosis HL.
  • Lymphocyte-rich classical HL.
  • Mixed-cellularity HL.
  • Lymphocyte-depleted HL.
  • Indolent lymphoma/leukemia. Follicular lymphoma (follicular small-cleaved cell [grade 1], follicular mixed small-cleaved, and large cell [grade 2], and diffuse, small-cleaved cell).
  • Chronic lymphocytic leukemia/small lymphocytic lymphoma. (Refer to the PDQ summary on Chronic Lymphocytic Leukemia Treatment for more information.)
  • Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia).
  • Extranodal marginal zone B-cell lymphoma (MALT lymphoma).
  • Nodal marginal zone B-cell lymphoma (monocytoid B-cell lymphoma).
  • Splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes).
  • Hairy cell leukemia. (Refer to the PDQ summary on Hairy Cell Leukemia Treatment for more information.)
  • Mycosis fungoides/Sézary syndrome. (Refer to the PDQ summary on Mycosis Fungoides/Sézary Syndrome Treatment for more information.)
  • T-cell granular lymphocytic leukemia. (Refer to the PDQ summary on Chronic Lymphocytic Leukemia Treatment for more information.)
  • Primary cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis (CD30+).
  • Nodular lymphocyte–predominant Hodgkin lymphoma. (Refer to the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.)
  • Aggressive lymphoma/leukemia. Diffuse large cell lymphoma (includes diffuse mixed-cell, diffuse large cell, immunoblastic, and T-cell rich large B-cell lymphoma).
    Distinguish:
    Mediastinal large B-cell lymphoma.
  • Follicular large cell lymphoma (grade 3).
  • Anaplastic large cell lymphoma (CD30+).
  • Extranodal NK-/T-cell lymphoma, nasal type/aggressive NK-cell leukemia/blastic NK-cell lymphoma.
  • Lymphomatoid granulomatosis (angiocentric pulmonary B-cell lymphoma).
  • Angioimmunoblastic T-cell lymphoma.
  • Peripheral T-cell lymphoma, unspecified.
      Subcutaneous panniculitis-like T-cell lymphoma.
    • Hepatosplenic T-cell lymphoma.
  • Enteropathy-type T-cell lymphoma.
  • Intravascular large B-cell lymphoma.
  • Burkitt lymphoma/Burkitt cell leukemia/Burkitt-like lymphoma.
  • Precursor B-cell or T-cell lymphoblastic lymphoma/leukemia. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)
  • Primary central nervous system (CNS) lymphoma. (Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information.)
  • Adult T-cell leukemia/lymphoma (HTLV 1+).
  • Mantle cell lymphoma.
  • Polymorphic posttransplantation lymphoproliferative disorder.
  • AIDS-related lymphoma. (Refer to the PDQ summary on AIDS-Related Lymphoma Treatment for more information.)
  • True histiocytic lymphoma.
  • Primary effusion lymphoma.
  • B-cell or T-cell prolymphocytic leukemia. (Refer to the PDQ summary on Chronic Lymphocytic Leukemia Treatment for more information.)
  • Indolent NHL
    Indolent non-Hodgkin lymphoma (NHL) includes the following subtypes:
    • Follicular lymphoma.
    • Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia).
    • Marginal zone lymphoma.
    • Splenic marginal zone lymphoma.
    • Primary cutaneous anaplastic large cell lymphoma.
    Follicular Lymphoma
    Follicular lymphoma comprises 20% of all NHLs and as many as 70% of the indolent lymphomas reported in American and European clinical trials. Most patients with follicular lymphoma are age 50 years and older and present with widespread disease at diagnosis. Nodal involvement is most common and is often accompanied by splenic and bone marrow disease. Rearrangement of the bcl-2 gene is present in more than 90% of patients with follicular lymphoma; overexpression of the bcl-2 protein is associated with the inability to eradicate the lymphoma by inhibiting apoptosis.
    Prognosis
    Despite the advanced stage, the median survival ranges from 8 to 15 years, leading to the designation of being indolent. Patients with advanced-stage follicular lymphoma are not cured with current therapeutic options. The rate of relapse is fairly consistent over time, even in patients who have achieved complete responses to treatment. Watchful waiting, i.e., the deferring of treatment until the patient becomes symptomatic, is an option for patients with advanced-stage follicular lymphoma. An international index for follicular lymphoma (i.e., the Follicular Lymphoma International Prognostic Index [FLIPI]) identified five significant risk factors prognostic of overall survival (OS):
  • Age (≤60 years vs. >60 years).
  • Serum lactate dehydrogenase (LDH) (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 none or one risk factor have an 85% 10-year survival rate, while three or more risk factors confer a 40% 10-year survival rate. As a revised FLIPI, an elevated beta-2-microglobulin and lymph node size of more than 6 cm are proposed prognostic factors instead of serum LDH and the number of nodal areas. 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).
    Follicular, small-cleaved cell lymphoma and follicular mixed small-cleaved and large cell lymphoma do not have reproducibly different disease-free survival or OS.

    Therapeutic approaches
    Therapeutic options include watchful waiting; rituximab, an anti-CD20 monoclonal antibody, alone or with purine nucleoside analogs; oral alkylating agents; and combination chemotherapy. Radiolabeled monoclonal antibodies, vaccines, and autologous or allogeneic bone marrow or peripheral stem cell transplantation are also under clinical evaluation. Currently, no randomized trials have mature results to guide clinicians about the initial choice of rituximab, nucleoside analogs, alkylating agents, combination chemotherapy, radiolabeled monoclonal antibodies, or combinations of these options. On a comparative basis, it is difficult to prove benefit when relapsing disease is followed with watchful waiting, or when the median survival is more than 10 years. Follicular lymphoma in situ and primary follicular lymphoma of the duodenum are particularly indolent variants that rarely progress and rarely require therapy. A so-called pediatric-type nodal follicular lymphoma has indolent behavior and rarely recurs; adult patients with this histologic variant are characterized by a lack of bcl-2 rearrangement in conjunction with a Ki-67 proliferation index greater than 30% and a localized stage I presentation.
    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. 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. In this series, high-risk factors for subsequent histologic transformation were advanced stage, high-risk FLIPI, and expectant management. The 5-year OS rate was more than 50% for 172 patients who had biopsy-proven, aggressive-histology transformation in a multicenter cohort study employing rituximab plus anthracycline or platinum-based chemotherapy, or similar therapy followed by autologous or allogeneic stem cell transplantation (ASCT).

    Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia)
    Lymphoplasmacytic lymphoma is usually associated with a monoclonal serum paraprotein of immunoglobulin M (IgM) type (Waldenström macroglobulinemia). Most patients have bone marrow, lymph node, and splenic involvement, and some patients may develop hyperviscosity syndrome. Other lymphomas may also be associated with serum paraproteins.
    Asymptomatic patients can be monitored for evidence of disease progression without immediate need for chemotherapy.
    Prognostic factors associated with symptoms requiring therapy include the following:
    • Age 70 or older.
    • Beta-2-microglobulin of 3 mg/dL or more.
    • Increased serum LDH.
    Therapeutic approaches
    The management of lymphoplasmacytic lymphoma is similar to that of other low-grade lymphomas, especially diffuse, small lymphocytic lymphoma/chronic lymphocytic leukemia. If the viscosity relative to water is greater than four, the patient may have manifestations of hyperviscosity. Plasmapheresis is useful for temporary, acute symptoms (such as retinopathy, congestive heart failure, and central nervous system dysfunction) but should be combined with chemotherapy for prolonged control of the disease. Symptomatic patients with a serum viscosity of not more than four are usually started directly on chemotherapy. Therapy may be required to correct hemolytic anemia in patients with chronic cold agglutinin disease; rituximab, cyclophosphamide, and steroids are often employed. Occasionally, a heated room is required for patients whose cold agglutinins become activated by even minor chilling.
    First-line regimens include rituximab, the nucleoside analogs, and alkylating agents, either as single agents or as part of combination chemotherapy. 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.[Level of evidence: 3iiiDiv] The rise of IgM after rituximab can be avoided with the concomitant use of an alkylating agent such as cyclophosphamide or the proteosome inhibitor bortezomib. The nucleoside analogs 2-chlorodeoxyadenosine and fludarabine have shown similar response rates for previously untreated patients with lymphoplasmacytic lymphoma.[Level of evidence: 3iiiDiv] Single-agent alkylators, bendamustine, bortezomib, and combination chemotherapy with or without rituximab also show similar response rates.[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. A combination of bortezomib, dexamethasone, and rituximab has been proposed for its high response rate, rapidity of action, and avoidance of an IgM rebound.
    Interferon-alpha also shows activity in this disease, in contrast to poor responses in patients with multiple myeloma. Myeloablative therapy with autologous or allogeneic hematopoietic stem cell support is under clinical evaluation. Candidates for this approach should avoid long-term use of alkylating agents or purine nucleoside analogs, which can deplete hematopoietic stem cells or predispose patients to myelodysplasia or acute leukemia. After relapse from alkylating-agent therapy, 92 patients with lymphoplasmacytic lymphoma were randomly assigned to either fludarabine or cyclophosphamide, doxorubicin, and prednisone. Although relapse-free survival favored fludarabine (median duration of 19 months vs. 3 months, P < .01), no difference was observed in OS.[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.[Level of evidence: 3iiiDiv]

    Marginal Zone Lymphoma
    Marginal zone lymphomas were previously included among the diffuse, small lymphocytic lymphomas. When marginal zone lymphomas involve the nodes, they are called monocytoid B-cell lymphomas or nodal marginal zone B-cell lymphomas, and when they involve extranodal sites (e.g., gastrointestinal tract, thyroid, lung, breast, orbit, and skin), they are called mucosa-associated lymphatic tissue (MALT) lymphomas.
    Gastric MALT
    Many patients have a history of autoimmune disease, such as Hashimoto thyroiditis or Sjögren syndrome, or of Helicobacter gastritis. Most patients present with stage I or stage II extranodal disease, which is most often in the stomach. Treatment of Helicobacter pylori infection may resolve most cases of localized gastric involvement. 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. The clinical implication of this finding is unknown. Translocation t(11;18) in patients with gastric MALT predicts for poor response to antibiotic therapy, for H. pylori–negative testing, and for poor response to oral alkylator chemotherapy. Stable asymptomatic patients with persistently positive biopsies have been successfully followed on a watchful waiting approach until disease progression. Patients who progress are treated with radiation therapy, rituximab, surgery (total gastrectomy or partial gastrectomy plus radiation therapy), chemotherapy, or combined–modality therapy. The use of endoscopic ultrasonography may help clinicians to follow responses in these patients. Four case series (encompassing more than 100 patients with stage IE or IIE diffuse, large, B-cell lymphoma with or without associated MALT (but H. pylori-positive) reported durable complete remissions in more than 50% of the patients after treatment of H. pylori.

    Extragastric MALT
    Localized involvement of other sites can be treated with radiation or surgery. 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. 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. A prospective, randomized trial of 252 patients with nongastric, extranodal MALT compared chlorambucil with rituximab plus chlorambucil. With a median follow-up of 62 months, the event-free survival was better for the rituximab arm (68% vs. 50%, P = .002), however, the 5-year OS was 89% in both arms.[Level of evidence: 1iiDi] This trial was extended with a third arm using rituximab alone, the results of which are not yet available. For patients with ocular adnexal MALT, antibiotic therapy using doxycycline that targeted Chlamydia psittaci resulted in durable remissions for almost half of the patients in a review of the literature that included 131 patients.[Level of evidence: 3iiiDiv] Large B-cell lymphomas of MALT sites are classified and treated as diffuse large cell lymphomas.

    Monocytoid B cell lymphoma (Nodal marginal zone lymphoma)
    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.[Level of evidence: 3iiiDiv]

    Mediterranean abdominal lymphoma
    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. Campylobacter jejuni has been identified as one of the bacterial species associated with IPSID, and antibiotic therapy may result in remission of the disease.

    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. This type of lymphoma is otherwise known as splenic lymphoma with villous lymphocytes. Splenectomy may result in prolonged remission.
    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. Splenic marginal zone lymphoma responds less well to chemotherapy, which would ordinarily be effective for chronic lymphocytic leukemia. 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.; [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. 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.
    (Refer to the PDQ summaries on Chronic Lymphocytic Leukemia Treatment; Mycosis Fungoides/Sézary Syndrome Treatment; Hairy Cell Leukemia Treatment; and Adult Hodgkin Lymphoma Treatment for more information.)

    Aggressive NHL
    Aggressive non-Hodgkin lymphoma (NHL) includes the following subtypes:
    • Diffuse large B-cell lymphoma.
    • Mediastinal large B-cell lymphoma (primary mediastinal large B-cell lymphoma).
    • Follicular large cell lymphoma.
    • Anaplastic large cell lymphoma.
    • Extranodal NK-/T-cell lymphoma.
    • Lymphomatoid granulomatosis.
    • Angioimmunoblastic T-cell lymphoma.
    • Peripheral T-cell lymphoma.
    • Enteropathy-type intestinal T-cell lymphoma.
    • Intravascular large B-cell lymphoma (intravascular lymphomatosis).
    • Burkitt lymphoma/diffuse small noncleaved-cell lymphoma.
    • Lymphoblastic lymphoma.
    • Adult T-cell leukemia/lymphoma.
    • Mantle cell lymphoma.
    • Polymorphic posttransplantation lymphoproliferative disorder (PTLD).
    • True histiocytic lymphoma.
    • Primary effusion lymphoma.
    Diffuse Large B-cell Lymphoma
    Diffuse large B-cell lymphoma (DLBCL) is the most common of the NHLs and comprises 30% of newly diagnosed cases. Most patients present with rapidly enlarging masses, often with both local and systemic symptoms (designated B symptoms with fever, recurrent night sweats, or weight loss). (Refer to the PDQ summary on Hot Flashes and Night Sweats and the PDQ summary on Nutrition in Cancer Care for more information on weight loss.)
    Some cases of large B-cell lymphoma have a prominent background of reactive T cells and often of histiocytes, so-called T-cell/histiocyte-rich large B-cell lymphoma. This subtype of large cell lymphoma has frequent liver, spleen, and bone marrow involvement; however, the outcome is equivalent to that of similarly staged patients with DLBCL. Some patients with DLCBL at diagnosis have a concomitant indolent small B-cell component; while overall survival (OS) appears similar after multidrug chemotherapy, there is a higher risk of indolent relapse.
    Prognosis
    The vast majority of patients with localized disease are curable with combined–modality therapy or combination chemotherapy alone. For patients with advanced-stage disease, 50% of presenting patients are cured with doxorubicin-based combination chemotherapy and rituximab.
    An International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS:
  • Age (≤60 years vs. >60 years).
  • 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, central nervous system (CNS), liver, lung, and spleen. Age-adjusted and stage-adjusted modifications of this IPI are used for younger patients with localized disease. The bcl-2 gene and rearrangement of the myc gene or dual overexpression of the myc gene, or both, confer a particularly poor prognosis. Patients at high risk of relapse may be considered for clinical trials. 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. Patients who have DLBCL with coexpression of CD20 and CD30 may define a subgroup with a unique molecular signature, a more favorable prognosis, and possible therapeutic implication for the use of anti-CD30–specific therapy, such as brentuximab vedotin.

    CNS prophylaxis
    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. CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, others do not. 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.[Level of evidence: 3iiiDiii] The addition of rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-based regimens has significantly reduced the risk of CNS relapse in retrospective analyses.

    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. Patients are usually female and young (median age of 30–40 years). Patients present with a locally invasive anterior mediastinal mass that may cause respiratory symptoms or superior vena cava syndrome.
    Prognosis and therapy is the same as for other comparably staged patients with DLCBL. Uncontrolled, phase II studies employing dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) plus rituximab or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) show high cure rates while avoiding any mediastinal radiation.[Level of evidence: 3iiiA] These results suggest that patients who receive R-CHOP-based regimens may avoid the serious long-term complications of radiation therapy when given with chemotherapy. Posttreatment fluorine-18-fluorodeoxyglucose–positron-emission tomography–computed tomography (FDG-PET-CT) scans appear unreliable with many false positives. The only randomized trial showing an OS advantage for combined modality therapy was retracted. (Refer to the Superior Vena Cava Syndrome section in the PDQ summary on Cardiopulmonary Syndromes for more information.)

    Follicular Large Cell Lymphoma
    Prognosis
    The natural history of follicular large cell lymphoma remains controversial. 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). Other investigators report a plateau in freedom from progression at levels expected for an aggressive lymphoma (40% at 10 years). 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.

    Therapeutic approaches
    Treatment of these patients is more similar to treatment of aggressive NHL than it is to the treatment of indolent NHL. In support of this approach, treatment with high-dose chemotherapy and autologous hematopoietic peripheral stem cell transplantation (SCT) shows the same curative potential in patients with follicular large cell lymphoma who relapse as it does in patients with diffuse large cell lymphoma who relapse.[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-anaplastic lymphoma kinase (ALK).
    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.
    Patients with ALK-positive ALCL are generally treated the same as patients with diffuse large cell lymphomas using the CHOP regimen and have a prognosis that is as good as comparably staged patients. For patients with relapsed disease, anecdotal responses have been reported for brentuximab vedotin (anti-tubulin agent attached to a CD30-specific monoclonal antibody), romidepsin, and pralatrexate.[Level of evidence: 3iiiDiv] For patients with relapsed disease, autologous stem cell transplantation showed a 50% 3-year progression-free survival (PFS) for 39 patients in a retrospective review.[Level of evidence: 3iiiDiii]
    ALCL in children is usually characterized by systemic and cutaneous disease and has high response rates and good OS with doxorubicin-based combination chemotherapy.

    Extranodal NK-/T-cell Lymphoma
    Extranodal natural killer (NK)-/T-cell lymphoma (nasal type) is an aggressive lymphoma marked by extensive necrosis and angioinvasion, most often presenting in extranodal sites, in particular the nasal or paranasal sinus region. 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. In most cases, Epstein-Barr virus (EBV) genomes are detectable in the tumor cells and immunophenotyping shows CD56 positivity. Cases with blood and marrow involvement are considered NK-cell leukemia.
    The increased risk of CNS involvement and of local recurrence has led to recommendations for radiation therapy locally, concurrently, or before the start of chemotherapy, and for intrathecal prophylaxis and/or prophylactic cranial radiation therapy. The highly aggressive course, with poor response and short survival with standard therapies, especially for patients with advanced-stage disease or extranasal presentation, has led some investigators to recommend autologous or allogenic peripheral SCT consolidation. L-asparaginase-containing regimens have shown anecdotal response rates greater than 50% for relapsing, refractory, or newly diagnosed stage IV patients. NK-/T-cell lymphoma that presents only in the skin has a more favorable prognosis, especially in patients with coexpression of CD30 with CD56. A benign NK-cell enteropathy (EBV negative) on endoscopic biopsy should be distinguished from NK-/T-cell lymphoma.

    Lymphomatoid Granulomatosis
    Lymphomatoid granulomatosis is an EBV-positive large B-cell lymphoma with a predominant T-cell background. 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 (AITL) or (ATCL) was formerly called angioimmunoblastic lymphadenopathy with dysproteinemia. Characterized by clonal T-cell receptor gene rearrangement, this entity is managed like diffuse large cell lymphoma. Patients present with profound lymphadenopathy, fever, night sweats, weight loss, skin rash, a positive Coombs test, and polyclonal hypergammaglobulinemia. (Refer to the information on night sweats in the PDQ summary on Hot Flashes and Night Sweats, information on weight loss in the in the PDQ summary on Nutrition in Cancer Care, and information on skin rash in the PDQ summary on Pruritus.) Opportunistic infections are frequent because of an underlying immune deficiency. B-cell EBV genomes are detected in most affected patients.
    Doxorubicin-based combination chemotherapy, such as the CHOP regimen, is recommended as it is for other aggressive lymphomas. The International Peripheral T-Cell Lymphoma Project involving 22 international centers identified 243 patients with AITL or ATCL; the 5-year OS and failure-free survival rates were 33% and 18%. Myeloablative chemotherapy and radiation therapy with autologous or allogeneic peripheral stem cell support has been described in anecdotal reports. Anecdotal responses have been reported for cyclosporine, pralatrexate, bendamustine, and the histone deacetylase inhibitor romidepsin.[Level of evidence: 3iiiDiv] Occasional spontaneous remissions and protracted responses to steroids only have been reported.

    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. Peripheral T-cell lymphoma encompasses a group of heterogeneous nodal T-cell lymphomas that will require future delineation. This includes the so-called Lennert lymphoma, a T-cell lymphoma admixed with a preponderance of lymphoepithelioid cells.
    Prognosis
    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. 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.

    Therapeutic approaches
    Therapy involves doxorubicin-based combination chemotherapy (such as CHOP), which is also used for DLBCL. Consolidation using high-dose chemotherapy with autologous or allogeneic hematopoietic stem cell support has been applied to patients with advanced-stage peripheral T-cell lymphoma after induction therapy with CHOP-based regimens and after response to reinduction therapy at first relapse. Evidence for this approach is anecdotal. For relapsing patients, pralatrexate has shown a 30% response rate and a median 10-month duration of response for 109 evaluable patients in a prospective trial.[Level of evidence: 3iiiDiv] Also for relapsing patients, similar response rates were seen for romidepsin for 130 evaluable patients in a prospective trial.[Level of evidence: 3iiiDiv] Anecdotal responses have been seen with pralatrexate and with bendamustine.[Level of evidence: 3iiiDiv] Anecdotal responses have also been seen with alemtuzumab, an anti-CD52 monoclonal antibody, or denileukin diftitox, a toxin-antibody ligand, after relapse from previous chemotherapy. The median PFS after first relapse was less than 6 months in one series of 163 patients with peripheral T-cell lymphoma.
    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. Another variant, subcutaneous panniculitis-like T-cell lymphoma, is localized to subcutaneous tissue associated with hemophagocytic syndrome. 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. These patients may manifest involvement of the epidermis, dermis, subcutaneous region, or mucosa. These entities have extremely poor prognoses with an extremely aggressive clinical course and are treated within the same paradigm as the highest-risk groups with DLBCL.

    Enteropathy-type Intestinal T-cell Lymphoma
    Enteropathy-type intestinal T-cell lymphoma involves the small bowel of patients with gluten-sensitive enteropathy (celiac sprue). 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. Complications of treatment include gastrointestinal bleeding, small bowel perforation, and enterocolic fistulae; patients often require parenteral nutrition. (Refer to the PDQ summaries on Gastrointestinal Complications and Nutrition in Cancer Care for more information on parenteral nutrition.) Multifocal intestinal perforations and visceral abdominal involvement are seen at the time of relapse. High-dose therapy with hematopoietic stem cell rescue has been applied in first remission or at relapse.[Level of evidence: 3iiiDiii] Evidence for this approach is anecdotal.

    Intravascular Large B-cell Lymphoma (Intravascular Lymphomatosis)
    Intravascular lymphomatosis is characterized by large cell lymphoma confined to the intravascular lumen. The brain, kidneys, lungs, and skin are the organs most likely affected by intravascular lymphomatosis.
    With the use of aggressive combination chemotherapy, the prognosis is similar to more conventional presentations.

    Burkitt Lymphoma/Diffuse Small Noncleaved-cell Lymphoma
    Burkitt lymphoma/diffuse small noncleaved-cell lymphoma typically involves younger patients and represents the most common type of pediatric NHL. These types of aggressive extranodal B-cell lymphomas are characterized by translocation and deregulation of the C-myc gene on chromosome 8. 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).[Level of evidence: 3iiiA]
    In some patients with larger B cells, there is morphologic overlap with DLBCL. These Burkitt-like large cell lymphomas show C-myc deregulation, extremely high proliferation rates, and a gene-expression profile as expected for classic Burkitt lymphoma. Endemic cases, usually from Africa, involve the facial bones or jaws of children, mostly containing EBV genomes. Sporadic cases usually involve the gastrointestinal system, ovaries, or kidneys. Patients present with rapidly growing masses and a very high LDH but are potentially curable with intensive doxorubicin-based combination chemotherapy.
    Therapeutic approaches
    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). Aggressive combination chemotherapy, which is patterned after that used in childhood Burkitt lymphoma, has been described in CLB-9251 (NCT00002494), for example, and has been very successful for adult patients with more than 60% of advanced-stage patients free of disease at 5 years. Adverse prognostic factors include bulky abdominal disease and high serum LDH. In some institutions, treatment includes the use of consolidative bone marrow transplantation (BMT). 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. (Refer to the PDQ summaries on Primary CNS Lymphoma Treatment and AIDS-Related Lymphoma Treatment for more information.)

    Lymphoblastic Lymphoma
    Lymphoblastic lymphoma (precursor T-cell) is a very aggressive form of NHL. It often occurs in young patients but not exclusively. 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. Radiation therapy is sometimes given to areas of bulky tumor masses. Because these forms of NHL tend to progress quickly, combination chemotherapy is instituted rapidly once the diagnosis has been confirmed. Careful review of the pathologic specimens, bone marrow aspirate, biopsy specimen, cerebrospinal fluid cytology, and lymphocyte marker constitute the most important aspects of the pretreatment staging workup. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)

    Adult T-cell Leukemia/Lymphoma
    Adult T-cell leukemia/lymphoma (ATL) is caused by infection with the retrovirus human T-lymphotrophic virus 1 and is frequently associated with lymphadenopathy, hypercalcemia, circulating leukemic cells, bone and skin involvement, hepatosplenomegaly, a rapidly progressive course, and poor response to combination chemotherapy. ATL has been divided into four clinical subtypes: acute, lymphoma, chronic, and smoldering.
    The acute and lymphoma types of ATL have done poorly with strategies of combination chemotherapy and ASCT with a median OS under 1 year. Using combination chemotherapy, less than 10%of 807 patients were alive after 4 years. Anecdotal durable remissions have been reported after ASCT and even after subsequent donor lymphocyte infusion for relapses after transplant.[Level of evidence: 3iiiDiv] Among 585 patients who underwent ASCT, the 3-year OS was 36%.[Level of evidence: 3iiiA]
    The combination of zidovudine and interferon-alpha has activity against ATL, even for patients who failed previous cytotoxic therapy. Durable remissions are seen in the majority of presenting patients with this combination but are not seen in patients with the lymphoma subtype of ATL. Symptomatic local progression for all subtypes responds well to palliative radiation therapy.

    Mantle Cell Lymphoma
    Mantle cell lymphoma is found in lymph nodes, the spleen, bone marrow, blood, and sometimes the gastrointestinal system (lymphomatous polyposis). 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.
    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. 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. 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. A high cell-proliferation rate (increased Ki-67, mitotic index, beta-2-microglobulin) may be associated with a poorer prognosis.
    Therapeutic approaches
    It is unclear which chemotherapeutic approach offers the best long-term survival in this clinicopathologic entity; early refractoriness to chemotherapy is a usual feature. In a prospective randomized trial, 532 patients older than 60 years and not eligible for SCT were given either R-CHOP or R-FC (rituximab, fludarabine, cyclophosphamide) for 6 to 8 cycles, followed by maintenance therapy in responders randomly assigned to rituximab or interferon-alpha maintenance therapy. With a median follow-up of 37 months, the OS was significantly shorter after R-FC than after R-CHOP (47% vs. 62%, P = .005; hazard ratio [HR]death, 1.50; 95% CI, 1.13–1.99).[Level of evidence: 1iiA] Event-free survival favored rituximab over interferon-alpha (57% PFS at 4 years vs. 34%, P = .01; HR, 0.55; 95% CI, 0.36–0.87), but OS did not differ significantly (79% vs. 67% at 4 years, P = .13).[Level of evidence: 1iiDi] However, patients who received R-CHOP induction showed an OS benefit for rituximab maintenance over interferon-alpha maintenance (87% vs. 63% at 4 years, P = .005).[Level of evidence: 3iiiA] A randomized trial compared bendamustine plus rituximab with R-CHOP and showed improved PFS (35 vs. 22 months; HR, 0.49; 95% CI, 0.28–0.79; P = .004) but no difference in OS.[Level of evidence: 1iiDiii]
    Patients with low risk on the IPI may do well when initial therapy is deferred.[Level of evidence: 3iiiDiv] Many investigators are exploring high-dose chemoradioimmunotherapy with stem cell/marrow support or nonmyeloablative ASCT. Thus far, randomized trials have not shown OS benefits from these newer approaches. 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.[Level of evidence: 3iiiDiv] The combination of lenalidomide and rituximab also shows response rates of around 50% in relapsed patients.[Level of evidence: 3iiDiv]

    Polymorphic PTLD
    Patients who undergo transplantation of the heart, lung, liver, kidney, or pancreas usually require lifelong immunosuppression. This may result in PTLD in 1% to 3% of recipients, which appears as an aggressive lymphoma. Pathologists can distinguish a polyclonal B-cell hyperplasia from a monoclonal B-cell lymphoma; both are almost always associated with EBV.
    Prognosis
    Poor performance status, grafted organ involvement, high IPI, elevated LDH, and multiple sites of disease are poor prognostic factors for PTLD.

    Therapeutic options
    In some cases, withdrawal of immunosuppression results in eradication of the lymphoma. 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. Sometimes, a combination of acyclovir and interferon-alpha has been used. If these measures fail, doxorubicin-based combination chemotherapy is recommended, although most patients can avoid cytotoxic therapy. 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. Multifocal, rapidly progressive disease occurs late after transplantation (>1 year) and is usually phenotypically monoclonal and associated with EBV. These patients may have durable remissions using standard chemotherapy regimens for aggressive lymphoma. Instances of EBV-negative PTLD occur even later (median, 5 years posttransplant) and have particularly poor prognoses. 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). An anti-interleukin-6 monoclonal antibody is also under clinical evaluation.

    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. Care must be taken with immunophenotypic tests to exclude ALCL or hemophagocytic syndromes caused by viral infections, especially EBV.
    Therapeutic options
    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. Patients are usually human immunodeficiency virus seropositive, and the tumor usually contains Kaposi sarcoma–associated herpes virus/human herpes virus 8.
    Prognosis
    The prognosis of primary effusion lymphoma is extremely poor.

    Therapeutic approaches
    Therapy is usually modeled after the treatment of comparably staged diffuse large cell lymphomas.

    Stage Information for Adult NHL
    Stage is important in selecting a treatment for patients with non-Hodgkin lymphoma (NHL). Chest and abdominal computed tomography (CT) scans are usually part of the staging evaluation for all lymphoma patients. The staging system is similar to the staging system used for Hodgkin lymphoma.
    Common among patients with NHL is involvement of the following:
    • Noncontiguous lymph nodes.
    • Waldeyer ring.
    • Epitrochlear nodes.
    • Gastrointestinal tract.
    • Extranodal presentations. (A single extranodal site is occasionally the only site of involvement in patients with diffuse lymphoma.)
    • Bone marrow.
    • Liver (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. Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose can be used for initial staging and for follow-up after therapy as a supplement to CT scanning. Interim PET scans after two to four cycles of therapy did not provide reliable prognostic information because of problems of interobserver reproducibility in a large cooperative group trial (ECOG-E344 [NCT00274924]) and lack of difference in outcome between PET-negative and PET-positive/biopsy-negative patients in two prospective trials.
    Staging Subclassification System
    Table 2. Anatomic Stage/Prognostic Groupsa
    StagePrognostic Groups IInvolvement of a single lymphatic site (i.e., nodal region, Waldeyer ring, thymus or spleen) (I).ORLocalized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement (IE) (rare in Hodgkin lymphoma).IIInvolvement of two or more lymph node regions on the same side of the diaphragm (II).ORLocalized involvement of a single extralymphatic organ or site in association with regional lymph node involvement with or without involvement of other lymph node regions on the same side of the diaphragm (IIE). The number of regions involved may be indicated by a subscript Arabic numeral, for example, II3.IIIInvolvement of lymph node regions on both sides of the diaphragm (III), which also may be accompanied by extralymphatic extension in association with adjacent lymph node involvement (IIIE) or by involvement of the spleen (IIIS) or both (IIIE, IIIS). Splenic involvement is designated by the letter S.IVDiffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement.ORIsolated extralymphatic organ involvement in the absence of adjacent regional lymph node involvement, but in conjunction with disease in distant site(s). Stage IV includes any involvement of the liver or bone marrow, lungs (other than by direct extension from another site), or cerebrospinal fluid.aReprinted with permission from American Joint Committee on Cancer: Hodgkin and non-Hodgkin lymphomas. In Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 607–11.
    The Ann Arbor staging system is commonly used for patients with NHL. In this system, stage I, stage II, stage III, and stage IV adult NHL can be subclassified into A and B categories: B for those with well-defined generalized symptoms and A for those without such symptoms. The B designation is given to patients with any of the following symptoms:
    • Unexplained loss of more than 10% of body weight in the 6 months before diagnosis.
    • Unexplained fever with temperatures above 38°C.
    • Drenching night sweats.
    Occasionally, specialized staging systems are used. The physician should be aware of the system used in a specific report.
    The E designation is used when extranodal lymphoid malignancies arise in tissues separate from, but near, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver. If pathologic proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed.
    Table 3. Notation to Identify Specific Sites
    N = nodesH = liverL = lungM = bone marrowS = spleenP = pleuraO = boneD = skin
    Current practice assigns a clinical stage (CS) based on the findings of the clinical evaluation and a pathologic stage (PS) based on the findings made as a result of invasive procedures beyond the initial biopsy.
    For example, on percutaneous biopsy, a patient with inguinal adenopathy and a positive lymphangiogram without systemic symptoms might be found to have involvement of the liver and bone marrow. The precise stage of such a patient would be CS IIA, PS IVA(H+)(M+).
    A number of other factors that are not included in the above staging system are important for the staging and prognosis of patients with NHL. These factors include the following:
    • Age.
    • Performance status (PS).
    • Tumor size.
    • Lactate dehydrogenase (LDH) values.
    • The number of extranodal sites.
    To identify subgroups of patients most likely to relapse, an international prognostic index was compiled for 2,031 patients with aggressive NHL. 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).
    • PS (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, liver, lung, and spleen. The bcl-2 gene and rearrangement of the myc gene or dual overexpression of the myc gene, or both, confer a particularly poor prognosis. Patients at high risk of relapse may benefit from consolidation therapy or other approaches under clinical evaluation. 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.

    Treatment Option Overview for Adult NHL
    Treatment of non-Hodgkin lymphoma (NHL) depends on the histologic type and stage. Many of the improvements in survival have been made using clinical trials (experimental therapy) that have attempted to improve on the best available accepted therapy (conventional or standard therapy).
    In asymptomatic patients with indolent forms of advanced NHL, treatment may be deferred until the patient becomes symptomatic as the disease progresses. When treatment is deferred, the clinical course of patients with indolent NHL varies; frequent and careful observation is required so that effective treatment can be initiated when the clinical course of the disease accelerates. Some patients have a prolonged indolent course, but others have disease that rapidly evolves into more aggressive types of NHL that require immediate treatment.
    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.
    Table 4. Standard Treatment Options for NHL
    StageStandard Treatment OptionsCNS = central nervous system; CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone; IF-XRT = involved-field radiation therapy; NHL = non-Hodgkin lymphoma; R-CHOP = rituximab, an anti-CD20 monoclonal antibody, cyclophosphamide, doxorubicin, vincristine, and prednisone.Indolent, Stage I and Contiguous Stage II Adult NHL Radiation therapyRituximab with or without chemotherapy Watchful waitingOther therapies as designated for patients with advanced-stage diseaseIndolent, Noncontiguous Stage II/III/IV Adult NHLWatchful waiting for asymptomatic patients Rituximab Purine nucleoside analogs Alkylating agents (with or without steroids) Combination chemotherapy Yttrium-90–labeled ibritumomab tiuxetan Maintenance rituximabIndolent, Recurrent Adult NHLChemotherapy (single agent or combination)RituximabLenalidomideRadiolabeled anti-CD20 monoclonal antibodiesPalliative radiation therapyAggressive, Stage I and Contiguous Stage II Adult NHLR-CHOP with or without IF-XRTAggressive, Noncontiguous Stage II/III/IV Adult NHLR-CHOPOther combination chemotherapyAdult Lymphoblastic LymphomaIntensive therapyRadiation therapyDiffuse, Small, Noncleaved-Cell/Burkitt LymphomaAggressive multidrug regimensCentral nervous system (CNS) prophylaxisAggressive, Recurrent Adult NHLBone marrow or stem cell transplantationRe-treatment with standard agentsPalliative radiation 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.
    Aggressive lymphomas are increasingly seen in human immunodeficiency virus (HIV)-positive patients; treatment of these patients requires special consideration. (Refer to the PDQ summary on AIDS-Related Lymphoma Treatment for more information.)
    In addition to screening for HIV among patients with aggressive lymphomas, active hepatitis B or hepatitis C should be assessed prior to treatment with rituximab and/or chemotherapy. Even patients with undetectable hepatitis B viral loads after remote past infection benefit from prophylaxis with entecavir in the context of rituximab therapy. Similarly, prophylaxis for herpes zoster with acyclovir or valcyclovir and prophylaxis for pneumocystis with trimethoprim/sulfamethoxazole or dapsone are usually applied with rituximab with or without combination chemotherapy.
    Several unusual presentations of lymphoma occur that often require somewhat modified approaches to staging and therapy. The reader is referred to reviews for a more detailed description of extranodal presentations in the gastrointestinal system, thyroid, spleen, testis, paranasal sinuses, bone, orbit, and skin.
    (Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information.)
    Cheson BD, Horning SJ, Coiffier B, et al.: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17 (4): 1244, 1999.Niitsu N, Hagiwara Y, Tanae K, et al.: Prospective analysis of hepatitis B virus reactivation in patients with diffuse large B-cell lymphoma after rituximab combination chemotherapy. J Clin Oncol 28 (34): 5097-100, 2010.Dong HJ, Ni LN, Sheng GF, et al.: Risk of hepatitis B virus (HBV) reactivation in non-Hodgkin lymphoma patients receiving rituximab-chemotherapy: a meta-analysis. J Clin Virol 57 (3): 209-14, 2013.Huang YH, Hsiao LT, Hong YC, et al.: Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol 31 (22): 2765-72, 2013.Maor MH, Velasquez WS, Fuller LM, et al.: Stomach conservation in stages IE and IIE gastric non-Hodgkin's lymphoma. J Clin Oncol 8 (2): 266-71, 1990.Salles G, Herbrecht R, Tilly H, et al.: Aggressive primary gastrointestinal lymphomas: review of 91 patients treated with the LNH-84 regimen. A study of the Groupe d'Etude des Lymphomes Agressifs. Am J Med 90 (1): 77-84, 1991.Taal BG, Burgers JM, van Heerde P, et al.: The clinical spectrum and treatment of primary non-Hodgkin's lymphoma of the stomach. Ann Oncol 4 (10): 839-46, 1993.Tondini C, Giardini R, Bozzetti F, et al.: Combined modality treatment for primary gastrointestinal non-Hodgkin's lymphoma: the Milan Cancer Institute experience. Ann Oncol 4 (10): 831-7, 1993.d'Amore F, Brincker H, Grønbaek K, et al.: Non-Hodgkin's lymphoma of the gastrointestinal tract: a population-based analysis of incidence, geographic distribution, clinicopathologic presentation features, and prognosis. Danish Lymphoma Study Group. J Clin Oncol 12 (8): 1673-84, 1994.Haim N, Leviov M, Ben-Arieh Y, et al.: Intermediate and high-grade gastric non-Hodgkin's lymphoma: a prospective study of non-surgical treatment with primary chemotherapy, with or without radiotherapy. Leuk Lymphoma 17 (3-4): 321-6, 1995.Koch P, del Valle F, Berdel WE, et al.: Primary gastrointestinal non-Hodgkin's lymphoma: I. Anatomic and histologic distribution, clinical features, and survival data of 371 patients registered in the German Multicenter Study GIT NHL 01/92. J Clin Oncol 19 (18): 3861-73, 2001.Koch P, del Valle F, Berdel WE, et al.: Primary gastrointestinal non-Hodgkin's lymphoma: II. Combined surgical and conservative or conservative management only in localized gastric lymphoma--results of the prospective German Multicenter Study GIT NHL 01/92. J Clin Oncol 19 (18): 3874-83, 2001.Koch P, Probst A, Berdel WE, et al.: Treatment results in localized primary gastric lymphoma: data of patients registered within the German multicenter study (GIT NHL 02/96). J Clin Oncol 23 (28): 7050-9, 2005.Blair TJ, Evans RG, Buskirk SJ, et al.: Radiotherapeutic management of primary thyroid lymphoma. Int J Radiat Oncol Biol Phys 11 (2): 365-70, 1985.Junor EJ, Paul J, Reed NS: Primary non-Hodgkin's lymphoma of the thyroid. Eur J Surg Oncol 18 (4): 313-21, 1992.Morel P, Dupriez B, Gosselin B, et al.: Role of early splenectomy in malignant lymphomas with prominent splenic involvement (primary lymphomas of the spleen). A study of 59 cases. Cancer 71 (1): 207-15, 1993.Zucca E, Conconi A, Mughal TI, et al.: Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the International Extranodal Lymphoma Study Group. J Clin Oncol 21 (1): 20-7, 2003.Vitolo U, Chiappella A, Ferreri AJ, et al.: First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial. J Clin Oncol 29 (20): 2766-72, 2011.Cheah CY, Wirth A, Seymour JF: Primary testicular lymphoma. Blood 123 (4): 486-93, 2014.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.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.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.Sasai K, Yamabe H, Kokubo M, et al.: Head-and-neck stages I and II extranodal non-Hodgkin's lymphomas: real classification and selection for treatment modality. Int J Radiat Oncol Biol Phys 48 (1): 153-60, 2000.Ferreri AJ, Reni M, Ceresoli GL, et al.: Therapeutic management with adriamycin-containing chemotherapy and radiotherapy of monostotic and polyostotic primary non-Hodgkin's lymphoma of bone in adults. Cancer Invest 16 (8): 554-61, 1998.Dubey P, Ha CS, Besa PC, et al.: Localized primary malignant lymphoma of bone. Int J Radiat Oncol Biol Phys 37 (5): 1087-93, 1997.Martinet S, Ozsahin M, Belkacémi Y, et al.: Outcome and prognostic factors in orbital lymphoma: a Rare Cancer Network study on 90 consecutive patients treated with radiotherapy. Int J Radiat Oncol Biol Phys 55 (4): 892-8, 2003.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.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.Stefanovic A, Lossos IS: Extranodal marginal zone lymphoma of the ocular adnexa. Blood 114 (3): 501-10, 2009.Sjö LD: Ophthalmic lymphoma: epidemiology and pathogenesis. Acta Ophthalmol 87 Thesis 1: 1-20, 2009.Geelen FA, Vermeer MH, Meijer CJ, et al.: bcl-2 protein expression in primary cutaneous large B-cell lymphoma is site-related. J Clin Oncol 16 (6): 2080-5, 1998.Pandolfino TL, Siegel RS, Kuzel TM, et al.: Primary cutaneous B-cell lymphoma: review and current concepts. J Clin Oncol 18 (10): 2152-68, 2000.Sarris AH, Braunschweig I, Medeiros LJ, et al.: Primary cutaneous non-Hodgkin's lymphoma of Ann Arbor stage I: preferential cutaneous relapses but high cure rate with doxorubicin-based therapy. J Clin Oncol 19 (2): 398-405, 2001.Grange F, Bekkenk MW, Wechsler J, et al.: Prognostic factors in primary cutaneous large B-cell lymphomas: a European multicenter study. J Clin Oncol 19 (16): 3602-10, 2001.Mirza I, Macpherson N, Paproski S, et al.: Primary cutaneous follicular lymphoma: an assessment of clinical, histopathologic, immunophenotypic, and molecular features. J Clin Oncol 20 (3): 647-55, 2002.Smith BD, Glusac EJ, McNiff JM, et al.: Primary cutaneous B-cell lymphoma treated with radiotherapy: a comparison of the European Organization for Research and Treatment of Cancer and the WHO classification systems. J Clin Oncol 22 (4): 634-9, 2004.Willemze R, Jaffe ES, Burg G, et al.: WHO-EORTC classification for cutaneous lymphomas. Blood 105 (10): 3768-85, 2005.El-Helw L, Goodwin S, Slater D, et al.: Primary B-cell lymphoma of the skin: the Sheffield Lymphoma Group Experience (1984-2003). Int J Oncol 25 (5): 1453-8, 2004.Zinzani PL, Quaglino P, Pimpinelli N, et al.: Prognostic factors in primary cutaneous B-cell lymphoma: the Italian Study Group for Cutaneous Lymphomas. J Clin Oncol 24 (9): 1376-82, 2006.Senff NJ, Noordijk EM, Kim YH, et al.: European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas. Blood 112 (5): 1600-9, 2008.

    Treatment for Indolent, Stage I and Contiguous Stage II Adult NHL
    Although localized presentations are uncommon in non-Hodgkin lymphoma (NHL), the goal of treatment should be to cure the disease in patients who are shown to have truly localized occurrence after undergoing appropriate staging procedures.
    Standard Treatment Options for Indolent, Stage I and Contiguous Stage II Adult NHL
    Standard treatment options for indolent, stage I and contiguous stage II adult NHL include the following:
  • Radiation therapy.
  • Rituximab with or without chemotherapy.
  • Watchful waiting.
  • Other therapies as designated for patients with advanced-stage disease.
  • The National Lymphocare Study identified 471 patients with stage I follicular lymphoma. Of those patients, 206 were rigorously staged with a bone marrow aspirate and biopsy, and computed tomography (CT) scans or positive-emission tomography (PET-CT) scans. Nonrandomized treatments included radiation therapy (27%), rituximab-chemotherapy (R-chemotherapy) (28%), watchful waiting (17%), R-chemotherapy plus radiation therapy (13%), and rituximab alone (12%), although more than one-third of the patients started with expectant therapy. With a median follow-up of 57 months, progression-free survival favored R-chemotherapy or R-chemotherapy plus radiation therapy, but overall survival was nearly identical, all over 90%.[Level of evidence: 3iiiD] Clinical trials are required to answer questions such as:
    • If the PET-CT scan is clear after excisional biopsy, is watchful waiting or radiation therapy preferred?
    • Should rituximab be added to radiation therapy for stage I follicular lymphoma?
    • Is there any role for R-chemotherapy plus radiation therapy?
    Radiation therapy
    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. Almost half of all patients treated with radiation therapy alone will relapse out-of-field within 10 years.

    Rituximab with or without chemotherapy
    For symptomatic patients who require therapy, when radiation therapy is contraindicated or when an alternative treatment is preferred, rituximab with or without chemotherapy can be employed (as outlined below for more advanced-stage patients). The value of adjuvant treatment with radiation to decrease relapse, plus rituximab (an anti-CD20 monoclonal antibody) either alone or in combination with chemotherapy, has been extrapolated from trials of patients with advanced-stage disease and has not been confirmed.

    Watchful waiting
    Watchful waiting can be considered for asymptomatic patients. Watchful waiting has never been compared with upfront radiation therapy in a prospective randomized trial; a retrospective analysis of the Surveillance, Epidemiology and End Results Program (SEER) database over 30 years showed improved outcomes for upfront radiation therapy.

    Other therapies as designated for patients with advanced-stage disease
    Patients with involvement not encompassable by radiation therapy are treated as outlined for patients with stage III or stage IV low-grade lymphoma.

    Current Clinical Trials
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with indolent, stage I adult non-Hodgkin lymphoma and indolent, contiguous stage II adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    Treatment for Indolent, Noncontiguous Stage II/III/IV Adult NHL
    Optimal treatment of advanced stages of low-grade non-Hodgkin lymphoma (NHL) is controversial because of low cure rates with the current therapeutic options. Numerous clinical trials are in progress to settle treatment issues, and patients should be urged to participate. The rate of relapse is fairly constant over time, even in patients who have achieved complete response to treatment. Indeed, relapse may occur many years after treatment. Currently, no randomized trials guide clinicians about the initial choice of watchful waiting, rituximab, nucleoside analogs, alkylating agents, combination chemotherapy, radiolabeled monoclonal antibodies, or combinations of these options.; [Level of evidence: 1iiDiii]
    For patients with indolent, noncontiguous stage II and stage III non-Hodgkin lymphoma, central lymphatic radiation therapy has been proposed but is not usually recommended as a form of treatment.
    Numerous prospective clinical trials of interferon-alpha, including SWOG-8809, have shown no consistent benefit; the role of interferon in patients with indolent lymphoma remains controversial.
    Standard Treatment Options for Indolent, Noncontiguous Stage II/III/IV Adult NHL
    Standard treatment options for indolent, noncontiguous stage II/III/IV adult NHL include the following:
  • Watchful waiting for asymptomatic patients.
  • Rituximab.
  • Obinutuzumab.
  • Purine nucleoside analogs.
  • Alkylating agents (with or without steroids).
  • Bendamustine.
  • Combination chemotherapy.
  • Yttrium-90–labeled ibritumomab tiuxetan.
  • Maintenance rituximab.
  • Watchful waiting for asymptomatic patients
    The rate of relapse is fairly constant over time, even in patients who have achieved complete responses to treatment. Indeed, relapse may occur many years after treatment. In this category, deferred treatment (i.e., watchful waiting until the patient becomes symptomatic before initiating treatment) should be considered.
    Evidence (watchful waiting):
  • Three randomized trials compared watchful waiting with immediate chemotherapy.; [Level of evidence: 1iiA]
      All three trials showed no difference in cause-specific or overall survival (OS).
    • For patients randomly assigned to watchful waiting, the median time to require therapy was 2 to 3 years and one-third of patients never required treatment with watchful waiting (half died of other causes and half remained progression free after 10 years).
  • A selected group of 107 patients with advanced stage follicular lymphoma were managed with initial watchful waiting; with a median delay of 55 months, subsequent therapy resulted in equivalent freedom from treatment failure and OS compared with a similar cohort treated immediately with rituximab.[Level of evidence: 3iiiDiii] This implies that watchful waiting remains a relevant approach even in the rituximab era.
  • Rituximab
    Rituximab may be considered as first-line therapy, either alone or in combination with other agents.
    • Rituximab alone, as was shown in the ECOG-E4402 (NCT00075946) trial, for example.
    • R-Bendamustine: rituximab + bendamustine.
    • R-F: rituximab + fludarabine.
    • R-CVP: rituximab + cyclophosphamide + vincristine + prednisone.
    • R-CHOP: rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone. A Cochrane meta-analysis could not identify any OS benefit to adding doxorubicin to chemotherapy regimens with rituximab or to chemotherapy regimens without rituximab.[Level of evidence: 1iiA]
    • R-FM: rituximab + fludarabine + mitoxantrone.
    • R-FCM: rituximab + fludarabine + cyclophosphamide + mitoxantrone.
    Standard therapy includes rituximab, an anti-CD20 monoclonal antibody, either alone or in combination with purine nucleoside analogs such as fludarabine or 2-chlorodeoxyadenosine, alkylating agents (with or without steroids), or combination chemotherapy.
    A prospective, randomized trial of 534 patients with previously untreated, advanced-stage follicular lymphoma compared R-CHOP, R-FM, and R-CVP. With a median follow-up of 34 months, there was no difference in OS, but the 3-year PFS favored R-CHOP (68%) and R-FM (63%) over R-CVP (52%) (P for the three regimens = .011).[Level of evidence: 1iiDiii]
    Evidence (rituximab):
    • 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.; [Level of evidence: 1iiA]Rituximab plus chemotherapy was superior in terms of event-free survival or progression-free survival (PFS) (ranging from 2–3 years) in all of the studies and in terms of OS in all but one study (absolute benefit ranging from 6%–13% at 4 years, P < .04 and hazard ratio [HR] = 0.63 [0.51–0.79] for the meta-analysis).
    • All of these trials were performed in symptomatic patients who required therapy. These results do not negate watchful waiting when appropriate.
    • FDG-PET-CT (fluorine-18-fluorodeoxyglucose–positron-emission tomography–computed tomography) scan status at the completion of rituximab plus chemotherapy induction therapy is strongly predictive of outcome. It is not yet known if acting on the results of the scans translates into better outcomes.

    Obinutuzumab
    Obinutuzumab is an alternative CD20-binding monoclonal antibody with alternative epitope binding and is being studied in patients with recurrent follicular lymphoma. This agent has shown responses in 20% to 30% of patients when used alone and in 80% of patients when combined with CHOP or FC (fludarabine and cyclophosphamide) in relapsed follicular lymphoma patients.[Level of evidence: 3iiiDiv]

    Purine nucleoside analogs
    • Fludarabine.
    • 2-chlorodeoxyadenosine.

    Alkylating agents (with or without steroids)
    • Cyclophosphamide (oral or intravenous).
    • Chlorambucil (oral).

    Bendamustine
    Evidence (bendamustine):
  • In a prospective randomized trial NCT00991211, 527 patients with indolent and mantle cell lymphoma were randomly assigned to a bendamustine-plus-rituximab arm versus an R-CHOP arm.[Level of evidence: 1iiDiii]
      With a median follow-up of 45 months, the median PFS favored the bendamustine arm (69 months vs. 31 months [HR, 0.58; 95 % confidence intervaI (CI), 0.44–0.74; P < .0001]) but with no difference in OS.
    • The bendamustine arm was associated with significantly lower rates of alopecia, hematologic toxicity, stomatitis, peripheral neuropathy, and infections than was the R-CHOP arm.

    Combination chemotherapy
    • CVP: cyclophosphamide + vincristine + prednisone.
    • CVP followed by rituximab maintenance.
    • C-MOPP: cyclophosphamide + vincristine + procarbazine + prednisone.
    • CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone. A Cochrane meta-analysis could not identify any OS benefit to adding doxorubicin to chemotherapy regimens with rituximab or to chemotherapy regimens without rituximab.[Level of evidence: 1iiA]
    • FND: fludarabine + mitoxantrone +/- dexamethasone, as evidenced in the SWOG-9501 trial, for example.

    Yttrium-90–labeled ibritumomab tiuxetan
    Yttrium-90–labeled ibritumomab tiuxetan is available for previously untreated and relapsing patients with minimal (<25%) or no marrow involvement with lymphoma (iodine-131–labeled tositumomab is no longer available because of commercial disengagement). In a randomized, prospective trial, 554 patients with previously untreated advanced-stage follicular lymphoma received either R-CHOP times six cycles or CHOP times six cycles followed by I-131 tositumomab radioimmunotherapy (RIT); with a median follow-up of 4.9 years, there was no significant difference between the PFS and OS (2-year OS, R-CHOP, 97%; CHOP-RIT, 93%; P = .08).[Level of evidence: 1iiD] Because a significant prolongation of PFS was seen for R-CHOP followed by rituximab maintenance compared with R-CHOP alone, this lack of benefit for CHOP-RIT was particularly disappointing. Iodine-131–labeled tositumomab became commercially unavailable in 2013.
    In a randomized trial of 409 patients with stage III or IV follicular lymphoma who achieved a complete or partial response, yttrium-90 ibritumomab tiuxetan consolidation versus no consolidation was evaluated. The radiolabelled antibody consolidation improved median PFS by 3 years (P < .001), and median time to next treatment was improved by 5.1 years (P < .001); however, there was no change in OS.[Level of evidence: 1iiDiii]

    Maintenance rituximab
    Evidence (maintenance rituximab):
  • 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.[Level of evidence: 1iiDiii]
      At 6 years' median follow-up, rituximab maintenance was better for median PFS (44 months vs. 16 months, P < .001) and borderline for 5-year OS (74% vs. 64%, P = .07).
    • This benefit for maintenance was evident even for patients who received rituximab during induction therapy. Most patients in both arms received extensive rituximab during post-protocol salvage treatment.
  • In the PRIMA (NCT00140582) study, 1,019 high-risk patients who required treatment achieved complete or partial response after induction therapy with immunochemotherapy (usually R-CHOP) and were then randomly assigned to 2 years of maintenance rituximab versus no maintenance.[Level of evidence: 1iiDiii]
      With a median follow-up of 36 months, PFS favored rituximab maintenance 74.9% to 57.6% (HR, 0.56; 95% confidence interval [CI], 0.44–0.68; P <.0001) but with no difference in OS.
  • In a prospective, randomized trial of 280 patients with relapsed follicular lymphoma, responders to chemotherapy and autologous stem cell transplantation consolidation were randomly assigned to four doses of rituximab maintenance or no maintenance.[Level of evidence: 1iiDiii]
      With an 8.3 year median follow-up, the 10-year PFS favored maintenance (54% vs. 37% [HR, 0.66; 95%CI, 0.47–0.91, P = .012]), but there was no difference in OS.
  • A meta-analysis of 2,586 patients with follicular lymphoma in nine randomized clinical trials that compared rituximab maintenance with no maintenance showed improved OS for rituximab maintenance in previously treated patients (HRdeath, 0.72; 95% CI, 0.57–0.91).[Level of evidence: 1iiA]
  • Many questions remain about rituximab maintenance, particularly about truncating therapy at 2 years and long-term safety and efficacy. The most salient question is whether a strategy of observation after induction with rituximab therapy at time of symptomatic progression is equivalent or superior to mandated rituximab maintenance.

    Treatment Options Under Clinical Evaluation for Indolent, Noncontiguous Stage II/III/IV Adult NHL
    Since none of the standard therapies listed above are curative for advanced-stage disease, innovative approaches are under clinical evaluation. The approaches include intensive therapy with chemotherapy and total-body irradiation (TBI) followed by autologous or allogeneic bone marrow transplantation (BMT) or peripheral stem cell transplantation (PSCT), and the use of idiotype vaccines and radiolabeled monoclonal antibodies.
  • Intensive therapy with chemotherapy with or without TBI or high-dose radioimmunotherapy followed by autologous or allogeneic BMT or PSCT is under clinical evaluation.
  • Phase III trials comparing chemotherapy alone versus chemotherapy followed by anti-idiotype vaccine.
  • Extended-field radiation therapy (stage III patients only).
  • Ofatumumab—human anti-CD20 monoclonal antibody.
  • Short-course low-dose, palliative radiation therapy (2 × 2 Gy).
  • Current Clinical Trials
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with indolent, noncontiguous stage II adult non-Hodgkin lymphoma, indolent, stage III adult non-Hodgkin lymphoma and indolent, stage IV adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    Treatment for Indolent, Recurrent Adult NHL
    In general, treatment with standard agents rarely produces a cure in patients whose disease has relapsed. Sustained remissions after relapse can often be obtained in patients with indolent lymphomas, but relapse will usually ensue. Favorable survival after relapse has been associated with an age younger than 60 years, complete remission rather than partial remission, and duration of response longer than 1 year. Even the most favorable subset, however, has a tenfold greater mortality compared with age-adjusted U.S. population rates.
    Patients who experience a relapse with indolent lymphoma can often have their disease controlled with single agent or combination chemotherapy, rituximab (an anti-CD20 monoclonal antibody), lenalidomide, radiolabeled anti-CD20 monoclonal antibodies, or palliative radiation therapy. Long-term freedom from second relapse, however, is uncommon and multiple relapses will usually occur. Patients with indolent lymphoma may experience a relapse with a more aggressive histology. If the clinical pattern of relapse suggests that the disease is behaving in a more aggressive manner, a biopsy should be performed. Documentation of conversion to a more aggressive histology requires an appropriate change to therapy applicable to that histologic type. Rapid growth or discordant growth between various disease sites may indicate a histologic conversion.
    In a retrospective review of 325 patients between 1972 and 1999, the risk of histologic transformation was 30% by 10 years from diagnosis. In this series, high risk factors for subsequent histologic transformation were advanced stage, high-risk Follicular Lymphoma International Prognostic Index, and expectant management. The median survival after transformation was 1 to 2 years, with 25% of patients alive at 5 years and with approximately 10% to 20% of patients alive 10 years after re-treatment.
    A prospective trial of 631 patients with follicular lymphoma and with a median follow-up of 60 months in the rituximab era (2002–2009) found a 5-year transformation rate (11%) to a higher-grade histology. The median overall survival (OS) after transformation was 50 months, and the 5-year OS rate was 66%, if the transformation occurred more than 18 months after a diagnosis of follicular lymphoma. This series describes a better prognosis for patients with transformation than was experienced by patients in the prerituximab era.
    (Refer to the Treatment for Aggressive, Recurrent Adult NHL section of this summary for descriptions of the regimens used to treat histologic conversions.) The durability of the second remission may be short, and clinical trials should be considered.
    Standard Treatment Options for Indolent, Recurrent Adult NHL
    Standard treatment options for indolent, recurrent adult NHL include the following:
  • Chemotherapy (single agent or combination).
  • Rituximab.
  • Lenalidomide.
  • Radiolabeled anti-CD20 monoclonal antibodies.
  • Palliative radiation therapy.
  • Chemotherapy (single agent or combination)
    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. Patients may respond to the original induction regimen again, especially if the duration of remission exceeds 1 year. For relapsing patients, rituximab alone or in combination with agents not previously used may induce remissions.

    Rituximab
    Rituximab results in a 40% to 50% response rate in patients who relapse with indolent B-cell lymphomas. Rituximab can also be combined with combination chemotherapy.
    Evidence (rituximab):
    • In three randomized, prospective studies involving previously treated patients with relapsed indolent lymphoma, patients were randomly assigned to rituximab maintenance after retreatment with combination chemotherapy (with or without rituximab during induction) or rituximab alone; all trials showed prolongation of response duration, and one trial demonstrated improvement in median progression-free survival (PFS) (3.7 years vs. 1.3 years, P < .001) and OS (74% vs. 64%, P = .07) at 5 years with a median follow-up of 39 months favoring maintenance rituximab.

    Lenalidomide
    Responses of 20% to 30% have been reported for lenalidomide, especially for follicular lymphoma and small lymphocytic lymphoma.[Level of evidence: 3iiiDiv]

    Radiolabeled anti-CD20 monoclonal antibodies
    Durable responses to radiolabeled monoclonal antibodies, such as yttrium-90 ibritumomab (commercially available) and iodine-131 tositumomab (commercially unavailable), have also been reported before and after cytotoxic chemotherapy.[Level of evidence: 1iiDiii]
    A prospective trial of 409 patients with follicular lymphoma who responded to induction chemotherapy were randomly assigned to yttrium-90 ibritumomab or no further consolidation; with a median follow-up of 7.3 years, the 8-year PFS favored ibritumomab (41% vs. 22% [HR, 0.47; P < .001), but there was no difference in OS.[Level of evidence: 1iiDiii]

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

    Treatment Options Under Clinical Evaluation for Indolent, Recurrent Adult NHL
    Treatment options under clinical evaluation include the following:
    • Stem cell transplant. In many institutions, autologous or allogeneic stem cell transplantations are being used for patients whose disease has relapsed. Such an approach is still under evaluation but should be considered in the context of a clinical trial.
    Evidence (stem cell transplant):
    • The German Low-Grade Lymphoma Study Group treated 307 patients with follicular lymphoma with two cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like induction chemotherapy and then randomly assigned them to autologous stem cell transplantation versus interferon maintenance. With a median follow-up of 4.2 years, the 5-year PFS was 65% for transplantation versus 33% for interferon (P < .001), but with no difference in OS.[Level of evidence: 1iiDiii]

    Current Clinical Trials
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with indolent, recurrent adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    Treatment for Aggressive, Stage I and Contiguous Stage II Adult NHL
    Patients with stage I or contiguous stage II diffuse large B-cell lymphoma are candidates for combination chemotherapy with or without involved-field radiation therapy (IF-XRT).
    The following drug combinations are referred to in this section:
    • R-CHOP: rituximab, an anti-CD20 monoclonal antibody, + cyclophosphamide + doxorubicin + vincristine + prednisone.
    Standard Treatment Options for Aggressive, Stage I and Contiguous Stage II Adult NHL
    Standard treatment options for aggressive, stage I and contiguous stage II adult non-Hodgkin lymphoma (NHL) include the following:
  • R-CHOP with or without IF-XRT.
  • R-CHOP with or without IF-XRT
    Four prospective randomized trials have evaluated the comparison of CHOP or more intensive CHOP-based chemotherapy alone versus combined–modality therapy with CHOP and IF-XRT.
    Evidence (CHOP vs. CHOP with IF-XRT):
  • In a randomized trial 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).[Level of evidence: 1iiA]
  • A randomized trial of 401 patients comparing eight cycles of CHOP with three cycles of CHOP with IF-XRT was initially reported as having an OS advantage for the combined–modality arm at 5 years, but a re-evaluation for OS at 9 years showed no difference in either arm of the study.[Level of evidence: 1iiA]
  • A randomized study (EST-1484) of 210 patients who attained a radiologic complete remission after eight cycles of CHOP compared IF-XRT with no further therapy; there was no difference in OS at 10 years (68% vs. 65%, P = .24).[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).[Level of evidence: 1iiA]
  • The confirmation of efficacy for rituximab in advanced-stage disease as evidenced in SWOG-S0014 (NCT00005089), for example, has suggested the use of R-CHOP with or without radiation therapy but its use is only supported by retrospective comparisons.[Level of evidence: 3iiiDiii]
    • R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone); four to six cycles.
    • R-CHOP (three to six cycles) + IF-XRT.
    Evidence (R-CHOP vs. CHOP):
    • A randomized study (DSHNHL-1999-1A [NCT00052936]) of 1,222 patients older than 60 years compared R-CHOP given every 2 weeks for six or eight cycles with CHOP given every 2 weeks for six or eight cycles. Although patients with early-stage disease were included in this trial, most patients had advanced-stage disease. With a median follow-up of 72 months, the EFS favored R-CHOP given every 2 weeks for six or eight cycles (EFS at 6 y, 74% vs. 56%; P < .001).
    • The OS favored R-CHOP for only six cycles because of increased toxicity in the eight-cycle arm (OS at 6 y, 90% vs. 80%, P = .0004.[Level of evidence: 1iiA]
    • There has been no comparison to standard R-CHOP or CHOP given every 3 weeks. There are no comparative studies to establish an optimal number of chemotherapy cycles for patients with early-stage disease.

    Treatment Options Under Clinical Evaluation for Aggressive, Stage I and Contiguous Stage II Adult NHL
    Treatment options under clinical evaluation include the following:
    • R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone).

    Current Clinical Trials
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with aggressive, stage I adult non-Hodgkin lymphoma and aggressive, contiguous stage II adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    Treatment for Aggressive, Noncontiguous Stage II/III/IV Adult NHL
    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.
      The following drug combinations are referred to in this section:
    • ACVBP: doxorubicin + cyclophosphamide + vindesine + bleomycin + prednisone.
    • CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone.
    • CNOP: cyclophosphamide + mitoxantrone + vincristine + prednisone.
    • m-BACOD: methotrexate + bleomycin + doxorubicin + cyclophosphamide + vincristine + dexamethasone + leucovorin.
    • MACOP-B: methotrexate + doxorubicin + cyclophosphamide + vincristine + prednisone fixed dose + bleomycin + leucovorin.
    • ProMACE CytaBOM: prednisone + doxorubicin + cyclophosphamide + etoposide + cytarabine + bleomycin + vincristine + methotrexate + leucovorin.
    • R-CHOP: rituximab, an anti-CD20 monoclonal antibody, + cyclophosphamide + doxorubicin + vincristine + prednisone.
    Standard Treatment Options for Aggressive, Noncontiguous Stage II/III/IV Adult NHL
    Standard treatment options for Aggressive, Noncontiguous Stage II/III/IV Adult NHL include the following:
  • R-CHOP.
  • Other combination chemotherapy.
  • R-CHOP
    The following studies established R-CHOP as the standard regimen for newly diagnosed patients with DLBCL. Dose intensification of R-CHOP by a 14-day versus a 21-day cycle did not result in improved outcomes.
    Evidence (R-CHOP):
  • R-CHOP showed improvement in event-free survival (EFS) and overall survival (OS) compared with CHOP alone in 399 advanced-stage patients with DLBCL older than 60 years (EFS, 57% vs. 38%; P = .002, and OS, 70% vs. 57%; P = .007 at 2 years).[Level of evidence: 1iiA] At 10-years' median follow-up, the OS of patients who received R-CHOP compared with patients who received CHOP was 44% versus 28%, P < .0001.
  • Similarly, for 326 evaluable patients younger than 61 years, R-CHOP showed improvement in EFS and OS compared with CHOP alone (EFS, 79% vs. 59%, P = .001, and OS, 93% vs. 84%, P = .001 at 3 years).[Level of evidence: 1iiA]
  • A randomized study (DSHNHL-1999-1A [NCT00052936]) of 1,222 patients older than 60 years compared R-CHOP given every 2 weeks for six or eight cycles with CHOP given every 2 weeks for six or eight cycles. With a median follow-up of 72 months, the EFS favored R-CHOP given every 2 weeks for six or eight cycles (EFS at 6 years, 74% vs. 56%; P < .0001). The OS favored R-CHOP for only six cycles because of increased toxicity in the eight-cycle arm (OS at 6 years, 90% vs. 80%; P = .0004).[Level of evidence: 1iiA] There was no comparison to standard R-CHOP or CHOP given every 3 weeks.
  • Evidence (CHOP with or without other therapies):
  • A trial of 380 patients younger than 60 years with DLBCL and an age-adjusted International Prognostic Index (IPI) rating of 1 randomized treatment to ACVBP + rituximab (R-ACVBP) + consolidation with methotrexate, ifosfamide, etoposide, and cytarabine versus CHOP + rituximab. With a median follow-up of 44 months, 3-year OS favored R-ACVBP (92% vs. 84%; hazard ratio, 0.44; 95% confidence interval (CI), 0.28–0.81, P = .007).[Level of evidence: 1iiA] The significantly worse toxicities with R-ACVBP, the narrow target population (<60 y with either elevated lactate dehydrogenase (LDH) or stage III/IV disease, but not both), and the lack of a confirmatory trial may inhibit adoption of R-ACVBP as a new standard of care.
  • 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 (DFS) and OS.; [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.; [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.[Level of evidence: 1iiA]
  • A preliminary study using CHOP with or without etoposide for patients older than 60 years suggested improvement in EFS and OS for treatment delivered every 2 weeks versus the standard 3-week regimen..
  • As SWOG-9349 did, clinical trials continue to explore modifications of CHOP and rituximab with CHOP by increasing doses, reducing intervals between cycles, and combining new drugs with new mechanisms of action. None of these trials establishes a survival advantage for reduced intervals between cycles or for increasing doses of the chemotherapy.

    Other combination chemotherapy
    Doxorubicin-based combination chemotherapy produces long-term DFS in 35% to 45% of patients. Higher cure rates have been reported in single-institution studies than in cooperative group trials.
    Evidence (other combination chemotherapy):
  • A prospective, randomized trial of four regimens (CHOP, ProMACE CytaBOM, m-BACOD, and MACOP-B) for patients with DLBCL showed no difference in OS or time-to-treatment failure at 3 years.[Level of evidence: 1iiA]
  • Other randomized trials have confirmed no advantage among the standard doxorubicin-based combinations versus CHOP.; Level of evidence: 1iiA]
  • A randomized clinical trial failed to demonstrate a beneficial effect of adjuvant radiation therapy in advanced-stage aggressive NHL.

    Stage IE or IIE gastric DLBCL
    Four case series involving more than 100 patients with stage IE or IIE disease (with or without associated mucosa-associated lymphatic tissue) and with positive Helicobacter pylori infection reported that more than 50% of patients attained a durable complete remission after appropriate antibiotic therapy to eradicate H. pylori.[Level of evidence: 3iiiDiv]

    Prognostic factors
    An IPI for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of 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).
  • 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. The bcl-2 gene and rearrangement of the myc gene or dual overexpression of the myc gene, or both, confer a particularly poor prognosis. Patients at high risk of relapse may be considered for clinical trials. 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.

    Treatment of tumor lysis syndrome
    Patients with bulky and extensive lymphadenopathy and elevations of serum uric acid and LDH are at increased risk of tumor lysis syndrome resulting in metabolic derangements such as hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and subsequent acute renal failure. Treatment options include: alkaline hydration, allopurinol, and rasburicase, a recombinant urate oxidase.

    CNS prophylaxis
    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. CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, and others do not.
    • 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% CI, 7%–28%) versus 2.8% (95% CI, 2.7%–2.9%) for the remaining patients.[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.

    Treatment Options Under Clinical Evaluation for Aggressive, Noncontiguous Stage II/III/IV Adult NHL
    Treatment options under clinical evaluation include the following:
    • Bone marrow transplant (BMT) or stem cell transplantation (SCT).
      Several randomized, prospective trials evaluated the role of autologous BMT or SCT consolidation versus chemotherapy alone in patients in first remission with diffuse large cell lymphoma.; [Level of evidence: 1iiA] Although some of these trials demonstrated significant increases in EFS (by 10% to 20%) among patients who received high-dose therapy, significant differences in OS could not be demonstrated prospectively in any of the series.
      Retrospective analyses of high-intermediate (two risk factors) or high-risk (more than three risk factors) patients as defined by IPI suggest improved survival with BMT in two of the trials. 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.
    • Radiation therapy consolidation to sites of bulky disease.
      After R-CHOP induction chemotherapy (or similar regimens), the addition of involved-field radiation therapy to sites of initial bulky disease (≥5–10 cm) or to extralymphatic sites remains controversial. Increased risks, such as long-term toxicities (e.g., second malignancies), must be considered.

    Current Clinical Trials
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with aggressive, noncontiguous stage II adult non-Hodgkin lymphoma, aggressive, stage III adult non-Hodgkin lymphoma and aggressive, stage IV adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    Treatment for 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). The treatment paradigms are based on trials for acute lymphoblastic leukemia (ALL) since lymphoblastic lymphoma and ALL are considered different manifestations of the same biologic disease. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.) Treatment is usually patterned after ALL. Intensive combination chemotherapy with CNS prophylaxis is the standard treatment of this aggressive histologic type of NHL. Radiation therapy is sometimes given to areas of bulky tumor masses. Since these forms of NHL tend to progress quickly, combination chemotherapy is instituted rapidly once the diagnosis has been confirmed.
    The most important aspects of the pretreatment staging workup include careful review of the following pathological specimens:
    • Bone marrow aspirate.
    • Biopsy specimen.
    • Cerebrospinal fluid cytology.
    • Lymphocyte marker.
    Standard Treatment Options for Adult Lymphoblastic Lymphoma
    Standard Treatment Options for Adult Lymphoblastic Lymphoma include the following:
  • Intensive therapy.
  • Radiation therapy.
  • (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)
    Intensive therapy
    Standard treatment is intensive combination chemotherapy with CNS prophylaxis.

    Radiation therapy
    Radiation therapy is sometimes given to areas of bulky tumor masses.

    Treatment Options Under Clinical Evaluation for Adult Lymphoblastic Lymphoma
    New treatment approaches are being developed by the national cooperative groups. Other approaches include the use of bone marrow transplantation for consolidation. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)

    Current Clinical Trials
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult lymphoblastic lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    Treatment for Diffuse, Small Noncleaved-Cell/Burkitt Lymphoma
    Diffuse, small, noncleaved-cell/Burkitt lymphoma typically involves younger patients and represents the most common type of pediatric NHL.
    Standard Treatment Options for Diffuse, Small Noncleaved-Cell/Burkitt Lymphoma
    Standard treatment options for diffuse, small, noncleaved-cell/Burkitt lymphoma include the following:
  • Aggressive multidrug regimens.
  • Central nervous system (CNS) prophylaxis.
  • Aggressive multidrug regimens
    Standard treatment for diffuse, small, noncleaved-cell/Burkitt lymphoma is usually with aggressive multidrug regimens similar to those used for the advanced-stage aggressive lymphomas (such as diffuse large cell). In some institutions, treatment includes the use of consolidative bone marrow transplantation. Adverse prognostic factors include bulky abdominal disease and high serum lactate dehydrogenase.
    Evidence (aggressive multidrug regimens):
    • An intensive clinical trial (CLB-9251 [NCT00002494]) used aggressive combination chemotherapy patterned after that used in childhood Burkitt lymphoma and has been very successful for adult patients. More than 60% of advanced-stage patients were free of disease at 5 years.

    Central nervous system (CNS) prophylaxis
    Patients with diffuse, small, noncleaved-cell/Burkitt lymphoma have a 20% to 30% lifetime risk of CNS involvement. CNS prophylaxis with methotrexate is recommended for all patients, usually given as four to six intrathecal injections. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information).
    Evidence (CNS prophylaxis):
    • 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. CNS relapse patterns were similar whether or not patients received radiation therapy, but increased neurologic deficits were noted among those patients who received radiation therapy.

    Current Clinical Trials
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult Burkitt lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    Treatment for Aggressive, Recurrent Adult NHL
    Standard Treatment Options for Aggressive, Recurrent Adult NHL
    Standard treatment options for aggressive, recurrent adult non-Hodgkin lymphoma (NHL) include the following:
  • Bone marrow or stem cell transplantation.
  • Re-treatment with standard agents.
  • Palliative radiation therapy.
  • Bone marrow or stem cell transplantation
    Bone marrow transplantation (BMT) is the treatment of choice for patients whose lymphoma has relapsed. 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.
    Evidence (BMT):
  • In a prospective, randomized study, (EORTC-PARMA), 215 patients in first or second relapse of aggressive lymphoma, younger than 60 years, and with no bone marrow or central nervous system involvement, were given two cycles of intensive combination chemotherapy. The 109 patients who responded were randomly assigned to receive four more cycles of chemotherapy and involved-field radiation therapy (IF-XRT) versus autologous BMT followed by IF-XRT. With a 5-year median follow-up, the event-free survival (EFS) was significantly improved with transplantation (46% vs. 12%). Overall survival (OS) was also significantly better with transplantation (53% vs. 32%).[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 responded to conventional therapy for relapse prior to the BMT have had the best results.
  • In a prospective trial, patients who relapsed late (>12 months after diagnosis) had better OS than patients who relapsed earlier (8-year survival was 29% vs. 13%, P = .001).[Level of evidence: 3iiiA]
  • Peripheral stem cell transplantation (SCT) has yielded results equivalent to standard autologous transplantation. Even patients who never experienced complete remission with conventional chemotherapy may have prolonged progression-free survival (31% at 5 years) after high-dose chemotherapy and hematopoietic SCT if they retain chemosensitivity to reinduction therapy.[Level of evidence: 3iiiDiii] Some patients who relapse after a previous autologous transplantation can have durable remissions after myeloablative or nonmyeloablative allogeneic SCT.; [Level of evidence: 3iiiDiv]
    Evidence (peripheral SCT):
    • In a randomized prospective trial, 396 patients with diffuse large B-cell lymphoma in first relapse or who were refractory to first-line therapy received either R-ICE (rituximab, ifosfamide, etoposide, and carboplatin) or R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin) followed by autologous SCT; there was no difference in 3-year EFS or OS.[Level of evidence: 1iiA]

    Re-treatment with standard agents
    In general, re-treatment with standard agents rarely produces a cure in patients whose lymphomas relapse. Several salvage chemotherapy regimens are available.
    • Rituximab alone can induce responses in 33% of patients with relapsing aggressive lymphoma of appropriate phenotype (CD20-positive).; [Level of evidence: 3iiiDiv]
    • Radiolabeled anti-CD20 monoclonal antibodies, such as iodine-131 tositumomab (no longer commercially available) and yttrium-90 ibritumomab, induce 60% to 80% response rates in patients with relapsed or refractory B-cell lymphoma.; [Level of evidence: 3iiiDiv]
    • Denileukin diftitox, a fusion protein combining diphtheria toxin and interleukin-2, resulted in a 25% objective response rate in 45 heavily pretreated patients, as evidenced in E-1497 (NCT00003615), for example, with aggressive B-cell NHL (CD25, i.e., interleukin-2 receptor, expression was not correlated with response).[Level of evidence: 3iiiDiv]
    • In two phase II trials, 49 patients showed a 19% to 35% overall response rate to lenalidomide with or without rituximab.[Level of evidence: 3iiiDiv]
    Durable responses to radiolabeled monoclonal antibodies have been reported for transformed low-grade B-cell lymphoma. 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.

    Palliative radiation therapy
    In general, patients with aggressive lymphoma who relapse with indolent histology will benefit from palliative therapy. Palliation may be achieved with very low-dose (4 Gy) IF-XRT for patients with indolent and aggressive relapsed disease.

    Treatment Options Under Clinical Evaluation for Aggressive, Recurrent Adult NHL
    Treatment options under clinical evaluation include the following:
    • SCT. 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 SCT, should be considered.

    Current Clinical Trials
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with aggressive, recurrent adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    Non-Hodgkin Lymphoma During Pregnancy
    General Information About NHL During Pregnancy
    Non-Hodgkin lymphomas (NHLs) occur more frequently than Hodgkin lymphoma in an older population. This age difference may account for fewer reports of NHL in pregnant patients.

    Stage Information for NHL During Pregnancy
    To avoid exposure to ionizing radiation, magnetic resonance imaging is the preferred tool for staging evaluation. (Refer to the Stage Information for Adult NHL section of this summary for more information.)

    Treatment Option Overview for NHL During Pregnancy
    Table 5. Treatment Options for NHL During Pregnancy
    StageStandard Treatment OptionsIndolent NHL During PregnancyDelay treatment until after deliveryAggressive NHL During PregnancyImmediate therapyEarly delivery, when feasibleTermination of pregnancy

    Indolent NHL During Pregnancy
    Treatment may be delayed for those women with an indolent NHL.

    Aggressive NHL During Pregnancy
    Immediate therapy
    According to anecdotal case series, most NHLs in pregnant patients are aggressive, and delay of therapy until after delivery appears to have poor outcomes. Consequently, some investigators favor immediate therapy, even during pregnancy. In a review of 121 patient case reports from 74 papers, one-half of the patients had very aggressive lymphomas, such as Burkitt lymphoma, and one-half of the patients had involvement of the breast, ovaries, uterus, or placenta. One-half of the patients received therapy antepartum, and the 6-month survival was reported at 53%, with a live-birth rate of 83%.[Level of evidence: 3iiiDiv]

    Early delivery when feasible
    For some women, early delivery, when feasible, may minimize or avoid exposure to chemotherapy or radiation therapy.

    Termination of pregnancy
    Termination of pregnancy in the first trimester may be an option that allows immediate therapy for women with aggressive NHL.
    Evidence (treatment effect on children exposed in utero):
    • 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. 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.

    Changes to This Summary (01/09/2015)
    The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
    General Information About Adult Non-Hodgkin Lymphoma
    Updated statistics with estimated new cases and deaths for 2015 (cited American Cancer Society as reference 2).
    This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

    About This PDQ Summary
    Purpose of This Summary
    This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult non-Hodgkin lymphoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

    Reviewers and Updates
    This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
    Board members review recently published articles each month to determine whether an article should:
    • be discussed at a meeting,
    • be cited with text, or
    • replace or update an existing article that is already cited.
    Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
    The lead reviewers for Adult Non-Hodgkin Lymphoma Treatment are:
    • Mark J. Levis, MD, PhD (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins)
    • Eric J. Seifter, MD (Johns Hopkins University)
    Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

    Levels of Evidence
    Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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    The preferred citation for this PDQ summary is:
    National Cancer Institute: PDQ® Adult Non-Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/HealthProfessional. Accessed <MM/DD/YYYY>.
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